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Crystallographic studies on new Pt(IV) anti-cancer agents and their reaction products

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Crystallographic studies on new Pt(IV) anti-cancer agents and their reaction products

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Content CRYSTALLOGRAPHIC STUDIES O N N E W Pt(IV) ANTI-CANCER AGENTS AND THEIR REACTION PRODUCTS by Hok-Kin Choi A Dissertation Presented to the FACULTY O F THE GRADUATE SCH O O L UNIVERSITY O F SOUTHERN CALIFORNIA In Partial Fulfillm ent of the Requirements for the Degree DO C TO R O F PHILOSOPHY (Chemistry) August 1988 UMI Number: DP21966 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI DP21966 Published by ProQuest LLC (2014). Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 4 8 1 0 6 -1 3 4 6 UNIVERSITY OF SOUTHERN CALIFORNIA THE GRADUATE SCHOOL UNIVERSITY PARK LOS ANGELES, CALIFORNIA 90089 This dissertation, written by under the direction of h .J ? Dissertation Committee, and approved by all its members, has been presented to and accepted by The Graduate School, in partial fulfillment of re quirements for the degree of P/..D. k < ? > H o k -K in C h o i DO CTO R OF PH ILO SO PHY Dean of Graduate Studies A u g u s t 8 , 1 9 8 8 DISSERTATION COMMITTEE Chairperson To My Parents, Jade, Don, and Xiao-Qing i i ACKNO W LEDG EM ENTS I wish to express m y sincere thanks to m y advisor, Professor j Robert Bau, for his valuable advice and guidance throughout m y j i graduate studies both in and out of the lab. ’ i f , I am grateful for a ll the assistance and valuable discussions on j i chemistry and crystallography with Dr. Marianne Patch and Mr. Raymond i t Stevens. I I wish to express m y deep appreciation for the friendship and | I help of Sharon Huang, Hanna Yuan and Diana Ma and their husbands. I i t t To Dr. Saeed Khan, Dr. Christine Schwertfeger, Dr. Luigi ; t Garlaschel 1 i, Dr. A ristid is Terzis, Teresa Wen, the rest of the Bau i group, and al 1 m y friends, I thank you for sharing good times with m e j and keeping m e company when I had to work days and nights in the lab. ; 5 j To al 1 m y tennis partners, I thank you for sharing good times with m e j j j j on the tennis court especially when I wanted to find an excuse to takej [ a break. ! Thanks also goes to the undergraduate research assistants that worked with m e in the lab, Mr. Jameal Misto, Ms. Thizar Tintut and Mr. John Lim. W arm thanks to Michele Dea for her typing assistance and the fin a l completion of this thesis. F in a lly , to m y Mom, Dad, Jade, Don, and Xiao Qing, I thank them for th eir love, patience, encouragement and support throughout m y years of graduate education. TABLE O F CONTENTS Page DEDICATION if ACKNOW LEDGEM ENTS i i i LIST O F TABLES v ii LIST O F FIGURES xi ABSTRACT xiv CHAPTER 1 - CRYSTALLOGRAPHIC STUDIES O N THE ISOMERS O F A N E W OCTAHEDRAL ANTI-CANCER (TETRACHLORO-l,2-DIAMINOCYCLO- HEXANE)Pt(IV) COM PLEX 1 Introduction 1 Experimental Section 4 A. (Tetrachloro-cis-l,2-diaminocyclohexane)Pt(IV) 4 B. (Tetrachloro-trans-d-1,2-diaminocyclo- hexane)Pt(IV)*2(dioxane) (monoclinic form) 12 C. (Tetrach1oro-trans-d-1,2-di ami nocyc1o- hexane)Pt(IV) (rhombohedral form) 14 D. (Tetrach1oro-trans-d,1-1,2-di ami nocyc1o- hexane)Pt(IV) (rhombohedral form) 24 Final Remarks 28 33 Page CHAPTER 2 - REACTION PRODUCTS OF A N E W ANTI-CANCER AGENT, Pt(IV)(CYCLOHEXANEDIAMINE)Cl4, WITH GUANOSINE A N D 9-METHYLGUANINE 76 Introduction 76 Experimental Section 76 A. [Pt(cis-dach)(guanosine)2]C l^ ^(CIO^Jq 5*3H20 76 B. [Pt(trans-d,l-dach)(9-methylguanine)](C10 4 )2 80 General Discussion 93 Summary 95 CHAPTER 3 - CRYSTALLOGRAPHIC STUDIES O N OCTAHEDRAL COMPLEXES Pt{IV)(1,2-DIAMIN0CYCL0HEXANE) WITH NUCLEOBASES 111 Introduction 111 Experimental Section 112 A. [Pt(trans-d, 1 -dach)(9-methyl guanine)2Cl 2]- (N03) 2*11H20 112 B. [Pt(cis-dach)(9-methylguanine)2Cl 2]C12*2H20 120 C. [Pt(cis-dach)(9-methylguanine)2(0H)2]C l 2 128 General Discussion 133 Conclusion 134 APPENDIX A - SYNTHESIS AND CRYSTALLIZATION O F £is-[P t (NH3) 2(D I NUCLEOTIDE) ] COMPLEXES 161 APPENDIX B - THE DEFINITION O F VARIOUS DNA AND RNA CONSTITUENTS 166 v Page APPENDIX C - THE W ORKING CONDITIONS O F THE HIGH PERFORMANCE (PRESSURE) LIQUID CHROM ATOGRAPHY (HPLC) 168 APPENDIX D - CRYSTALLOGRAPHIC STUDIES O N Pt(TRANS-: £-DACH)(GUAN0SINE)2C11>5(C104)0 >5*2H20 171 REFERENCES 189 LIST O F TABLES Table Page 1.1 Summary of Crystal Data and Refinement Results for (Tetrach1oro-c i s -1 ,2-di ami nocyc1ohexane) P t( IV ) 37 1.2 Final Atomic Coordinates for (Tetrachloro-cis-1,2- diaminocyclohexane)Platinum(IV) 38 1.3 Anisotropic Temperature Factors for (Tetrachloro- cis-1,2-diaminocyclohexane)PI atinum(IV) 39 1.4 O Bond Distances (A) for (Tetrachloro-cis-1,2- diaminocyclohexane)PI atinum(IV) 40 1.5 Bond Angles (deg) for (Tetrachloro-cis-1,2- diaminocyclohexane)Platinum(IV) 41 2.1 Summary of Crystal Data and Refinement Results for (Tetrachloro-trans-d-l,2-diaminocyclohexane)Pt(IV)* 2(dioxane) 43 2.2 Final Atomic Coordinatesfor (Tetrachloro-trans-d- 1,2-diaminocyclohexane)PI atinum(IV)*2(dioxane) 44 2.3 Anisotropic and Isotropic Temperature Factors for (Tetrach1oro-trans-d-1,2-diaminocyclohexane)- Platinum(IV)-2(dioxane) 45 2.4 O Bond Distances (A) for (Tetrach1oro-trans-d-1,2- diaminocyclohexane)Platinum(IV)*2(dioxane) 46 2.5 Bond Angles (deg) for (Tetrachloro-trans-d-1,2- diaminocyclohexane)PI atinum(IV)*2(dioxane) 47 3- 1 Summary of Crystal Data and Refinement Results for (Tetrach1oro-trans-d-1,2-diaminocyclohexane)Pt(IV) 49 3.2 Final Atomic Coordinates for (Tetrachloro-trans-d- 1, 2-d i ami nocyc1ohexane) Pt( IV ) 50 3.3 Anisotropic Temperature Factors for (Tetrachloro- trans-d-l,2-diaminocyclohexane)Pt(IV) 52 v ii Table Page 3.4 O Bond Distances (A) for (Tetrachloro-trans-d-1,2- diaminocyclohexane)Pt(IV) 55 3.5 Bond Angles (deg) for (Tetrach!oro-trans-d-1,2- diaminocyclohexane)Pt(IV) 58 4.1 Summary of Crystal Data and Refinement Results for (Tetrachloro-trans-d,1 -1 ,2-diamino- cyclohexane)Pt(IV) 63 4.2 Final Atomic Coordinates for (Tetrach1oro-trans- d ,1 -1 ,2-diaminocyclohexane)Pt(IV) 64 4.3 Anisotropic and Isotropic Temperature Factors for (Tetrachloro-trans-d,1 -1 ,2-diamino- cyclohexane)Pt(IV) 66 4.4 O Bond Distances (A) for (Tetrachloro-trans-d,l-1,2- diaminocyclohexane)Pt(IV) 68 4.5 Bond Angles (deg) for (Tetrachloro-trans-d,l-1,2- d i ami nocyc1ohexane) P t( IV ) 71 5.1 Summary of Crystal Data and Refinement Results for Pt( I I )(cis-dach)(guanosine) 2^ 104)0 ^ 1.]^ 5* 3H20 96 5.2 Final Atomic Coordinates for Pt(II)(cis-dach)- (guanosine)2(C104)Q>5Cl-]^5*3H20 97 5.3 Anisotropic Temperature Factors for P t(II)(c is - dach)(guanosine)2(C104)0 ^gCl^^5*3H20 99 5.4 O Bond Distances (A) for Pt(II)(cis-dach)- (guanosine) 2( 0104) 0 ^ 1 i . 5*3H20 101 5.5 Bond Angles (deg) for P t(II)(cis-dach)- (guanosine) 2( 0104)0 ^5011. 5*31120 103 6.1 Summary of Crystal Data and Refinement Results for P t ( I I ) (trans-d,1-dach)(9-methyl guanine)2( 0104)2 106 6.2 Final Atomic Coordinates for P t(II)(tra n s -d ,l- dach) (9-methyl g u a n i n e ^ C ^ ^ 107 6.3 Anisotropic Temperature Factors for P t(II)(tra n s - d,l-dach)(9-methyl guanine)2(0104)2 108 v iii Table Page 6.4 Bond Distances (A) for P t(II)(trans-d,l-dach) (9-methylguanine)2(C10^ )£ 109 6.5 Bond Angles (deg) for P t(II)(trans-d,l-dach) (9-methyl guanine)2( 0104)£ 110 7.1 Summary of Crystal Data and Refinement Results for [Pt(IV)(trans-d,l-dach)(9-m ethyl guanine)pCl0]- ( NO3) 2*11H 0 135 7.2 Final Atomic Coordinates for [P t(IV )(tra n s -d ,l- dach) (9-methyl guanine ) 2C12KNO3) 2" HH 2O 136 7.3 Anisotropic Temperature Factors for [ Pt(IV)(trans- d, 1-dach )(9-meth.yl guanine) 2Cl2](N03) 2*llH 20 138 7.4 Bond Distances (A) for i[Pt(IV)(trans-d,l-dach)- (9-methyl guanine) 2C12](N03) 2*HH 20 140 7.5 Bond Angles (deg) for [ Pt(IV)(trans-d,l-dach)- ( 9-methyl guanine)3d 2](N03) 2*11H20 142 8.1 Summary of Crystal Data and Refinement Results for [P t(IV ) (cis-dach) (9-methylguanine)3d 3] Cl 2'2 ^ 0 144 8.2 Final Atomic Coordinates for [P t(IV)(cis-dach)- (9-methyl guan i ne) £C 1 C12* 2H£0 145 8.3 Anisotropic Temperature Factors for [P t(IV )(cis- dach) (9-methyl guanine) 2^ 2^ ^ 2* ^2® 147 8.4 Bond Distances (A) for [Pt(IV)(cis-dach)- (9-methylguanine)2Cl 149 8.5 Bond Angles (deg) fo r [Pt(IV)(cis-dach)- (9-methylguanine) 2Cl2]Cl 2*2 ^ 0 151 9.1 Summary of Crystal Data and Refinement Results for [Pt(IV)(cis-dach)(9-meth.ylguanine)2(0H)2]Cl 2(1- methylcytosine) 153 9.2 Final Atomic Coordinates for [Pt(IV)(cis-dach)- (9-methy1gu an i ne) 2(OH) 3] C12 * 2( 1-methylcytos i ne) 154 9.3 Anisotropic Temperature Factors for [ P t(IV )(cis- dach)(9-methylguanine)2(0H)2] C l 2(1- methylcytosine) 156 ix Table Page 9.4 Bond Distances (A) for. [Pt(IV)(cis-dach) (9-methyl guanine) 2(011) 2] Cl 2*2(l-methylcytosine) 158 9.5 Bond Angles (deg) for [Pt(IV)(cis-dach)(9-m ethyl- guanine) 2(OH)2]C12*2( 1-methylcytosine) 159 10.1 Summary of Crystal Data and Refinement Results for P t( I I ) (trans-1-dach)(guanosine)2(Cl04 )o>5Cl 3 ^ 5*2H20 179 10.2 Final Atomic Coordinates for Pt(trans-1- dach)Guo2(C104)CL5(C l)1<5- 2H20 180 10.3 Anisotropic Temperature Factors for Pt(trans-1- dach)Guo2C104)o 5(C1)^ 5* ^ 2^ 182 10.4 Bond Distances for Pt(trans-1- dach)Guo2(C104) 0 >5rC l)1>5‘ 2H20 184 10.5 Bond Angles (deg) for Pt(trans-1- dach)GuO2(C104)0 >5 (C l)1#5* 2H20 186 X LIST O F FIGURES Isomeric forms of 1,2-cyclohexanediamine Structure of Pt(cis-dach)Cl4, showing the mirror- image relationship betwen tne eq/ax ( le ft) and ax/eq (right) conformations Structure of Pt(cis-dach)Cl4, showing the isomers in the 6 ( le f t ) and \ (right) conformations Structure of the 6-isomer of Ptfcis-dachjCl^, showing the c h a ra c te ris tic a lly L-shaped geometry of the Pt(dach) portion Structure of Pt(trans-d-dach)Cl4 (monoclinic form), showing the twisted, almost boat-shaped appearance of the eye 1ohexane ring Structure of Pt(trans-d-dach)Cl 4*2(dioxane), showing the two dioxane molecules of c ry s ta lliz a tio n , one above and one below the trans- d-dach ligand Structure of Pt(trans-d-dach)Cl4*2(dioxane), showing that the two dioxane molecules of c ry s ta lliz a tio n are both hydrogen-bonded to one of the NH? groups of the trans-d-dach ligand (dotted lines) Structure of Pt(trans -l-dach)C l4 (monoclinic form), showing a normal chair appearance of the eye 1ohexane ring Structure of one of the independent molecules of Pt(trans-d-dach)Cl4 (rhombohedral), showing the normal chair appearance of the eye 1ohexane ring Structure of one of the 1-isomer of P t(tran s-d ,l- dach)Cl4 (rhombohedral), showing a normal chair appearance of the eye 1ohexane ring Structure of one of the d-isomer of P t(tran s-d ,l- dach)Cl4(rhombohedral), again showing the normal chair appearance of the eye 1ohexane ring Figure Page 12 The relation of conformation to DNA molecules of Pt(dach) complexes (a fter Kidani, et a l., ref. 12b) 33 13 Conformation of the chelate ring in the Pt(trans- dach) unit for the molecules with 1-trans-dach ( le f t ) and d-trans-dach (right) 36 14 Structure of the [(cis-dach)Pt(guanosine)o]2+ cation (View #1) 81 15 Structure of the [(cis-dach)Pt(guanosine)2] 2+ cation (View #2) 83 16 Structure of the [ (cis-dach)Pt(guanosine)2] 2+ cation (View #3) 85 17 Structures of the [(cis-dach)Cl(guanosine)2 ]^+ (this chapter) ( le f t ) and [ (tran s-1-dach)- Pt(guanosine)2]^ + (Appendix D) (right) cations, showing some steric interaction of the L-shaped cis-dach ligand with a ribose group 87 18 Structure of the [(tr^ns-d-dach)- Pt(9-methylguanine)2]^ cation 91 19 Structure of the [ (trans-d-dach)Pt(9-methyl - guanine)2:C l 2] cation 114 20 A side view of the structure of [(trans-d-dach)- Pt(9-methyl(guanine)2C l2 ] , showing the f l a t appearance of the trans-dach ligand. 116 21 Another side view of the structure of [(trans-d-dach)- Pt(9-methylguanine)2C l2] , showing the f l a t and twist-boat conformation of the trans-d-dach ligand 118 22 A side view of the structure of [(cis-dach)- Pt(9-methylguanine)2C l2] , showing the L-shaped configuration of the cis-dach ligand 122 23 Structure of the [(cis-dach)Pt(9-methyl- guanine)2Cl 2] cation, showing v ir tu a lly the same orientation of the guanine rings as in the trans- dach complex, with the cis-dach ligand p a r tia lly obscured by the upper chloride ligand 124 x ii Figure 24 25 26 27 28 29 Page Another side view of the structure af [(cis-dach)P t(9-methylguanine)201 o] cation, showing the L-shape of the cis-dacn ligand 126 Unit c e ll packing diagram o f the [(cis-dach)- P t(9-methylguanine)£ (OH)2] 2(1-methyl cytosine) cation, showing the intermol ecu! ar Watson-Crick type hydrogen bonding between platinated guanine and non-coordinated cytosine (dotted lines) 131 Rotation photograph (20 minute exposure) of [Pt(NHo)2(0pG)] Cl" showing strong d iffraction spots (up to the outer lim its of the photograph) on an ultra-sm all crystal using synchrotron radiation 164 Structure of cation (View Structure of cation (View Structure of cation (View the [ (trans-1 -dach)Pt(guanosine)o]^+ #1) 173 the [(trans-1-dach) Pt(guanosine)p]2+ #2) 175 the l(trans-l-dach)- Pt(guanosine)?] 2+ #3) 177 x iii ABSTRACT i I I A new octahedral Pt(IV) anti-cancer agent, Pt(IV)(dach)Cl4 (dach = 1, 2-cyclohexanediamine), has been reported to be active against certain types of L-1210 leukemia that have acquired resistance against the well-established anti-tumor drug cis-PtCNHg^Cl 2 (c isp latin ). Unlike cis-PtfNHg^Cl which has two leaving groups (the two chlorine atoms), and hence two points of attachment to DNA, the course of platinatio n with Pt(dach)Cl4 is less predictable. In order to see i f there are any significant differences in the way Pt(I V)(dach)Cl 4 and cis-Pt(II)(N H 3) 2Cl 2 bind to DNA fragments, the complexation behavior of this new platinum anti-cancer agent (a novel octahedral Pt(IV) complex in contrast to the commonly-used square planar P t(II) complex) with various DNA constituents have been studied. First of a l l , the absolute configurations of the three isomeric forms of the parent compound were determined since they had not been confirmed before (Chapter 1). The results were shown to be consistent with what is known in the lite ra tu re . Secondly, the reaction products of Pt(dach)Cl4 with guanosine and 9-methyl guanine have been analyzed by single-crystal X-ray diffractio n (Chapter 2). In both cases, the resulting complexes, [Pt(dach)(guanosine)2]^+ and [Pt(dach)(9-methylguanine)2] 2+ respectively, indicated an unanticipated reduction of the octahedral Pt(IV) starting material to xiv a square planar P t(II) species. They are the f ir s t crystal structures of Pt(cyclohexanediamine) drugs with a nucleobase and a nucleoside. The nature of the reducing agent is presently unknown. However, in the presence of suitable oxidizing agents, the P t(IV )-to -P t(II) reduction can be suppressed. In Chapter 3, the preparation and structure determinations of [Pt(dach)(9-methylguanine)2X£]^+ (X=C1_, OH") are described. The existence of these complexes shows that i t j_s possible to accommodate two purine bases (in a cis configuration) and four other ligands around a Pt(IV) atom. The geometries of these complexes have very different orientations of the guanine rings as compared to th eir corresponding P t(II) counterparts. xv CHAPTER 1 CRYSTALLOGRAPHIC STUDIES O N THE ISOMERS O F A N E W OCTAHEDRAL ANTI-CANCER AGENT (TETRACHLORO-1, 2-^DI A M INOCYCLOHEXANE) Pt ( IV ) Introduction The development of analogs to cis-PtfNHg^Cl2 (cisp latin ) has been a f e r t i l e area of investigation based on the documented c lin ic a l efficacy of cisplatin-*- either alone or in combination in the treatment of te s tic u la r, ovarian, bladder and other cancers.2" 4 However, observations that cisp latin has several undesirable side effects (nephrotoxicity, ototoxicity, myelosuppression, neurotoxicity, severe nausea and vomiting, etc.) as well as a c tiv ity in only a lim ited number of tumor types, has stimulated the synthesis and evaluation of many new agents in search of complexes with reduced to x ic ity and differen t biological properties.®"® To this date, a large number of metal complexes have been tested for antitumor a c tiv ity , especially c is p la tin analogs.^ Cis-Pt(NH3)2C l2 analogs are usually made by varying the amine ligand, substituting the chloride ligands by d ifferen t "leaving groups" or, in a few cases, by varying the oxidation state to Pt(IV). Recently, a new Pt(IV) anti-cancer agent*-® has been shown to be active against certain types of L-1210 leukemia that have acquired resistance against cis-Pt(NH3) 2C l2* This new octahedral Pt(IV) drug, P t(l,2-cyclohexanediamine)Cl4, [abbreviated Pt(dach)Cl4 .] is less toxic 1 and has higher anti-tumor properties, than cisplatin and its square planar P t(II) analogs.^ I t represents a significant development in second generation platinum complexes because of its improved s o lu b ility , s ta b ility , purity, ease of preparation, and spectrum of anti-neoplastic a c tiv ity . The free (uncomp 1exed) ligand 1,2-cyclohexanediamine exists in diastereotopic isomeric forms: the cis isomer (featuring axial and equatorial NH2 groups) and the trans isomer (containing two equatorial NH2 groups). The trans isomer, in turn, is o p tic a lly active, and hence exists as two enantiomeric forms, trans-d-dach and tra n s -1-dach. These three isomers: cis-dach (1R, 2S), trans-d-dach (IS, 2S) and trans-1-dach (1R, 2R) are shown below. trans-A trans-1 trans-(+) tra n s -i-) 1S.2S 1R,2R Figure 1. Isomeric forms of 1,2-cyclohexanediamine. The la tte r two, trans-d-dach and trans-1-dach, are d if f ic u lt to separate and hence Pt(trans-dach)Cl4 is often administered as a racemic mixture. Tests with complexes made from the separated isomers have shown that they have differen t a c tiv itie s . I t was found, for example, that the antitumor properties Pt(trans-1-dach)Cl4 > _ Pt(trans- d,l-dach)Cl4_ ^ Pt(trans-d-dach)C 14 » Pt(cis-dach)Cl4 on a 2 mg/kg/dose b a s is .^ Ffom the differences in anti-cancer effects, i t seems to follow that the various [PtX^dach)] complexes interact d iffe re n tly with DNA. This point has been addressed^ and i t was proposed on the basis of | steric arguments [in the case of P t(II) complexes] that the [P t(trans- dach)] complexes could more easily enter the large groove of the DNA double-helix to interact with the DNA bases than those of [P t(c is - dach)] (see Figure 12 in the Discussion and Conclusion section; page 33). This may account for the higher a c tiv ity of trans versus cis, j t but i t does not explain the difference between the trans-l-dach and ! trans-d-dach a c tiv itie s . This la tte r difference probably lie s in the geometric details of how the two enantiomers interact with the chiral DNA helix; however, the exact nature of the binding of Pt-drugs to DNA 1 o I is s t i l l only p a rtial ly resol ved. Until now, the absolute configurations of the various dach isomers of platinum (IV) complexes (i.e., the anti-cancer agents j themselves) have not been confirmed, even though several crystal I I ! \ structures of the corresponding platinum (II) dach complexes have been j reported in the 1 ite ra tu re .*4 -* 6 In this chapter, the c ry s ta lliz a tio n and structure determinations of Pt(cis-dach)Cl4, Pt(trans-d-dach)Cl4*2(dioxane), P t(tra n s -d - dachjCl^ and Pt(trans-d,l-dach)Cl4 are described. The stereochemistry of each dach isomer w ill be b rie fly discussed. 3 Experimental Section A. (Tetrachloro-cis-1,2-diaminocyclohexane)Pt(IV) a) Crystallization of Pt(cis-dach)Cl4 To 2 ml of d o u b ly -d is tilled water, 3.7 m g of Pt(cis-dach)Cl4*0 was added. The solution was warmed up to about 50°C u n til a clear yellow solution was observed. The solution was allowed to cool down to room temperature slowly. After about two days, crystals with a roughly cubic form appeared; these crystals were of a q u ality suitable for an X-ray analysis. b) Data collection and structure analysis A yellow cubic crystal with approximate dimensions (0.3 x 0.3 x 0.3 m m ) was chosen for the structure analysis. A Nicolet/Syntex P 2-^ automatic four c irc le diffractometer with Mo K a radiation and a graphite monochromator was used for data col lection. Accurate unit c e ll parameters were obtained by c a re fu lly centering fifte e n high- angle reflections and are listed together with other relevant crystal data in Table 1.1. The space group was found to be 92^2^2-^ (orthorhombic). One quadrant of data (+h, +k, f l ) was collected using the e/2escan technique with Mo Ka radiation up to a 26 lim it of 50° at room temperature. Throughout data co llection, three reflections [(039), (402), and (322)] were monitored p e rio d ic ally (after every 50 reflections) and no decay was observed. The data were processed with a Lorentz, polarization and an empirical absorption corrections,^ the la tte r interpolated from the psi scan intensities of refle c tio n (313). 4 Of 4516 reflections collected, 1970 independent reflections (after averaging equivalent reflections) with intensities greater than three a(I) were retained for the structure analysis. The in it ia l positions of the two independent platinum atoms were obtained through direct methods,^ while the remaining non-hydrogen atoms were located through the usual combination of 1 east-squares refinement cycles and difference-Fourier syntheses.^ The fin a l least-squares refinement cycles, where a ll the atoms were refined anisotropical ly , gave agreement factors of R = 0.033 and R w = 0.036. (See Tables 1.2 through 1.5 for fin a l atomic coordinates, temperature factors, bond distances and bond angles.) c) Description Since the two amine groups in the cis-dach molecule are in axial and equatorial positions, in solution the two forms interconvert (ax/eq or X -*-> ■ eq/ax or 5) and one obtains only a racemic mixture (in effec t, only one net isomer). In the solid, however, each conformer is "frozen out" and becomes in trin s ic a lly c h ira l. In the present example, there are two independent molecules (ax/eq or X and aq/ax or 6 forms) in the crystal, corresponding to the two enantiomers. The structures of them are shown in Figures 2 and 3. This is the f ir s t crystal structure determination of a Pt(IV) compound containing cis-dach as a ligand, although the corresponding square-planar P t(II) complex which has only one independent molecule in the crystal structure had been reported e a r lie r .^ In comparing 5 Figure 2. Structure of Pt(cis-dach)Cl4» showing the mirror- image relationship betwen the eq/ax ( le f t ) and ax/eq (right) conformations. C2 C3 ' s j Figure 3. Structure of Pt(cis-dach)Cl^, showing the isomers in the < 5 ( le f t ) and X (rig h t) conformations. Note the conformation of the PtNCCN ring. 9 Figure 4. Structure of the 6 -isomer of Pt(cis-dach)Cl4, showing the c h a ra c te ris tic a lly L-shaped geometry of the Pt(dach) portion. 10 the average Pt-Cl and Pt-N bond distances with those from the Pt( I I ) complex, both of them are longer in the Pt(IV) complex. For example, O the average Pt(IV)-C 1 distance is 2.323(5) A in comparison to 2.293(6) A in the P t(II) compound. The average Pt(IV)-N bond length is 2.08(1) A in comparison to 2.03(2) A for the average Pt ( 11 )-N bond ! [length. The cis-dach complex forms a c h a ra c teris tica lly L-shaped gross geometry (Figure 4), in contrast to the r e la tiv e ly f l a t appearance of trans-dach complexes.-^5^ * ^ The contrast between the L-shaped and f l a t appearances of the cis- and trans-isomers (respectively) may account for the difference in anti-tumor a c tiv ity between cis-dach and trans-dach complexes (see Figure 12 in the Discussion and Conclusion section; page 33). B. (Tetrach 1 oro-trans-d-l,2-diaminocyclohexane)Pt(IV)*2(dioxane) (monoclinic form) The rest of this chapter (Sections B, C and D) is devoted to the structure determinations of trans-dach complexes, a) C ry s ta lliza tio n of Pt(trans-d-dach)Cl4*2(dioxane) About 0.5 ml of a d ilu te Pt(trans-d-dach)Cl4 ^ aqueous solution (concentration = 10 mg/ml) was put into a test tube and vapor-diffused against dioxane (about 5 ml) inside a 25 ml Erlenmeyer flask at room temperature. Yellow crystals came out as rectangular prisms overnight. 12 b) Data collection and structure analysis A yellow crystal with approximate dimensions 0.2 x 0.2 x 0.4 m m was chosen for structure analysis and sealed in a glass c a p illa ry with one drop of mother liquid . The crystal was centered and unit c e ll parameter were determined as described above. A summary of the crystal data is shown in Table 2.1. The space group was found to be P2^ (monoclinic). Two F ried el-re late d quadrants (+h, +k, ±1) and (+h, -k, ±1) were collected for the determination of the absolute configuration of the molecule at room temperature using the w scan technique with Mo radiation up to a 20 lim it of 50°. Three standard reflections [(351), (171), (-143)] were measured at 50-reflectio n in tervals throughout the data c o llec tio n , and they showed no sign of decomposition. The data were processed as described above. Of the 4053 reflections measured, 3586 reflections with I > 3o(I) were retained for the ensuing structure analysis. 1 P The platinum atom was determined from a Patterson map, while the remaining non-hydrogen atoms were located from subsequent difference-Fourier maps*8 with the y-coordinate of the Pt atom fixed. This was followed by several cycles of fu l 1-matrix 1east-squares refinement, in which the Pt atom and Cl atoms were assigned anisotropic temperature factors while a ll carbon, oxygen, and nitrogen atoms were assigned isotropic temperature factors. Convergence resulted in fin a l agreement factors of R = 0.037 and Rw= 0.058. Refinement of the mirror image of the molecule resulted in 13 s ig n ific an tly worse bond lengths, bond angles and especially temperature factors, but with agreement factors s till at R =0.037 and Rw = 0.058. Since both configurations had the same R-value, i t was j impossible to compare them by using Hamilton's "R-factor ratio" I m e th o d .H o w e v e r, the in ferio r molecular parameters resulting from I J the refinement of the mirror image indicated that the f ir s t set of atomic coordinates had the correct absolute configuration. (See j Tables 2.2 through 2.5 for fin a l atomic coordinates, temperature factors, bond distances, and bond angles.) j c) Description j j In this piece of work, the absolute configuration of the j s Pt(IV)(trans-d-dach) complex (and hence the trans-d-dach ligand) was | i determined. The c h a ra c te ris tic a lly f l a t appearance of the trans-d- j dach ligand with its two equatorial NH2 groups was found as reported j before. 15,16 However, the cyclohexane ring had a twisted, almost boat-shaped appearance (Figure 5). One amine group of the d-isomer was H-bonded to two dioxane molecules of c ry s ta lliz a tio n (Figures 6 j and 7). i i i C. (Tetrachloro-trans-d-l,2-diaminocyclohexane)Pt(IV) (rhombohedral j form) a) C rystallization of Pt(trans-d-dach)Cl4 In the absence of dioxane, this same complex c ry s ta lliz e s in a j i differen t (rhombohedral) crystal form. About 10 m g of Pt(trans-d- dachjCl^l® was stirred with 2 ml of d o u b ly-d istilled 14 j Figure 5. Structure of Pt(trans-d-dach)Cl4 (monoclinic form), showing the twisted, almost boat-shaped appearance of the cyclohexane ring. .15 Figure 6. S tructure of Pt(trans-d-dach)Cl4*2(dioxane), showing the two dioxane molecules of crystal 1ization, one above and one below the trans-d-dach ligand. 17 © Figure 7. Structure of Pt(trans-d-dach)Cl^*2(dioxane), showing that the two dioxane molecules of crys tallizatio n are both hydrogen-bonded to one of the NH2 groups of the trans-d-dach ligand (dotted 1in es). Figure 8. Structure of P t(tra n s '- 1 -dachJCl^ (monoclinic form), showing a normal chair appearance of the cyclohexane ring. (S. Huang, unpublished results.) 21 CI1 ro ro water at about 50°C. A ll the undissolved materials were filte r e d quickly while the solution was s t i l l hot and the f i l t r a t e was allowed to cool down slowly. A drop of the clear yellow solution (about 0.1 ml) was sucked into the middle of an open-ended c a p illa ry tube (diameter = 1.5 m m ). The whole set-up was kept in a dark room at about 18°C. A yellow crystal with a hexagonal-prismatic form came out from the mother liquor in two weeks with size large enough fo r structure analysis. b) Data collection and structure analysis Only one crystal turned out to be suitable for an x-ray analysis. This crystal had approximate dimensions 0.45 x 0.45 x 0.35 m m , and was centered as described above. A summary of the crystal data is shown in Table 3.1. The space group was R32 (rhombohedral). One quadrant of data (+h, +k, ± 1) was collected at room temperature using the to scan technique with Mo K radiation up to a 2e lim it of 45°. Three a standard reflections [(8,6,10), (5,0,6) and (1,7,4)] were measured at 50-reflection in tervals throughout the data c o llec tio n , and they showed no sign of decomposition. The data were processed as described above. Of the 19871 reflectio ns measured, 11681 reflectio ns with I > 3a(I) were retained for the ensuing structure analysis and averaged to 3540 independent reflectio ns. The in it ia l positions of the six independent platinum atoms were found by conventional Patterson-search techniques using the SHELX84^k system of computing programs. Since the q u a lity of the data set was not that good, there were d iffic u ltie s in locating 23 the positions of the carbon atoms of the dach ring from difference- Fourier maps. The structure was f i n a l l y solved by using the coor dinates (with reversed signs) from the solved structure (Figure 8) of the isomorphous enantiomer Pt(trans-1 -dach)Cl/| (rhombohedral Several cycles of ful 1-matrix least-squares refinement were then carried out. The temperature factors of a l l the Pt atoms were refined anisotropical ly while a l l the rest were refined isotropical ly. Convergence resulted in fin a l agreement factors of R = 0.0772 and Rw = 0.0579. Refinement of the mirror-image of the molecule resulted in a s ig n ific a n tly higher R-value (R = 0.0783 and R w = 0.0588). This indicated that the f ir s t set of atomic coordinates had the proper absolute configuration. [Note: The ra tio of the R-value is 1.014. This re s u lt independent ly determines that the absolute configuration shown in Figure 9 is correct to a prob ab ility lev el better than 99.5%.-^] (See Tables 3.2 through 3.5 for fin a l atomic coordinates, temperature factors, bond distances, and bond angles.) c) Description In this example (as opposed to section B), a l l the six cyclo- hexane rings from the trans-d-dach ligands were found to have normal chair conformations. The structure of one of them is shown in Figure 9. D) (Tetrachloro-trans-d,l-1,2-diaminocyclohexane)Pt(IV) (rhombohedral form) a) C rystallization of P t(trans-d,l-dach)C l4 The c ry s ta lliz a tio n procedures were sim ilar to those described in section (C.a). Figure 9. Structure of one of the independent molecules of Pt(trans-d-dach)Cl4 (rhombohedral), showing the normal chair appearance of the cyclohexane ring. 25 26 b) Data collection and structure analysis A hexagonal prism -like crystal of approximate dimensions 0.3 x 0.3 x 0.7 m m was chosen for the structure analysis. The crystal was centered and unit c e ll parameters were determined as described above. A summary of the crystal data is shown in Table 4.1. Again, the space group was R32 (rhombohedral). One quadrant of data (+h, +k, ±1) was collected at room temperature using thecoscan technique with Mo K radiation up to a 28 lim it of 45°C. Three standard reflections [(6,10,8), (10,6,9) and (11,13,12)] were measured at 50-reflectio n in tervals throughout data co llectio n and they showed no sign of decomposition. The data were processed as described above. Of the 22637 reflections measured, 6233 independent reflectio n s with I > 3o(I) were retaining for the structure analysis after averaging the equivalent reflections. The in it ia l positions of the six independent platinum atoms were found by conventional Patterson-search techniques using the SHELX-842^ system of computing programs. The rest of the atoms were located from subsequent difference-Fourier maps using the SHELX76.^a This was followed by several cycles of f u l1-matrix 1east-squares refinement, in which the temperature factors of a ll the Pt and Cl atoms were refined anisotropical ly while the temperature factors of a l l the lig h t atoms were refined isotropical ly. Convergence resulted in fin a l agreement fa c to rs of R = 0.0385 and Rw = 0.0360. (See Tables 4.2 through 4.5 fo r fin a l atomic coordinates, temperature factors, bond distances, and bond angles.) This structure was solved by John Lim (an undergraduate 27 researcher in our lab) with the assistance of m y colleague Raymond Stevens and myself. c) Description In this example, three P t(IV )(trans-l-dach )C l4 and three Pt(IV)(trans-d-dach)Cl4 molecules were found. A ll the cyclohexane rings from the trans-d,l-dach ligands are in th e ir normal chair conformation. The structures of one representative example of each pair are shown in Figures 10 and 11. Discussion F irs t Conclusion This chapter describes the structural analysis of Pt(cis- dach)Cl4* Pt(trans-d-dach)Cl4*2(dioxane) (m onoclinic), P t(tra n s -d - dach)Cl4 (rhombohedral) and Pt(trans-d,l-dach)C l4 (rhombohedral). These resu lts, combined with the results of Pt(trans-1-dach)Cl4 and Pt(trans-1-dach)Cl4*2(dioxane) (solved by my co-worker Sharon Huang; see Table A, page 34), unambiguously confirmed that the compounds Drs. Wolpert-de F i1ippes, Haugwitz, and Narayanan (of the NCI) were using in th e ir L-1210 t e s t s did indeed have the assigned absolute configurations. Second Conclusion The most obvious differences among the three structures is that the cis-isomer (Figure 4) has a bent L-shaped geometry, very d ifferen t from the other two. This has been speculated by Kidani before*2 to 28 Figure 10. Structure of one of the 1-isomer of P t(trans-d,1-dach)Cl4 (rhombohedral), showing a normal chair appearance of the cyclohexane ring. 29 30 Figure 11. Structure of one of the d-isomer of P t(trans-d,1-dach)Cl^(rhombohedral), again showing the normal chair appearance of the cyclohexane ring. 31 32 account for their d ifferen t antitumor a c tiv itie s : the fact that steric factors arising from "vertical" cyclohexyl ring in this cis isomer may hinder the approach of the drug towards DNA (see notation "steric hinderance" on the right upper portion of Figure 12) and render i t less active than either of the trans isomers. At any rate, our crystal 1ographic results seem to support this argument: the f l a t configurations of the trans isomers can in fact be envisaged to offer less steric encumberance when Pt(dach)Cl4 attaches it s e lf to DNA. Figure 12. The re la tio n of conformation to DNA molecules of Pt(dach) complexes (a fter Kidani, et a l. , r e f. 12b). Final Remarks The results from the structure determinations of a l l the Pt(trans-dach)Cl^ isomers (both from my own work and those of m y co worker Sharon Huang20b) can be summarized as follows: J t t f l e hindrance A-gaucho \ | 1 33 Table A: A summary of Pt(trans-dach)Cl4 compounds studied by x-ray crystal lography. Compound Lattice No. of Conformation of Independent Cyclohexane Molecules Ring I Pt(trans-d-dach) Cl^ Monoclinic *2(dioxane) 1 twisted boat I I Pt(trans-d-dach)Cl4 rhombohedral I I I P t(trans-d,l-dach)C l4 rhombohedral 6 6 a ll chair form a ll chair form V dachjClfl* monoclinic 2(dioxane) V P t(trans-l-dach)C l4^ brhombohedral 6 1 chair form a ll chair form The cyclohexane ring of the trans-d-dach from Compound I (monoclinic) had a twisted, almost boat-shaped appearance (Figure 5) while normal chair appearance was found in Compound I I (rhombohedral). In the beginning we thought that the two dioxane molecules of c ry s ta lliz a tio n which are H-bonded to one of the amine groups in Compound I might affect the shape of the cyclohexane ring (Figure 7). After the structure determination of Compound I V , i t was evident that this argument was incorrect because the cyclohexane ring of the trans-l-dach isomer had a normal chair form (Figure 8). There is, therefore, the puzzling discrepancy between the conformations of what should be a mirror-image relationship between Pt(trans-d- dach)C 1 2*2(dioxane) (Figure 5) and Pt(trans-l-dach)Cl 2*2(dioxane) (Figure 8). Thus, we decided to examine the crystal structure of 34 Compound I I I which contained three trans-d-dach and three trans-l-dach isomers. I t turned out that the cyclohexane in the trans-d,l-dach complex were once again in a normal chair form. The abnormal configuration of the cyclohexane ring from Compound I (Figure 5) is the only one found in a l l the trans-dach isomers lis ted in the table above. One can only speculate that the conformational energy differences between the chair and boat forms of the cyclohexane rings are so small as to permit this anomaly to exist. The coordinated trans-dach molecule is always in the equatorial - equatorial conformation. The fact that the carbons to which the amino groups are attached are part of the cyclohexane ring produces an effect not observed with simple 1,2-diamine ligands lik e ethylene- diamine. S p e c ific a lly , the chelate ring is held in a single conforma tion by the cyclohexane ring: the 1 (1R, 2R) isomer leads to a a chelate ring, the d (IS, 2S) to a 5 ring (Figure 13). In contrast, chelated ethylenediamine can o s c illa te between the two equivalent A and 5 conformations without a high activation barrier. As a re su lt, in the dach complex, the region where N-H ... substrate hydrogen bonds can be formed is frozen in a chiral pattern. Because of the absence of conformer equilibrium in the Pt-N-C-C-N ring, the whole molecule is less fle x ib le than Pt complexes with ethyl enedi amine or (NHg^. This may allow the chiral character of the cyclohexane ring and its indirect effect on the hydrogen-bonding pattern around the amino groups to be expressed more easily. Although the high anti-tumor a c tiv ity of the complexes with trans-dach (especially the 1-isomer) 35 undoubtedly depends on a number of factors, the p eculiarities depicted here (Figure 13) may play a significant role in affecting Pt-DNA binding. / / v * A(1R,2R) 6<1S,2S) Figure 13. Conformation of the chelate ring in the Pt(trans-dach) unit for the molecules with 1-trans-dach (le f t ) and d-trans-dach (right). No interconversion can take place in solution (after Macquet, et a l., re f. 16). 36 Table 1.1: Sum m ary of Crystal Data and R efinem ent Results for (Tetrachloro-cis-1,2-diam inocyclohexahe)Pt(IV) m olecular w eight (g m ole-1) 451.11 crystal dim ensions (m m ) 0.3 x 0.3 x 0.3 space group P212 12 1 (N o .19) (orthorhom bic) m olecules/ unit cell 8 a (A) 8.443(5) b (A) 11.55(1) c (A) 24.56(2) ° , V (A3) 2394(3) calculated density (g cm -3) 2.50 O wavelength (A) used for data collection 0.71069 S in 0/X lim it (A-1) 0.5947 total num ber of reflections measured 4516 num ber of reflections used in structural analysis I > 3o(l) 1970 (after averaging equivalent reflections) num ber of variable param eters 235 final agreem ent factors R(F) = 0.033 R(wF) = 0.036 37 Table 1.2: Final Atomic Coordinates for (Tetrachloro-cis-1,2-diam inocyclohexane)Platinum (IV) Atom X y z Pt1 1.0011(1) 0.1180(0) 0.9387(1) CI1 0.7268(5) 0.1106(4) 0.9415(2) CI2 1.2756(5) 0.1268(4) 0.9344(2) CI3 1.0114(6) -0.0715(3) 0.9082(2) CI4 1.0141(7) 0.0670(3) 1.0297(2) Ml 0.987 (2) 0.2905(8) 0.9596(5) N2 0.980 (2) 0.181 (1) 0.8592(6) C1 0.913 (2) 0.353 (1) 0.9126(6) C2 0.988 (2) 0.313 (1) 0.8591(6) C3 1.154 (3) 0.354 (1) 0.8500(8) C4 1.154 (3) 0.492 (1) 0.8514(9) C5 1.102 (3) 0.529 (1) 0.9073(9) C6 0.928 (2) 0.485 (1) 0.9174(8) Pt2 2.1214(1) 0.1068(0) 1.2731(1) CI5 2.3479(5) 0.2213(4) 1.2697(2) CI6 1.8906(6) -0.0025(3) 1.2791(2) CI7 2.0855(5) 0.1238(5) 1.1796(2) CI8 2.2754(6) -0.0601(3) 1.2631(2) N3 2.139 (2) 0.1046(9) 1.3577(5) N4 1.989 (2) 0.2553(9) 1.2865(5) C7 2.120 (2) 0.228 (1) 1.3760(6) C8 1.978 (2) 0.281 (1) 1.3473(7) C9 1.818 (2) 0.242 (2) 1.3684(8) C10 1.809 (2) 0.262 (2) 1.4314(9) C11 1.938 (2) 0.196 (1) 1.4598(7) C12 2.106 (2) 0.235 (1) 1.4383(7) 38 Table 1.3: Anisotropic Tem perature Factors for (Tetrachloro-cis-1,2-diam inocyclohexane)Platinum (IV) Atom U n X 103 U 22X 103 U33X103 u 1 2 x io 3 U 13X 103 u 23x io 3 Ptl 27( 0) 29( 0) 29( 0) -1( 0) 3( 0) -3 ( 0) c n 30( 2) 51( 2) 57( 3) ~5< 2) 10( 2) -8 ( 3) CI2 26( 2) 45( 2) 48( 3) 1( 2) -1 ( 2) -7 ( 2) CI3 44( 3) 35( 2) 72( 4) -4 ( 2) IK 3) -1 4 ( 2) CI4 63( 3) 57( 2) 38( 3) -1 ( 3) -8 ( 3) 16( 2) N1 31 ( 7) 25( 5) 19( 7) 4( 6) -4 ( 6) -2 ( 5) N2 3 7( 8) 43( 7) 33( 9) 7( 7) 11( 7) -7 { 6) C l 39(10) 29( 7) 21(10) 3( 6) -4 ( 8) 1( 6) C2 44(10) 39( 8) 22( 9) -1 2 ( 8) -1 3 ( 9) -5< 7) C3 70(14) 37( 9) 49(13) -6( 9) 41(11) 4( 8) C4 75(15) 34( 9) 66(15) ~4( 9) 42(13) -7 ( 9) C5 68(14) 24( 8) 71(15) -9 ( 9) 28(13) -8 ( 8) C6 37(10) 23( 8) 62(14) 1( 7) 14( 9) -8 ( 8) Pt2 30( 0) 35( 0) 22{ 0) 2( 0) -3{ 0) -4 ( 0) CI5 46( 3) 71( 3) 36( 3) -1 3 ( 2) 10( 3) -1 5 ( 2) CI6 52( 3) 48( 2) 45( 3) -1 0 ( 2) 1( 3) -1 5 ( 2) CI7 44( 3) 89( 3) 26( 3) 5( 3) 1{ 2) - 2 ( 3) CI8 55( 3) 50( 2) 52( 4) 19( 2) -7 ( 3) -2 0 ( 2) N3 43( 7) 27( 5) 20( 7) 2( 7) -6 ( 6) -7 ( 5) N4 68(10) 31 ( 6) 16( 7) 16( 8) 5( 8) 2( 5) C 7 41(10) 33( 8) 20( 9) 4( 8) -1 ( 8) 1( 6) C8 33(10) 25( 7) 33(10) 4( 7) 9< 8) -5 ( 7) C9 29(10) 51(10) 53(14) -7 ( 8) -8 { 9) -1 0 ( 9) CIO 24(10) 54(10) 71(16) 9( 8) -6 (1 0 ) -5(1 0 ) C11 53(12) 42(10) 24(11) -1 1 ( 8) 6( 9) -1 0 ( 7) C12 55(11) 44( 8) 15( 9) -1 2 ( 8) 7( 9) -1 5 ( 7) The complete temperature factor is expt-2 n2(Ul1h2a*2 + U22k2b*2 + U 3 3 IV 2 + 2UT2h k a V + 2U13h la V + 2U23k lb V ] Table 1.4: Bond Distances(A) for (Tetrachloro-cis-1,2-diam inocyclohexane)Platinum (JV) Molecule 1 P tl----- CI1 2.319(4) Pt1----- CI2 2.322(4) P tl----- CI3 2.314(4) Pt1----- CI4 2.313(5) P tl----- N 1 2.06(1) P tl----- N2 2.09(1) N 1 ----- C1 1.50(2) N 2 ----- C2 1,53(2) C l — C2 1.53(2) C1 — C6 1.54(2) C3 — C2 1.49(3) C 3 ----- C4 1.59(2) C 5 ----- C4 1.50(3) C 5 ----- C6 1.58(3) Molecule 2 Pt2----- CI5 2.326(5) Pt2----- CI6 2.326(5) Pt2-----CI7 2.324(5) Pt2-----Cl 8 2.338(5) Pt2-----N3 2.08(1) Pt2-----N4 2.07(1) N 3 ----- C7 1.50(2) N 4 ----- C8 1.53(2) C 7 ----- C8 1.52(2) C 7 ----- C12 1.54(2) C 8 ----- C9 1.51(2) C 9 ----- CIO 1.57(3) C IO ----- C11 1.50(2) C12----- C11 1.58(2) Table 1.5: Bond Angles(deg) for (Tetrachloro-cis-1,2-diam m ocyclohexane)Pfatinum (IV) Molecule 1 N1 — Pt1— N2 83.9(5) N1 — P tl— CI4 90.5(3) N1 — Pt1— CI3 175.4(4) N1 — Pt1 CI1 88.4(4) (V II Pt 1 CI2 91.5(4) N 2 Pt1— CI4 174.0(3) N2 — P tl— CI3 91.6(4) N2 — P tl CI1 87.4(4) N2 — P tl CI2 91.7(4) CI1---- P tl--------CI2 179.0(2) CI3— P tl CI1 90.7(2) CI3— -P t1 CI2 89,4(2) CI4---- P tl— CI3 94.0(2) CI4---- Pt1------- CI1 90.5(2) C I4---- Pt1------- CI2 90.4(2) C 1 N 1 — Ptl 1072(8) C 2 N2 — Ptl 110.1(9) N 1 ----C 1 ------- C2 120(1) N 1 ----C 1 ------- C6 113(1) C 2 ----C 1 ------- C6 119(1) C 3 ----C 2 ------- N2 111(1) C 3 ---- C 2 --------C l 115(1) N 2 ----C 2 --------C1 106(1) C 2 ----C 3 ------- C4 109(2) C 5 ----C 4 ------- C3 108(2) C 4 C5 — C6 109(2) C l — C 6 C5 113(1) Molecule 2 N 3 ----Pt2--------CI7 174.7(4) N3 — Pt2 CI6 89.5(4) N 3 ----Pt2------- CI5 89.1(4) N 3 ----Pt2--------CI8 93.1(4) N4 — Pt2— N3 83.7(5) N 4 ----Pt2--------CI7 91.0(4) 41 Table 1.5 (continued) N4 — Pt2— CI6 89.3(5) N 4 -----Pt2------CI5 88.8(5) N 4 -----Pt2------CI8 176.8(4) CI5-----Pt2------CI8 90.4(2) CI6----- Pt2----- CI5 177.7(2) CI5----- Pt2------CI8 91.5(2) CI7— Pt2-----CI6 90.0(2) CI7----- Pt2----- CIS 91.4(2) CI7----- Pt2----- CI8 92.2(2) C 7 -----N 3 ------Pt2 106.2(9) C 8 -----N 4 ------Pt2 110.7(9) N 3 -----C7 — C8 110(1) N 3 -----C 7 ------C12 111(1) C 8 -----C7 — C12 112(2) C9 — C8 — C7 115(1) C 9 -----C8 — N 4 110(1) C 7 -----C8 — N4 109(1) C 8 -----C9 — C10 110(2) C 1 1-----C IO------C9 110(2) C 10-----C l l — C12 111(1) C 7 -----C 12— C11 113(2) Table 2.1: Summary of Crystal Data and Refinement Results for (Tetrachloro-trans-d-1,2-diaminocyclohexane)Pt(IV).2{dioxane) m olecular w eight (g m o le '1) 627.11 crystal dimensions (mm) 0.2 x 0.2 x 0.4 space group P21 (No.4) (m onoclinic) m olecules/ unit cell 2 a (A) 8.757(6) b (A) 16.156(7) c (A) 7.832(5) B (deg) 97.63(5) V (A3) 1098(1) calculated density (g cm -3) 1.90 O w avelength (A) used for data collection 0.71069 S in 0/X limit (A '1) 0.5947 total num ber of reflections measured 4053 num ber of reflections used in structural analysis 1 > 3a(l) 3586 num ber of variable param eters 125 final agreem ent factors R(F) = 0.037 R(wF) = 0.058 43 Table 2.2: Final Atom ic Coordinates for (Tetrachloro-trans-d-1,2-diam inocyclohexane)P latinum (IV )2(dioxane) Atom X V z Pt 0.6199(1) 0.7325(0) 0.1849(1) cn 0.4720(3) 0.7315(6) 0.4089(3) CI2 0.7797(3) 0.7314(7) -0.0295(3) CI3 0.471 (1) 0.836 (1) 0.048 (1) CI4 0.467 (1) 0.627 (1) 0.046 (1) N1 0.762 (2) 0.647 (1) 0.316 (2) N2 0.764 (3) 0.821 (1) 0.320 (3) C l 0.857 (2) 0.693 (1) 0.472 (2) C2 0.906 (2) 0.776 (1) 0.403 (2) C3 0.989 (3) 0.826 (1) 0.554 (3) C4 1.095 (3) 0.774 (1) 0.688 (3) C5 1.128 (2) 0.685 (1) 0.636 (3) C6 0.996 (3) 0.640 (1) 0.540 (3) Dioxane m olecule 1 011 0.356 (1) 0.444 (1) 0.482 (2) 012 0.637 (2) 0.529 (1) 0.550 (2) C11 0.366 (3) 0.523 (1) 0.575 (3) C12 0.632 (2) 0.443 (1) 0.470 (2) C13 0.483 (3) 0.423 (1) 0.358 (3) C14 0.534 (3) 0.530 (1) 0.646 (3) Dioxane m olecule 2 021 1.064 (2) 0.449 (1) -0.142 (2) 022 0.935 (2) 0.531 (1) 0.123 (2) C21 1.082 (3) 0.552 (1) 0.078 (3) C22 0.839 (3) 0.500 (1) -0 .0 2 8 (3) C23 0.910 (3) 0.425 (1) -0 .1 0 4 (3) C24 1.160 (2) 0.476 (1) 0.009 (2) Table 2.3: Anisotropic and isotropic Tem perature Factors for (Tetrachloro-trans-d-1,2-diam inocyclohexane)Platinum (IV)2(dioxane) Pt 29(1) Ci1 44(1) CI2 58(2) CI3 44(4) CI4 63(6) N1 25(4) N2 49(6) C l 37(3) C2 35(3) C3 50(6) C4 77(6) C5 71(5) C6 42(6) Dioxane m olecule 1 011 33(3) 0 1 2 52(4) C11 55(6) C12 34(4) C13 56(7) C14 41(6) Dioxane m olecule 2 021 42(3) 0 2 2 54(4) C21 52(6) C22 57(6) C23 50(5) C24 38(5) 2 X 103 U 33X 103 u 1 2 x io 3 U13X 103 U23X 103 33(1) 33(1) 5(1) 7(1) - 2(1) 49(1) 55(2) 2(5) 25(1) -2 (5 ) 57(2) 45(1) 0(6) 23(1) -4 (5 ) 53(5) 62(5) 13(3) 2(4) 16(4) 56(5) 55(5) -17(4) -3 (4 ) -7 (4 ) The com plete tem perature factor is exp[-2ir2(U n h2a*2 + U22k2b*2 + U33l2c*2 + 2 U 12hka*b* + 2U13hla*c* + 2U23klb'c ] 45 Table 2.4: Bond Distances(A) for (Tetrachloro-trans-d-1,2-diam inocyclohexane)Platinum (IV).2(dioxane) Pt----- CI1 2.315(4) Pt----- CI2 2.324(4) Pt— CI3 2.297(7) Pt— CI4 2.347(8) Pt----- N1 2.05 (2) P t — M2 2.10 (2) N 1----- C l 1.57 (2) N2----- C2 1.50 (3) C2— C l 1.54 (2) C3----- C2 1.53 (3) C3----- C4 1.55 (3) C4----- C5 1.53 (3) C6----- C5 1.49 (3) C6 ----- C1 1.53 (3) Dioxane m olecule 1 011 — C11 1.46 (2) 0 1 1 ----- C13 1.61 (3) 0 1 2 ----- C14 1.25 (3) 012 — C12 1.51 (2) C11----- C14 1.51 (3) C12----- C13 1.51 (3) Dioxane m olecule 2 0 2 1 — C24 1.42 (2) 0 2 1 — C23 1.47 (2) 022 — C21 1.42 (3) 022 — C22 1.44 (3) C21----- C24 1.54 (3) C 22----- C23 1.53 (3) Table 2.5: Bond Angles(deg) for (Tetrachloro-trans-d-1,2-diam inocyclohexane)Platinum (IV).2(dioxane) CI3— P t ----- CI1 91.1(3) CI3— -P t — CI2 91.6(3) CI3— Pt — CI4 93.4(1) C|1— Pt — CI2 176.9(1) CI1----- Pt — CI4 90.3(3) C I2----- Pt — CI4 91.1(3) N1 — P t ----- CI3 176.1(5) I\J1 — Pt — CI1 88.9(5) N 1 ----- Pt — CI2 88.4(5) N1 — P t ----- CI4 90.5(5) N2 — Pt — Ci3 90.6(7) N 2 ----- P t ------Cl 1 89.0(6) N2 — Pt — CI2 89.4(7) N2 — P t ----- CI4 176.0(7) N 1 — Pt — N2 85.5(3) C 1 ----- N 1 — Pt 106.9(9) C2 — N 2 ----- Pt 108(1) C6 — C l — N1 109(1) C2 — C l ----- N1 107(1) N2 — C 2 ----- C3 112(1) N2 — C2 — C1 108(1) C 3 ----- C 2 ------C1 109(1) C 2 ----- C 3 ------C4 115(2) C5 — C6 ----- C l 116(2) C 5 ----- C4 — C3 116(2) C6 — C 5 ----- C4 116(2) C6 — C1 — C2 111(1) Dioxane m olecule 1 C 11— 0 1 1 — C13 119(1) C 14----- 0 1 2 ------C12 106(2) O i l — C 11----- C14 104(2) C 13— C 12— 0 12 115(2) C 12— C13— 011 102(2) 0 1 2 ----- C 14------C11 121(2) Dioxane m olecule 2 C 24 0 2 1 — -C 2 3 112(1) Table 2.5 (continued) C 21----- 0 2 2 ----- C22 109(2) 0 2 2 — C 21----- C24 110(2) 0 2 2 — C22----- C23 112(2) 0 2 1 — C23----- C22 107(2) 0 2 1 — C24— C21 108(2) 48 Table 3.1: Sum m ary of Crystal Data and R efinem ent Results for (Tetrachloro-tran s-d -1,2-d iam in o cyclo h exan e)P t(IV ) m olecular w eight (g m ole-1) crystal dim ensions (m m ) space group m olecules/ unit cell a=b=c (A) a=B =y (deg) V (A3) calculated density (g cm -3) 0 w avelength (A) used for data collection S in 9/X lim it (A-1) total num ber of reflections measured num ber of reflections used in structural analysis I > 3a(l) num ber of variable param eters final agreem ent factors 451.11 0.45 x 0.35 x 0.45 R32 (N o.155) (rhom bohedral) 36 26.40(4) 55.09(8) 11519(8) 2.34 0.71069 0.5385 19871 3540 (after averaging equivalent reflections) 355 R(F) = 0.0772 R(wF) = 0.0579 49 Table 3.2: Final Atom ic Coordinates for (Tetrachloro-trans-d-1,2-diam inocyclohexane)Pt(IV) Atom X Y 2 Ptl -0.5262(1) -0.9780(1) -0.1207(1 C I11 -0,4670(1) -1.0490(1) -0.0493(1 Cl 12 -0.4559(1) -0.9180(1) -0.1882(1 CI13 -0.4600(1) -1.0485(1) -0.1782(1 Cl 14 -0.5836(1) -0.9060(1) -0.1927(1 N 11 -0.5976(1) - 1.0202(1) -0.0612(1 N 12 -0.5850(2) -0.9198(2) -0.0636(2 C 11 -0.6556(1) -0.9766(2) -0.0249(1 C 12 -0.6352(1) -0.9473(2) -0.0047(2 C 13 -0.6972(2) -0.8939(2) 0.0250(2 C 14 -0.7509(2) -0.9240(2) 0.0861(2 C 15 -0.7713(1) -0.9528(2) 0.0653(2 C 16 -0.7087(2) -1.0074(2) 0.0369(2 Pt2 -0.5138(0) -1.3850(0) 0.0220(0 CI21 -0.5662(1) -1.3178(1) -0.0529(1 CI22 -0.4490(1) -1.4601(1) -0.0272(1 CI23 -0.4384(1) -1.3330(1) -0.0453(1 CI24 -0.5793(1) -1.3105(1) 0.0778(1 IN I 21 -0.4644(2) -1.4517(1) 0.0876(1 N 22 -0.5832(1) -1.4299(2) 0.0892(1 C 21 -0.4901(2) -1.5052(2) 0.1382(1 C 22 -0.5653(2) -1.4706(1) 0.1481(1 C 23 -0.6002(2) -1.5226(2) 0.1988(2 C 24 -0.5924(2) -1.5556(2) 0.2667(1 C 25 -0.5175(2) -1.5893(1) 0.2573(1 C 26 -0.4822(2) -1.5378(2) 0.2061(2 Pt3 -0.6462(0) -1.0840(0) -0.1449(0 CI31 -0.6161(1) -1.1408(1) -0.0553(1 CI32 -0.6720(1) -1.0278(1) -0.2407(1 CI33 -0.7028(1) -0.9902(1) -0.1206(1 CI34 -0.7382(1) -1.1114(1) -0.0814(1 N 31 -0,5892(1) -1.1727(1) -0.1604(2 N 32 -0.5615(1) -1.0614(2) -0.2115(1 C 31 -0.5198(1) -1.1781(2) -0.1935(2 C 32 -0.5097(1) -1.1104(1) -0.2429(2 C 33 -0.4348(2) -1.1207(2) -0.2738(2 C 34 -0.3921(1) -1.1713(2) -0.3095(2 C 35 -0.4024(1) -1.2389(1) -0.2600(2 Table 3.2 (continued) C 36 -0.4778(2) -1.2278(2) -0.2304(2 Pt4 -0.3450(0) -0.8663(0) -0.4162(0 C141 -0.4352(1) -0.9011(1) -0.3543(1 CI42 -0.2504(1) -0.8392(1) -0.4783(1 CI43 -0.3731(1) -0.8074(1) -0.5105(1 CI44 -0,4071(1) -0.7756(1) -0.3817(1 N 41 -0.3202(2) -0.9236(1) -0.3329(1 N 42 -0.2942(2) -0.9535(1) -0.4332(1 C 41 -0.2644(2) -0.9838(1) -0.3448(2 C 42 -0.2809(2) -1.0084(2) -0.3736(2 C 43 -0.2203(2) -1.0699(2) -0.3916(2 C 44 -0.2050(2) -1.1274(1) -0.3276(2 C 45 -0.1894(2) -1.1034(2) -0.2976(2 C 46 -0.2487(2) -1.0410(2) -0.2811(2 Pt5 -0.7042(0) -1.1797(0) 0.2606(0 CI51 -0.7986(1) -1.1091(1) 0.2318(1 CI52 -0.6555(1) -1.1037(1) 0.1912(1 CI53 -0.6555(1) -1.2228(1) 0.1813(1 CI54 -0.7539(1) -1.1404(1) 0.3434(1 N 51 -0.6224(1) -1.2474(1) 0.2881(2 N 52 -0.7446(1) -1.2522(1) 0.3329(1 C 51 -0.6297(2) -1.3117(1) 0.3226(1 C 52 -0.7026(1) -1.3067(1) 0.3722(2 C 53 -0.7080(2) -1.3764(2) 0.4090(2 C 54 -0.6589(2) -1.4274(1) 0.4470(2 C 55 -0.5862(2) -1.4320(1) 0.3983(2 C 56 -0.5807(1) -1.3623(2) 0.3608(2 Pt6 -0.7950(0) -1.3095(0) 0.2307(0 CI61 -0.7022(1) -1.3722(1) 0.2584(1 CI62 -0.8452(1) -1.3910(1) 0.3061(1 C163 -0.8473(1) -1.2684(1) 0.3126(1 CI64 -0.7418(1) -1.3443(1) 0.1433(1 N 61 -0.7599(2) -1.2327(1) 0.1687(2 N 62 -0.8771(1) -1.2441(2) 0.2033(2 C 61 -0.8112(2) -1.1730(2) 0.1430(2 C 62 -0.8577(2) -1.1906(1) 0.1417(2 C 63 -0.9199(2) -1.1277(2) 0.1288(2 C 64 -0.8985(2) -1.0714(2) 0.0622(2 C 65 -0.8524(2) -1.0538(1) 0.0647(2 C 66 -0.7893(1) -1.1174(2) 0.0754(2 0 79 -0.9481(2) -0.3303(2) -0.5483(2 0 80 -0.8539(2) -0.4460(2) -0.0475(2 51 Table 3.3: Anisotropic Tem perature Factors for (Tetrachloro-trans-d-1,2-diam inocyclohexane)Pt(IV) Atom U n X103 U22X103 U33X IO 3 U12X 103 U 13X103 U23X 103 P tl 32{ 2 c m 55( 5 C I12 47( 5 CI13 45( 5 CI14 5Q( 5 N 11 26( 9 N 12 59(11 C 11 22( 9 C 12 37(10 C 13 31(10 C 14 55(11 C 15 69(12 C 16 50(11 Pt2 46( 2 CI21 46( 4 CI22 48( 5 CI23 52( 5 CI24 38( 4 N 21 27( 9 N 22 28( 9 C 21 50(11 C 22 33(10 C 23 47(11 C 24 69(11 C 25 49(11 C 26 59(12 Pt3 24( 2 CI31 52( 5 CI32 40( 4 C133 29( 4 CI34 73( 6 N 31 60(10 N 32 30{ 9 C 31 63(11 C 32 38(10 C 33 68(11 C 34 67(11 C 35 72(11 30( 2) 28( 2) -1 5 ( 2) -8( 2) -12( 1) 36( 2) 25( 2) -1 8 ( 2) - 12{ 2) -8( 2) 29( 2) 40( 2) -3 ( 1) -1 4 ( 1) -1 3 ( 2) 52 Table 3.3 (continued) C 36 48(11) Pt4 46( 2) CI41 48( 5) CI42 72( 5) CI43 61( 5) CI44 61( 5) N 41 34( 9) N 42 25( 9) C 41 40(10) C 42 54(11) C 43 75(11) C 44 62(11) C 45 86(11) C 46 67(11) Pt5 23( 2) CI51 34( 4) CI52 55( 5) CI53 39( 4) CI54 33( 4) N 51 12( 8) N 52 11( 7) C 51 20( 9) C 52 27( 9) C 53 64(12) C 54 67(11) C 55 68( 11) C 56 73(11) Pt6 28( 2) CI61 50( 5) CI62 62{ 6) CI63 55( 5) CI64 53{ 5) N 61 40(10) N 62 45(10) C 61 81(12) C 62 55(11) C 63 46(10) C 64 68(11) C 65 73(12) C 66 43(11) 0 79 82(10) 0 80 80(10) 37( 2) 30( 2) -1 5 ( 2) -1 6 ( 2) 29( 2) 34( 2) - 8( 1) -1 1 ( 1) 36( 2) 38( 2) -1 0 ( 1) -1 1 ( 2) -1 3 ( 2) -9 ( D -16( 2) 53 Table 3.3 (continued) 2 2 *2 The complete temperature factor is exp[-2 T i (Un h a ^ ^ + U22k2b*2 + U33l2c*2 + 2U12h k a V + 2U13h la V + 2U23klb c ] 54 Table 3.4: Bond Distances(A) for {Tetrachloro-trans-d-1,2-diam inocyclohexane)Pt(IV) Molecule 1 P tl — c m 2.34(2) P tl — Cl 12 2.34(2) Ptl — CI13 2.30(2) Ptl — CI14 2.32(2) P t l ----- IM 11 2.07(1) Pt1 — N 12 2.07(1) N 11— C 11 1.47(1) N 12----- C 12 1.47(1) C 11----- C 12 1.56(1) C 12----- C 13 1.56(1) C 13— C 14 1.57(1) C 14----- C 15 1.57(1) C 11— C 16 1.57(1) C 15— C 16 1.57(1) Molecule 2 P t 2 ----- CI21 2.30(2) P t 2 ----- CI22 2.25(2) P t 2 ----- CI23 2.30(2) P t 2 ----- Cl 24 2.35(2) P t 2 ----- N 21 2.06(1) P t 2 -----N 22 2.07(1) N 21— C 21 1.46(1) N 22----- C 22 1.46(1) C 21— C 22 1.57(1) C 22— C 23 1.57(1) C 23— C 24 1.57(1) C 24----- C 25 1.56(1) C 21----- C 26 1.57(1) C 25— C 26 1.56(1) 55 Table 3.4 (continued) Molecule 3 Pt3 — CI31 2.28(2) Pt3 — CI32 2.36(2) Pt3 — CI33 2.29(2) Pt3 — CI34 2.28(2) P t 3 ----- IN I 31 2.07(1) Pt3 — IM 32 2.07(1) N 31— C 31 1.47(1) N 32— C 32 1.46(1) C 31— C 32 1.56(1) C 32----- C 33 1.56(1) C 33----- C 34 1.56(1) C 34— C 35 1.56(1) C 31— C 36 1.57(1) C 3 5 — C 36 1.57(1) Molecule 4 Pt4 — CI41 2.35(2) Pt4 — CI42 2.33(2) Pt4 — CI43 2.35(2) Pt4 — CI44 2.36(2) Pt4 — N 41 2.06(1) Pt4 — N 42 2.06(1) N 41----- C 41 1.47(1) N 42----- C 42 1.46(1) C 41----- C 42 1.57(1) C 42----- C 43 1.57(1) C 4 3----- C 44 1.57(1) C 44----- C 45 1.57(1) C 41----- C 46 1.57(1) C 45— C 46 1.56(1) Molecule 5 Pt5 — CI51 Pt5 — CI52 P t 5 CI53 2.34(1) 2.25(2) 2.30(2) 56 Table 3.4 (continued) Pt5 — CI54 2.31(1) Pt5 — N 51 2.07(1) P t 5 ----- IM 52 2.07(1) N 51----- C 51 1.47(1) IM 52----- C 52 1.47(1) C 51— C 52 1.57(1) C 52----- C 53 1.56(1) C 53— C 54 1.56(1) C 54— C 55 1.56(1) C 51— C 56 1.56(1) C 55— C 56 1.56(1) Molecule 6 Pt6 ----- CI61 2.30(2) Pt6 ----- CI62 2.38(2) Pt6 — CI63 2.31(2) Pt6 — CI64 2.32(2) Pt6 — IM 61 2.07(1) Pt6 — IM 62 2.07(1) IM 61----- C 61 1.47(1) IM 62----- C 62 1.47(1) C 61— C 62 1.57(1) C 62----- C 63 1.56(1) C 63— C 64 1.57(1) C 64— C 65 1.57(1) C 61----- C 66 1.57(1) C 65— C 66 1.57(1) 57 Table 3.5: Bond Angles(deg) for (Tetrachloro-trans-d-1,2-diam inocyclohexane)Pt(IV) Molecule 1 C I12-P t1 - c m 90(1) CI13-Pt1 - c m 90(1) Cl 13— Pt 1 -C l 12 93(1) c n 4 -P ti - c m 179(1) CI14-Pt1 -C l 12 89(1) CI14-Pt1 -C l 13 90(1) n n - P t i - c m 95(1) N 11-Pt 1 -C l 12 173(1) N 11 -P t 1 -C I1 3 93(1) N 11-Pt1 -C l 14 87(1) N 12-P t 1 - c m 87(1) N 1 2-P tl — Cl 12 89(1) N 12-Pt1 -C I1 3 176(1) N 12— Pt 1 -C l 14 93(1) N 12-P11 -N 11 86(1) C 11-N 11-Pt1 106(2) C 12-N 12-Pt1 109(2) C 12-C 11-N 11 112(2) C 16-C 1 1-N 11 116(2) C 16-C 11-C 12 110(1) C 11-C 12-N 12 108(2) C 13-C 1 2-N 12 112(2) C 13-C 12-C 11 111(1) C 14-C 13-C 12 111(1) C 15-C 14-C 13 110(1) C 16-C 15-C 14 110(1) C 15-C 16-C 11 110(1) Molecule 2 CI22-Pt2 -C I21 90(1) 58 Table 3.5 (continued) C I23-Pt2 -CI21 91(1) CI23-Pt2 -CI22 92(1) C I24-Pt2 -CI21 93(1) CI24-Pt2 -C I22 177(1) C I24-Pt2 -C I23 89(1) N 21-P t2 -CI21 175(1) N 21-P t2 -C I22 86(1) N 21-P t2 -C I23 91(1) N 21-P t2 -€124 91(1) N 22-P t2 -CI21 92(1) N 22-P t2 -C I22 93(1) N 22-P t2 -C I23 175(1) N 22-P t2 -C I24 87(1) N 22-P t2 -N 21 86(1) C 21-N 21-P t2 112(2) C 22-N 22-P t2 103(2) C 22-C 21-N 21 103(3) C 26-C 21-N 21 116(2) C 26-C 21-C 22 110( 1) C 21-C 22-N 22 118(3) C 23-C 22-N 22 111(2) C 23-C 22-C 21 110(1) C 24-C 23-C 22 110(1) C 2 5-C 24-C 23 111( 1) C 2 6-C 25-C 24 111( 1) C 2 5-C 26-C 21 110(1) Molecule 3 C I32-Pt3 -CI31 177(1) C I33-Pt3 -CI31 89(1) C I33-Pt3 -C I32 93(1) C I34-Pt3 -C131 91(1) C I34-Pt3 -C132 91(1) C I34-Pt3 -C I33 91(1) N 31-P t3 -CI31 N 31-P t3 -C I32 85(1) 93(1) 59 Table 3.5 (continued) N 31-P t3 -C I33 173(1) N 31-P t3 -C I34 91(1) N 32-P t3 -CI31 95(1) N 32-P t3 -C I32 83(1) N 32-P t3 -C I33 93(1) N 32-P t3 -C I34 173(1) N 3 2-P t3 -N 31 85(1) C 31-N 31-P t3 107(2) C 32-N 32-P t3 112(2) C 32-C 3 1-N 31 114(3) C 3 6-C 3 1-N 31 109(2) C 3 6-C 3 1 -C 32 110( 1) C 3 1 -C 3 2 -N 32 108(3) C 3 3 -C 3 2 -N 32 122(2) C 33-C 3 2 -C 31 111(1) C 34-C 3 3 -C 32 110(1) C 3 5-C 3 4-C 33 111(1) C 3 6-C 3 5 -C 34 110(1) C 35-C 3 6 -C 31 109(1) Molecule 4 C I42-Pt4 -CI41 176(1) C I43-Pt4 -CI41 90(1) C I43-Pt4 -C I42 91(1) C I44-P t4 -C I41 92(1) C I44-Pt4 -C I42 92(1) C I44-Pt4 -C I43 95(1) N 4 1-P t4 -CI41 88(1) N 4 1-P t4 -C I42 91(1) N 4 1-P t4 -C I43 176(1) N 41 - Pt4 -C I44 89(1) N 4 2-P t4 -C I41 83(1) N 4 2-P t4 -C I42 93(1) N 4 2-P t4 -C I43 92(1) N 4 2-P t4 -C I44 172(1) N 4 2-P t4 -N 41 85(1) 60 Table 3.5 (continued) C 41-N 41-P t4 106(2) C 42-N 4 2-P t4 108(2) C 42-C 4 1 -N 41 108(2) C 46-C 4 1 -N 41 113(2) C 46-C 4 1-C 42 110(1) C 41-C 4 2 -N 42 107(2) C 43-C 4 2-N 42 110(3) C 43-C 4 2 -C 41 110(1) C 44-C 4 3 -C 42 110(1) C 45-C 4 4 -C 43 110(1) C 46-C 4 5 -C 44 111(1) C 45-C 4 6 -C 41 110(1) Molecule 5 C I52-Pt5 -CI51 94(1) C I53-Pt5 -C I51 91(1) C I53-Pt5 -C I52 93(1) C I54-Pt5 -CI51 90(1) C I54-P t5 -C I52 90(1) C I5 4 -P t5 -C I5 3 178(1) N 51-P t5 -CI51 176(1) N 51 -P t5 -C I52 90(1) N 51-P t5 -C I53 88(1) N 51-P t5 -C I5 4 92(1) N 52-P t5 -CI51 92(1) N 52-P t5 -C I52 173(1) N 52-P t5 -C I53 92(1) N 52-P t5 -C I5 4 86(1) N 52-P t5 -N 51 85(1) C 51 -N 51-P t5 105(2) C 52-N 52-P t5 111(2) C 52-C 5 1 -N 51 112(2) C 56-C 5 1 -N 51 108(2) C 56-C 5 1-C 52 110(1) C 51-C 5 2 -N 52 105(2) Table 3.5 (continued) C 53-C 5 2 -N 52 118(2) C 53-C 5 2-C 51 110(1) C 54-C 53-C 52 110(1) C 55-C 5 4-C 53 111(1) C 56-C 5 5-C 54 111(1) C 5 5-C 5 6-C 51 110(1) Molecule 6 CI62-Pt6 -CI61 96(1) C I63-Pt6 -CI61 89(1) C I63-Pt6 -C I62 90(1) C I64-Pt6 — C161 92(1) C I64-Pt6 -C I62 94(1) CI64-Pt6 -C I63 176(1) N 61 -P t6 -C I61 88(1) N 61 -P t6 -C I62 175(1) N 61-P t6 -C I63 87(1) N 61-P t6 -C I6 4 90(1) N 62-P t6 -C I61 174(1) N 62-P t6 -C I62 90(1) N 62-P t6 -C I63 88( 1) N 62-P t6 -C I6 4 91(1) N 6 2-P t6 -N 61 86( 1) C 61-N 6 1-P t6 108(2) C 6 2 -N 6 2-P t6 107(2) C 6 2-C 6 1 -N 61 112(3) C 66-C 6 1 -N 61 119(3) C 66-C 6 1 -C 62 110(1) C 6 1 -C 6 2 -N 62 111(3) C 6 3 -C 6 2 -N 62 111(3) C 6 3 -C 6 2 -C 61 110(1) C 64-C 6 3 -C 62 111(1) C 65-C 6 4 -C 63 110(1) C 66-C 6 5 -C 64 109(1) C 6 5-C 66-C 61 109(1) 62 Table 4.1: Sum m ary of Crystal Data and Refinem ent Results for (Tetrachloro-trans-d,l-1,2-diam inocyclohexane)P t(IV ) m olecular w eight (g m o le-1) 451.11 crystal dim ensions (mm) 0.3 x 0.3 x 0.7 space group R32 (N o .155) (rhom bohedral) m olecules/ unit cell 36 a=b=c (A) 26.32(2) a = 8 =Y (cleg) 54.43(7) V (A3) 11270(2) calculated density (g cm "3) 2.34 O w avelength (A) used for data collection 0.71069 S in 9 /\ lim it (A-1) 0.5385 total num ber of reflections m easured 22637 num ber of reflections used in structural analysis 1 > 3a(i) 6233 num ber of variable param eters (after averaging equivalent reflections) 474 final agreem ent factors R(F) = 0.0385 - R(wF) = 0.0360 63 TABLE 4.2: Final Atomic Coordinates fo r (T etrachloro-trans-d,£-l,2-d ia m ino cyclohe xane)P t(IV ) ATOM Ptl 0.5241(1) 0.9816(1) 0.1184(1) Call 0.4692(6) 1.0532(7) 0.0414(7) C2.12 0.4517(7) 0.9225(8) 0.1871(6) C2 ,l 3 0.4571(7) 1.0523(7) 0.1745(8) C£l4 0.5830(6) 0.9065(6) 0.1934(6) Nil 0.596 (1) 1.026 ( 1) 0.059 (1) N12 0.595 (1) 0.914 (1) 0.069 (1) Cl 1 0.661 ( 2) 0.976 (2) 0.029 (2) C12 0.640 (2) 0.949 (3) 0.001 ( 2) Cl 3 0.697 (2) 0.898 (2) -0.031 (2) Cl 4 0.749 (2) 0.926 (2) -0.091 (2) Cl 5 0.770 (1) 0.957 (1) -0.074 (1) Cl 6 0.705 (2) 1.009 (2) -0.037 (2) Pt2 0.5192(1) 1.3825(1) -0.0251(1) Cj z .2 1 0.5747(9) 1.3173(7) 0.0460(8) C2 .22 0.4519(6) 1.4550(7) 0.0299(7) C£23 0.4424(7) 1.3282(7) 0.0440(7) Q24 0.5817(6) 1.3124(6) -0.0788(7) N21 0.672 (1) 1.452 (1) -0.0923(1) N22 0.579 (1) 1.4317(1) -0.085 (1) C21 0.520 (2) 1.483 (1) -0.156 (1) C22 0.550 (3) 1.494 (2) -0.137 (2) C23 0.610 ( 2) 1.521 (2) -0.204 (2) C24 0.570 (2) 1.586 (2) -0.257 (2) C25 0.537 (1) 1.564 (1) -0.273 (1) C26 0.485 (2) 1.538 (2) - 0.210 ( 2) Pt3 0.6415(1) 1.0025(1) 0.1484(1) C£31 0.6073(3) 1.1405(2) 0.0605(2) Cz32 0.6713(3) 1.0275(3) 0.2401(3) C£33 0.6967(3) 0.9864(3) 0.1271(3) C£34 0.7330(3) 1.1140(3) 0.0847(3) N31 0.580 (1) 1.171 (1) 0.168 ( 1) N32 0.557 (1) 1.058 (1) 0.211 ( 1) C31 0.516 (1) 1.163 (1) 0.230 (1) C32 0.498 (1) 1.123 (1) 0.286 ( 1) C33 0.427 (1) 1.113 (1) 0.286 ( 1) C34 0.381 (1) 1.182 ( 1) 0.293 (1) C35 0.400 (1) 1.220 ( 1) 0.291 (1) C 36 0.471 (1) 1.226 ( 1) 0.243 (1) Pt4 0.3487(1) 0.8610(1) 0.4167(1) C g.41 0.4413(3) 0.8916(3) 0.3563(4) C£42 0.2552(3) 0.8336(3) 0.4743(3) C£43 0.3773(3) 0.7965(3) 0.5109(3) C£44 0.4118(4) 0.7690(4) 0.3863(4) 64 Table 4.2 (continued) ATOM X Y Z N41 0.323 1) 0.913 1) 0.335 (1) N42 0.289 1) 0.949 1) 0.434 (1) C41 0.270 1) 0.975 1) 0.345 (1) C42 0.285 1) 1.006 1) 0.371 (1) C43 0.221 1) 1.064 1) 0.389 (1) C44 0.210 1) 1 .124 1) 0.325 (1) C45 0.195 1) 1.097 1) 0.293 (1) C46 0.264 1) 1 .037 1) 0.275 (1) Pt5 0.7044 1) 1.1830 1) -0.2631(1) C£51 0.7991 6) 1.1144 5) -0.2358(6) Cl52 0.6554 8) 1.1046 7) -0.1908(7) CzS3 0.6538 7) 1.2249 8) -0.1824(7) C£54 0.7539 7) 1.1461 8) -0.3475(8) N51 0.622 1) 1 .249 1) 0.294 (1) N52 0.744 1) 1.257 1) -0.336 (1) C51 0.641 1) 1.314 1) -0.352 (1) C52 0.689 2) 1.322 2) -0.358 (2) C53 0.712 2) 1 .376 2) -0.420 (2) C54 0.659 1) 1.436 2) -0.443 (1) C55 0.606 1) 1.434 1) -0.431 (1) C56 0.583 1) 1.373 1) -0.369 (1) Pt6 0.7952 1) 1 .3148 1) -0.2352(1) C2.61 0.7035 6) 1.3823 7) -0.2653(7) C£62 0.8443 7) 1.3962 7) -0.3083(8) Q63 0.8447 6 ) 1.2754 6) -0.3166(6) Cst64 0.7446 5) 1.3508 6) -0.1498(6) N61 0.760 1) 1.238 1} -0.170 (1) N62 0.876 1) 1.246 1) -0.209 (1) C61 0.818 2) 1.176 2) -0.156 (2) C62 0.859 1) 1.198 1) -0.141 (1) C63 0.919 2) 1.135 2) -0.125 (2) C64 0.895 1) 1.083 1) -0.061 ( 1) C65 0.859 2) 1.056 2) -0.079 (2) C66 0.793 2) 1.117 2) -0.092 (2) 01 0.666 1) 0.055 1) 0.451 (1) 02 0.547 1) 0.151 1) 0.944 (1) 65 TABLE 4.3: Anisotropic and Is o tro p ic Temperature Factors fo r (Tetrachloro-trans-d,z-l,2-diam inocyc1ohexane)Pt(IV) ATOM Un x 103 U22 x 103 U33 x )03 U12 x 103 U,3 x 103 U23 x 103 Ptl 31(1) 38(2) 37(2) -17(1) -10(1) -20(1) Call 29(5) 59(6) 60(6) 5(5) -14(5) -36(5) Czl 2 52(6) 88(6) 33(5) -45(5) 9(5) -36(5) Czl3 46(6) 57(6) 69(6) -16(5) -20(5) -30(5) Czl4 39(5) 42(5) 45(5) -16(4) -24(4) -7(4) Nil 39(6) N12 33(6) Cl 1 54(8) Cl 2 60(8) Cl 3 21(8) C14 62(8) Cl 5 52(7) C16 40(8) Pt2 35(2) 25(1) 22(2) -12(1) -8(1) -2(1) CZ21 100(7) 49(6) 65(6) -18(6) -69(6) 0(5) Cz22 49(6) 64(6) 75(7) -10(5) -23(5) -49(5) Cz23 65(6) 61(6) 38(6) -56(5) 2(5) -10(5) Cz24 43(5) 29(5) 51(6) -4(4) -14(4) -15(4) N21 27(6) N22 35(6) C21 26(7) C22 34(8) C23 80(8) C24 68(8) C25 77(7) C26 62(8) Pt3 32(1) 22(1) 31(1) -6(0) -17(0) -6(0) Cz31 63(4) 18(3) 33(3) -19(3) -37 3) 12(2) CX.32 90(5) 37(3) 52(4) -5(4) -45(4) -13(3) C2.33 48(4) 50(4) 76(4) -3(3) -21(3) -47(3) Ci34 35(3) 53(4) 62(4) -27(3) -4(3) -29(3) N31 23(5) N32 56(5) C31 43(5) C32 42(5) C33 83(6) C34 80(5) C35 84(5) C36 70(5) Pt4 52(1) 35(1) 42(1) -14(1) -26(1) -31(0) Cz41 49(4) 67(4) 89(5) 1(4) -33(4) -31(4) Cz42 88(4) 44(3) 59(4) -47(3) -42(4) 9(3) Cz43 62(4) 56(4) 35(3) -33(3) -14(3) -11(3) Cz44 117(6) 68(5) 138(6) -9(4) -80(5) -45(5) 66 Table 4.3 (continued) ATOM Un x 103 U22 X 103 U33 x 103 U]2 x 103 0 13 x 103 U23 x 1 N41 59(5) N42 34(4) 041 77(7) C42 48(5) C43 41(5) 044 88(7) C45 77(6) C46 50(6) Pt5 19(1) 37(2) 35(2) -3(1) -3(1) -19(1) 02.51 40(5) 26(4) 74(6) 7(4) -47(5) • -16(4) 0252 63(6) 43(6) 55(6) -25(5) -35(5) 8(5) 0253 52(6) 76(7) 58(6) -22(6) 3(5) -43(6) 0254 62(7) 110(7) 106(7) ' -24(6) -26(6) -76(6) N51 40(6) N52 33(6) 051 55(7) 052 58(8) C53 56(7) 054 60(7) 055 71(6) 056 47(7) Pt6 31(1) 33(2) 44(2) -11(1) -19(1) -16(1) 02.61 40(6) 90(7) 44(6) -23(6) 0(5) -28(5) 0262 49(6) 54(6) 85(7) -26(5) 24(5) -24(5) 0263 42(5) 51(5) 38(5) -21(4) 16(4) -17(4) 0264 17(4) 44(5) 53(5) 10(4) 13(4) -36(4) N61 37(6) N62 25(6) 061 46(7) 062 33(6) 063 48(7) 064 65(7) C56 80(8) 066 60(8) 01 70(5) 02 54(4) The complete tem perature factor is exp[-2 ir2(U11h2a*2 + U22k V 2 * U33l2c*2 + 2U12h k a V + 2U13h la V + 2U23k lb V ] Table 4.4: Bond Distances(A) for (Tetrachloro-trans-d,l-1,2-diam inocyclohexane)Pt(IV) Molecule 1 Ptl — c m 2.36(2) Pt1 — 0112 2.35(2) P tl — CM 3 2.26(2) P t 1 -----Cl 14 2.38(2) P tl — N 11 2.09(3) P t 1 -----N 12 2.08(3) N 11-----C 11 1.51(4) N 12-----C 12 1.55(5) C 11-----C 12 1.69(12) C 12— C 13 1.51(7) C 13-----C 14 1.49(5) C 14— C 15 1.52(9) C 11— C 16 1.49(4) C 15— C 16 1.63(5) Molecule 2 P t 2 -----CI21 2.26(2) P t 2 -----CI22 2.28(2) P t 2 -----CI23 2.35(2) P t 2 -----CI24 2.22(2) P t 2 -----N 21 2.04(3) P t 2 -----N 22 2.03(3) N 21— C 21 1.50(4) N 22— C 22 1.49(6) C 21----- C 22 1.34(11) C 22— C 23 1.66(6) C 23----- C 24 1.67(5) C 24— C 25 1.63(9) C 21— C 26 1.61(6) C 25— C 26 1.50(4) 68 Table 4.4 (continued) Molecule 3 Pt3 — CI31 2.29(1) Pt3 — CI32 2.32(1) Pt3 — CI33 2.30(1) Pt3 — CI34 2.31(1) P t 3 -----N 31 2.09(2) Pt3 — N 32 2.07(2) N 31— C 31 1.54(3) N 32— C 32 1.60(3) C 31— C 32 1.39(6) C 32----- C 33 1.63(3) C 33— C 34 1.55(4) C 34— C 35 1.31(6) C 31— C 36 1.48(4) C 35— C 36 1.57(3) Molecule 4 Pt4 — CI41 2.33(1) P t 4 ----- CI42 2.31(1) Pt4 — CI43 2.32(1) Pt4 — CI44 2.30(1) P t 4 ----- N 41 2.04(3) P t 4 -----N 42 2.06(2) N 41— C 41 1.47(3) N 42— C 42 1.46(2) C 4 1 — C 42 1.63(7) C 42— C 43 1.53(3) C 43— C 44 1.54(3) C 44— C 45 1.66(7) C 41— C 46 1.63(3) C 45----- C 46 1.61(3) M olecule 5 P t 5 ----- CI51 2.31(2) Pt5 — C152 2.27(2) P t 5 ----- CI53 2.29(2) Table 4.4 (continued) P t 5 -----CI54 2.30(2) Pt5 — -IM 51 2.11(3) P t 5 -----N 52 2.08(3) N 51-----C 51 1.61(4) N 52-----C 52 1.51(4) C 51— C 52 1.31(8) C 52— C 53 1.49(5) C 53— C 54 1.47(4) C 54— C 55 1.27(6) C 51-----C 56 1.48(4) C 55— C 56 1.61(4) Molecule 6 Pt6 — CI61 2.29(2) Pt6 — CI62 2.35(2) Pt6 — CI63 2.27(2) Pt6 — CI64 2.30(2) Pt6 — N 61 2.06(3) Pt6 — N 62 2.02(3) N 61-----C 61 1.48(4) N 62-----C 62 1.45(3) C 61-----C 62 1.75(8) C 62-----C 63 1.53(4) C 63-----C 64 1.49(4) C 64-----C 65 1.82(8) C 61-----C 66 1.61(5) C 6 5 -----C 66 1.59(4) 70 g 2 O o o O o o o o o o O O Z N > o _u _» _» _ a _4 ~4 m ^ mm* N > A C J 1 C T ) cn 4k co C O — * o> a> NJ N ) mm* NJ 1 o f 1 i 1 i 1 1 1 I 1 1 1 1 “0 r-f c O o O O o O o o O o 2 2 “0 N J A mm* u U — A ■ vk ■4 •-k r + 1 NJ a > i U1 i 4k 1 U> ■ NJ I NJ 1 NJ 1 — 4 — * N ) -» 1 o f s ) i o I o 1 o I o 1 o 1 z 1 2 1 o i z 1 z 1 “ T D / - f 1 1 3 Z _ * mm* « « Ji • 4 —1 mm* — » —* 4k C O NJ — * NJ N> NJ — * (30 — 1 — * — > _ » - * CO CO _ 1 -_k _ i 0 0 — » — » — » — i O V I o . O o w —1 o C J 1 NJ c n o o OJ w s 3 4 k a t i b C O 4 k 2 w z z Z z z z Z z g g g g g O _» — 1 _ » — A mm * •i - a _ > mm * mm * o N J N J N J N J — »— » mm* • > 4 4 k i i 4 k 1 C O I C Oto A 1 X I 1 U 1 " O 1 " 0 1 U 1 “ 0 1 “ 0 i “ 0 i T3 i “ D 1 - o 1 T J 1 T J 1 " 0 n Q i — 4 r + r+ r + ! ■ + r * 4 f 4 » 4 — * “* “ 1 ■ 4 -* — 4 — » “ * —k 0 1 g 1 g I g 1 g 1 o 1 g 1 o 1 g 1 O 1 g 1 g i g I g J g “* — 4 _> mm* —* _» — a — > • o -a _» 4 k C ON J « fc k C ON ) C ONJ — 4 NJ - * CO —‘ C O C O C D C O —‘ CO ( i s J M l O s j W M U CO 00 _a CO CO CO w o t CD v j 00 NO N) — a - * -a ■ -k -a 0 1 o •y 0 H 1 St a sr u 3 (A I a N J I a S' A in a > o 3 a > 3 3 § 3 (o o •C ' r > a •< A 0 1 0 1 - ? o A ^ A 3 A N 31-Pt3 -CI31 86(1) N 31-Pt3 -CI32 92(1) g o o O o o 2 O o O o o o O O C O C O CO CO CO CO o I S O N O NO N O N O N O N O N O ■to 1 1 CO 1 C O 1 N O 1 C D c n t O O 1 c n I •P- 1 CO I C O | j O O 1 I TO ft 1 T O f t I TO f t 1 TO f t 1 " 0 ft 1 TO ft n c 1 O I O 1 O 1 o 1 O O O o CO CO C O CO CO CO C D N O IS) N O I S O N O N O N O I S O 1 I 1 1 1 1 CO O O c n •N C O N O N O N O g C O O CO O CO g CO g CO g CO 1 O i O 1 O 1 o 1 o 1 z 1 z 1 O C O NO NO N O m > N O • D s N O CO I S O N O N O I S O IS) iso N O NO NO C O t o (O t o - * U1 00 U w O VJ i n o ^ O J C O w w w X o — » -* o o (J l O M U (D U A A u 3 o -> 00 00 S c n N O C T > " v J rs o O o O O N O IS0 I S O N O O O I NO N O I I 1 o 1 o 1 z 1 z M N O N O N O i 1 N O 1 I 1 z 1 z 1 TO 1 TO f t N O _-k N O — A N O I S O NO IS O I T 3 r 4 (so I Z N O Z z Z z z z z 2 N O N O N O N O N O N O N O N O I IS> | NO NO 1 1 ro M l 1 T O f t I S O 1 TO ft N O 1 TO tt I S O 1 TO ft N O 1 TO I S O 1 T O ft N O -Pt2 -Pt2 1 g 1 g 1 O 1 g I g 1 g 1 o 1 o N O • I N I S O C O IS) N O N O — i N O D . NO C O N? hO fv -? n n n o n IS) I S O NO I S O NO ^ ^ u u I 13 I "0 I TO I TO I TJ ISO NO ISO IS ) IS O I I I I I onnno NO NO NO NO NO CO N O — * NO — * O O c d cn C O o o c n o o CO C D - » O O C D U O C D O O - * N . U I S C D O - j W O O S — t cn ' T no CO —> CD CD CD 00 sj CO —» £. ~ o o : Table 4.5 (continued) Table 4.5 (continued) N 31-P t3 -C I33 173(1) N 31 -P t3 -C I34 91(1) IM 32-P t3 -CI31 90(1) IS I 32-P t3 -C I32 89(1) N 32-P t3 -C I33 89(1) N 32-P t3 -C I34 175(1) N 32-P t3 -N 31 85(1) C 3 1-N 31-P t3 110(2) C 32-N 3 2-P t3 105(2) C 32-C 3 1-N 31 109(3) C 36-C 3 1-N 31 110(2) C 3 6-C 3 1-C 32 127(3) C 31-C 3 2 -N 32 117(2) C 33-C 3 2 -N 32 114(2) C 33-C 3 2 -C 31 117(1) C 3 4-C 3 3-C 32 103(1) C 3 5-C 3 4 -C 33 125(3) C 3 6-C 3 5 -C 34 123(2) C 3 5 -C 3 6 -C 31 106(2) Molecule 4 C I42-P t4 -C I41 178.2(2) C I43-Pt4 -C I41 89.8(3) C I43-Pt4 -C I42 91.9(3) C I44-P t4 -C I41 91.0(3) C I44-P t4 -C I42 89.7(3) C I44-P t4 -C I43 89.8(3) N 4 1 -P t4 -CI41 92(1) N 4 1-P t4 -C I42 86(1) N 41-P t4 -C I43 177(1) N 4 1-P t4 -C I44 87(1) N 42-P t4 -CI41 89(1) N 4 2 -P t4 -C I42 90(1) N 4 2-P t4 -C I43 97(1) N 4 2-P t4 -C I4 4 173(1) N 4 2-P t4 -N 41 8 6 ( 1) 73 Table 4.5 (continued) C 41-N 41-Pt4 103(2) C 42-N 42-Pt4 110(2) C 42-C 41-N 41 114(3) C 46-C 41-N 41 112(2) C 46-C 41-C 42 100(3) C 41-C 42-N 42 97(2) C 43-C 42-N 42 107(2) C 43-C 42-C 41 107(3) C 44-C 43-C 42 110(2) C 45-C 44-C 43 105(3) C 46-C 45-C 44 103(3) C 45-C 46-C 41 107(2) Molecule 5 CI52-Pt5 -CI51 94(1) CI53-Pt5 — CIS 1 90(1) CI53~Pt5 -CI52 91(1) CI54-Pt5 -CI51 91(1) CI54-Pt5 -CI52 91(1) CI54~Pt5 -CI53 177(1) N 51-Pt5 -CIS 1 176(1) N 51-Pt5 -CI52 89(1) N 51-Pt5 -CI53 92(1) N 51-Pt5 -C I54 87(1) N 52-Pt5 -CI51 91(1) N 52-Pt5 -CI52 174(1) N 52-Pt5 -CI53 92(1) N 52-Pt5 -C I54 86(1) N 52-Pt5 -N 51 86( 1) C 51-N 51-Pt5 103(2) C 52-N 52-Pt5 109(3) C 52-C 51-N 51 120(3) C 56-C 51-N 51 112(3) C 56-C 51-C 52 120(4) C 51-C 52-N 52 115(4) 74 Table 4.5 (continued) C 53-C 52-N 52 115(3) C 53-C 52-C 51 116(4) C 54-C 53-C 52 115(3) C 55-C 54-C 53 122(3) C 56-C 55-C 54 120(3) C 55-C 56-C 51 110(3) Molecule 6 CI62-Pt6 -CI61 94(1) CI63-Pt6 — CIS 1 88( 1) CI63-Pt6 -CI62 92(1) CI64-Pt6 -CI61 93(1) CI64-Pt6 -CI62 90(1) CI64-Pt6 -C I63 178(1) N 61-Pt6 -CI61 91(1) N 61-Pt6 -CI62 175(1) N 61-Pt6 -CI63 87(1) N 61-Pt6 -CI64 91(1) N 62-Pt6 -CI61 173(1) N 62-Pt6 -CI62 92(1) N 62-Pt6 -CI63 87(1) N 62-Pt6 -CI64 92(1) N 62-Pt6 -N 61 84(1) C 61-N 61-Pt6 106(3) C 62-N 62-Pt6 113(2) C 62-C 61-N 61 107(4) C 66-C 6 1 -N 61 110(3) C 66-C 61-C 62 111(1) C 61-C 6 2 -N 62 94(3) C 63-C 62-N 62 114(2) C 63-C 62-C 61 108(3) C 64-C 63-C 62 106(3) C 65-C 64-C 63 106(3) C 66-C 65-C 64 106(3) C 65-C 66-C 61 105(3) 75 CHAPTER 2 REACTION PRODUCTS O F A N E W ANTICANCER AGENT, Pt(IV)(CYCL0HEXANEDIAMINE)Cl4 , WITH GUANOSINE AND 9-METHYLGUANINE Introduction Pt(l,2-cyclohexanediamine)Cl4, abbreviated Pt(dach)C14, 22 is a new octahedral Pt(IV) anti-cancer agent* 0 that has the unique properties of being active against certain forms of leukemia that have acquired resistance towards the w ell-established drug cis-Pt(NH3)2 Cl2 (c is p la tin ). Unlike cis-PtCNHg^Cl 2, which has two leaving groups (the two chlorine atoms), and hence two points of attachment to DNA, Pt(dach)Cl4 has (in p rin ciple at least) up to four leaving groups. I t is thus of interest to study the complexation behavior of this new platinum anticancer agent (a novel octahedral Pt(IV) complex, in contrast to the commonly-used square planar P t(II) complex) with various DNA constituents22 to see i f there are any sig nificant differences in the way Pt(dach)Cl4 and cis-PttNHg^Cl 2 bind to DNA fragments. In this chapter, the reaction products of Pt(dach)Cl4 with 9-methyl guanine and guanosine are reported. I t was found ( vide in fra ) that square-planar P t(II) complexes were formed instead. Experimental Section A. [Pt(cis-dach)(guanosine)2] c i 1>5(C104)0<5*3H20 a) Preparation In 10 ml of d is t ille d water, 10.0 m g of Pt(IV)(cis-dach)C l4*° was 76 mixed with 12.6 m g of guanosine (two equivalents). The solution, at pH 5.6, was stirred for two weeks at 37°C u n til a major product was observed together with a small amount of unreacted starting m aterials using HPLC (High-Performance Liquid Chromatography) monitoring. (See Appendix C for the working conditions of the HPLC). The solution was concentrated to about 1 ml and a stochiometric amount of NaC104 was added. The yellow solution was vapor-diffused against isopropanol. Pale yellow diamond-like crystals formed in about two weeks. No reaction product was found when Pt(IV)(cis-dach)Cl4 was mixed with either cytidine, adenosine or thymidine under the same conditions. Only unreacted starting materials were observed (again using HPLC monitoring). b) Data collection and structure analysis A crystal of approximate dimensions 0.5 x 0.5 x 0.5 m m was chosen fo r structure analysis, and sealed in a glass c a p illa ry with one drop of mother liquor. The crystal was centered and unit c e ll parameters were determined as described in Chapter 1. A summary of the crystal data is shown in Table 6.1. The space group was found to be 14^ (tetragonal) One octant of data (+h, +k, +1) was collected using the w-scan technique with Mo Ka radiation up to a 20 lim it of 45° at room temperature. Throughout data c o lle c tio n , three refle ctio n s were monitored p e rio d ic a lly (a fte r every 50 reflectio n s) and no decay was observed. The data were processed as mentioned before. Of 2972 unique reflectio ns measured, 1709 reflectio ns with I > 3a(I) were 77 retained for the ensuing structure analysis. The position of Pt atom was obtained by Patterson methods using the computing package SHELX-86.^ k The rest of the structure was solved by SHELX-76^a and refined to fin a l agreement factors of R = 0.056 and Rw = 0.057. In this case, the cis-dach ligand is disordered: 50% in both <5- and X - conformations. The chlorine atom of the perchlorate ion is situated on a crystallographic two-fold axis and has a m u ltip lic ity of 0.5 (re la tiv e to 1.0 for Pt). Refinement of the occupancy factor of the * remaining two ions (shown la te r to be chlorides) resulted in a value I ! of about 0.75 for each of them. (See Tables 5.2 through 5.5 for fin a l j atomic coordinates, temperature factors, bond distances and bond j angles.) 1-Note: The cationic part of this complex, es p ecially the disordered cis-dach ligand, was b a s ic a lly solved by my colleague, Raymond Stevens. O rig in a lly , two oxygen atoms and the chlorine atom of the perchlorate anion were misassigned. In addition, a meaningless peak around the perchlorate anion and two water molecules of c ry s ta lliz a tio n were also misassigned as chloride anions with occupancies of 0.33 each. Thus, the entire structure analysis was stymied: a high R-factor, bad bond lengths and poor temperature factors. This situation remained stagnant for several weeks. Eventual ly , the correct assignments were made: the location of the [ two chloride anions, each with an occupancy of 0.75 and one additional J water of c ry s ta lliz a tio n were successfully found. A fter the problems | were corrected, the R-factor dropped to around 6% . Fol lowing a few 7 8 j cycles of fu l 1-matrix least-squares refinement of the entire structure, a l l the bond lengths, bond angles and temperature factors became acceptable. The fin a l R-factor dropped to 0.056. c) Results and Discussion The crystal lographic results show that when Pt(cis-dach)Cl4 is reacted with guanosine in the conventional way described here, the octahedral P t(IV ) starting material has been reduced to a bis-purine complex with a square planar Pt( I I ) geometry. I t is not obvious what the reducing agent is. The platinum atom is in the usual square planar arrangement, surrounded by two amino ligands from the cis-dach molecule and two guanine rings in a cis configuration. The guanosine ligand binds in a monodentate fashion through its N; atom: [Pt-N(107) = 2.01(2)A, Pt- O N(207) = 2.02(2)A=]. Other distances and angles around platinum are as fo llo w s : P t-N (l) = 2.07(1)A, P t-N (2) = 2.07(1)A, N(207)-Pt-N(107)A= 8 6 (1 )°, N(1 )— Pt — N(107) = 17 6(1)°, N (l)-P t-N (2 0 7 ) = 9 3 (1 )°, N (2 )-P t- N(107) = 9 7 (1 )°, N (2)-P t-N (207) = 174(1)° and N (2 )-P t-N (l) = 8 6 (1 )°. Figures 14, 15 and 16 show d ifferen t views of the [(cis-dach)Pt- (guanosine)2 ]2+ cation. Figure 14 shows the fa m ilia r h e a d -to -ta i1 orientation of the two guanosine rings. In contrast, recent X-ray studies by Lippard's group on cis-(Pt(NH3)2 d(pGpG) ) ^ a and Reedijk's group on cis-[Pt(NH3) 2{d(CpGpG)}]^k showed that at atomic resolution, an N(7)-Pt-N(7) intrastand chelate involving two adjacent guanines 79 axists in a head-to-head conformation). Figure 15 shows the expected chair conformation of the cyclohexane portion of the cis-dach ligand, while Figure 16 suggests some steric interaction of the L-shaped cis- dach ligand with a ribose group. As mentioned in Chapter 1, this has oeen speculated by Kidani and co-workers^2* 3 e a rlie r to account fo r the lower antitumor a c tiv ity of the cis-isomer than either of the trans isomers: the fact that the bulk of the cyclohexyl ring in the cis isomer may hinder the approach of the drug towards DNA (see Figure 12, oage 33). This speculation is further supported by comparing the crystal structures of the t i t l e compound with that of [(tra n s -1- dach)Pt(guanosine)2] 2+ (Figure 17). (Also see Appendix D, Figures 27, 28, and 29). The f l a t configurations of the trans isomers can in fact oe envisaged to offer less steric encumberance when Pt(trans-dach) complex attaches it s e lf to DNA. Since the rest of the structure, especially the guanosine ligands, is very sim ilar to the published results of [P t(en)(guanosine)]^+ and [PttNHg^guanosine)] 2+, 2^ i t would be redundant to elaborate further on th e ir geometrical configurations. 3. [Pt(trans-d,l-dach)(9-m ethyl guanine)1(010^)2 a) Preparation In an attempt to prepare an octahedral Pt(IV)(dach) complex with four guanine ligands, 10 milligram s of P t(IV )(trans-d,l -dach)Cl nere mixed with 14.6 m g of 9-methyl guanine (four equivalents) in 10 ml of d is t ille d water. The solution, at pH 5.3, was stirred for two Figure cation 14. Structure of the [(cis-dach)Pt(guanosine)2]^+ (View #1). 81 Figure 15. Structure of the [(cis-dach)Pt(guanosine)2] 2+ cation (View #2). 83 Q d o N 7 IV 7 0 c o b Figure 16. Structure of the [(cis-dach)Pt(guanosine)2] cation (View #3). 85 3 r > a 0~Q Figure 17. Structures of the [(cis-dach)Cl(guanosine)2]^+ (this chapter) ( le f t ) and [(trans -1 -dach)Pt(guanosine)2 ]2+ (Appendix D) (right) cations, showing some s te r if interaction of the L-shaped cis-dach ligand with a ribose group. weeks at 55°C u n til a major product peak was observed, together with significant amounts of unreacted starting m aterials. This was shown via HPLC monitoring. (See Appendix C for the working conditions of the HPLC.) The solution was concentrated to about 1 ml and kept in the refrig erato r overnight in order to precipitate the unreacted 9- Jmethylguanine, and filte r e d . Excess NaClO^ was added to the f i l t r a t e to precipitate the product. The pale yellow precipitate was collected and redissolved in hot d is t ille d water. Only three small pale-yello w le a f-lik e crystals formed in about a week from the mother liquor together with some pale yellow precipitate. No reaction product was found when P t(IV )(tran s-d,l-d ach )(C l4) was mixed with either 1-methyl cytosine, 9-methyl adenine or 1-methyl thymine under the same conditions. Only unreacted starting m aterials were observed. b) Data collection and structure analysis A crystal of approximate dimensions 0.1 x 0.2 x 0.3 m m was chosen for structure analysis, and was mounted on the tip of a glass fib e r. The crystal was centered and unit cel 1 parameters were determined as described above. A summary of the crystal data is shown in Table 5.1. One octant of data (+h, +k, +1) was collected using 9/26 scan techniques with Mo Ka radiation up to a 29 lim it of 45° at room temperature. Throughout data c o lle c tio n , three reflectio n s were monitored p e rio d ic a lly (after every 50 reflectio n s) and no decay was observed. The data were processed as mentioned before. Of 3369 unique re fle c tio n measured, 1756 reflectio n s with I > 3a(I) were retained for the ensuing structure analysis. I n i t i a l l y , the space group was incorrectly assigned as Ibca (orthorhombic). After identifying the space group co rrec tly to be 14^/acd (tetragonal), the k and 1 axes were switched and the data were averaged to y ie ld 954 refle ctio n s . The position of the Pt atom was obtained by Patterson-search techniques using the computing package SHELX-86.^*-1 The rest of the atoms were located from subsequent differen t-F ourier maps using the SHELX-76.^a The whole structure was refined to fin a l agreement factors of R = 0.0587 and Rw = 0.0586. In this case, the Pt atom was found to be situated on a two-fold rotation axis. The trans-dach ligand was found to be disordered (50% in the 1 configuration and 50% in the d configuration). (See Tables 6.2 through 6.5 for fin a l atomic coordinates, temperature factors, bond distances and bond angles.) (This structure, es p ecially the portion involving disordered trans-d, 1-dach ligands, was solved with the assistance of Professor A ris tid is Terzis who was on leave from the Greek Atomic Energy Commission Nuclear Research Center "Demokritos", A t t i k i , Greece.) c) Results and Discussion In contrast to the compound described in section A, which containedcis-dach and guanosine, in this case the ligands are trans- d,l-dach and 9-methyl guanine. A molecular plot (Figure 18) shows the 90 Figure 18. Structure of the [(trans-d-dach)Pt(9-methyl- guanine)2] 2+ cation. (The nitrogen and carbon atoms of the tra n s -1-dach ligand have been removed fo r c la rity .) cr _ 9 _ 2 J [ (tran s-d ,1-dach)Pt(9-methyquanine)2] 2+ cation, again with the normal head -to -tail arrangement of the purine rings, and once more showing a reduction from octahedral P t(IV) to square planar P t(II). Again, i t is not obvious what the reducing agent is. General Discussion In retrospect, the results described in this chapter cannot be considered e n tire ly unexpected. There had been speculation expressed in various a rtic le s that octahedral Pt(IV) complexes may be active as "precursor-drugs", f i r s t becoming reduced to the square planar P t(II) form prior to attached to guanine. 25 W e believe that our results provide some experimental support for this hypothesis. j On the other hand, i t is s t i l l puzzling fo r us to explain why no j reaction products were found when Pt(dach)Cl4 were mixed with the 1 other DNA consituents (i.e. cytosine, thymine and adenine deriva- j i tiv es): F ir s tly , a l l the isomers of the Pt(dach)Cl4 agent used in our studies are very stable in aqueous solution. No reduction products were observed a fte r leaving solutions of the starting m aterials [i.e ., the Pt(dach)Cl4 drugs themselves] in the open atmosphere fo r a few weeks during c ry s ta lliz a tio n (Chapter 1). Secondly, i f reduction r e a lly took place prior to complexation, Pt(dach)Cl4 should have been reduced in a l 1 cases. Reaction products from the reduced drug with a l l the other nucleotides should have been detected, despite the fact that square-planar P t(II)(d ach )C l2 reacts with cytosine, adenine or thymine derivatives slower25 than guanine derivatives. 93 Reedijk and co-workers speculated that i t was lik e ly that the electrons needed fo r the reduction came from the sugar (ribose) component of 5'-GMP when bis(5'-GMP)Platinum(II) amine adducts were obtained as reaction products from addition of Pt(IV)-amine compounds to 5'-GMP.2^a However, this speculation is not lik e ly to be true because: (i) cytidine, CMP, adenosine, AMP, thymidine and TMP, which [also contain ribose groups, could also have provided electrons for the reduction. No reaction was observed, ( i i ) Reduction was found to take place with 9-methyl guanine (Figure 18), which has no ribose groups, ( i i i ) Reedijk and co-workers recently reported^ * 3 in th e ir NM R studies that both Pt(IV) and P t(II) nucleobase compounds were obtained from reactions of Pt(IV)-amine compounds with 9-methyl- hypoxanthine (a molecule clo sely related to 9-methyl guanine) at high temperature, (iv ) A proton NM R spectrum (360 MHz) of the reaction mixture of P t(IV)(trans-1-dach)C l4 with guanosine (two days at 50°C) c le a rly showed an ^H signal with a chemical s h ift of 8.93 ppm and a 3j(195pt_lH) coupling constant of 17.8 Hz (internal reference: H2O at 4.5 ppm). The value of the coupling constant of the H(8) proton is characteristic of a guanine ligand coordinated to a P t(IV) atom, ^ * 3 which implies that P t(IV ) is not reduced to Pt( I I ) prio r to guanine complexation. F in a lly , considering the results of animal screening of a n ti tumor a c tiv ity , i f Pt(IV ) complexes are reduced to P t(II) and the reduced P t(II) complexes react with DNA, the toxic dose of Pt(IV) complexes should be nearly the same as those of P t(II). However, the 94 toxic dose of Pt(IV)(dach)Cl4 is sm aller, and the anti-tumor a c tiv ity is higher, than those of cis-PttNHg^Cl 2 and Pt(dach)Cl 2. ^ » ^ In conclusion, we favor the idea that complexation between the Pt(IV)-amine compounds and the guanine derivatives occurs f i r s t and then (through some s t i l l unresolved mechanism) they become reduced to square-planar P t(II) complexes. Further investigations are necessary in order to resolve the questions mentioned above. In the next chapter, we report that Pt(IV) reduction to P t(II) can be suppressed by the presence of oxidizing agents, and that octahedral complexes of Pt(IV)(dach)Cl4 with guanine derivatives can in fa ct be prepared. Summary Pt(dach)Cl4 (dach = eyelohexanediamine) was reacted with guanosine and 9-methyl guanine and th e ir reaction products analysed by sin gle-crystal X-ray d iffractio n . In both cases, the resulting complexes [(Pt(dach)(guanosine)2) 2+ and (Pt(dach)(9-methy 1 guanine)2) 2+ re sp ec tive ly], showed an unanticipated reduction of the octahedral Pt(IV) starting material to a square planar Pt( I I ) species. .95 Table 5.1: Summary of Crystal Data and Refinement Results for Pt(ll)(cis-dach)(guanosine)2(CIO4)0 g.3H20 molecular weight (g mole-1) 1103.5 crystal dimensions (mm) 0.5 x 0.5 x 0.5 space group I41 (No.80) (tetragonal) molecules/ unit cell 8 a=b (A) 17.99(1) c (A) 24.77(2) V (A3) 8019(2) calculated density (g cm-3) 1.83 O wavelength (A) used for data collection 0.71069 Sin9/X limit (A-1) 0.5385 total number of reflections measured 2972 number of reflections used in structural analysis 1 > 3a(l) 1709 number of variable parameters 580 final agreement factors R(F) = 0.0559 R(wF) = 0.0569 96 Table 5.2: Final Atom ic Coordinates for Pt{ll)(cis-dach)(guanosine)2(CIO4)0 5C I1 5-3H20 Atom X V z Pt 0.7327(1) 0.2328(1) 0.2695(0 N 101 0.6265(1) 0.0583(1) 0.4090(1 C l 02 0.6296(2) -0.0132(2) 0.3994(1 N 103 0.6715(1) -0.0406(1) 0.3581(1 C104 0.6991(1) 0.0146(2) 0.3231(1 C105 0.6920(1) 0.0883(2) 0.3315(1 C l 06 0.6512(1) 0.1146(2) 0.3804(1 N 107 0.7252(1) 0.1241(1) 0.2875(1 C108 0.7561(2) 0.0705(2) 0.2591(1 N 109 0.7378(1) 0.0013(1) 0.2789(1 N 110 0.6031(1) -0.0597(2) 0.4385(1 o m 0.6402(1) 0.1855(1) 0.3880(1 C l 12 0.7507(2) -0.0737(2) 0.2538(1 0 11 3 0.8285(1) -0.0666(1) 0.2334(1 C l 14 0.7037(2) -0.0842(2) 0.2047(2 0 11 5 0.6906(1) -0.1623(1) 0.1985(1 C116 0.7511(2) -0.0525(2) 0.1586(1 0117 0.7299(1) -0.0863(2) 0.1046(1 C 1 18 0.8297(2) -0.0786(2) 0.1791(1 C 1 19 0.8974(2) -0.0357(2) 0.1540(1 0120 0.8844(1) 0.0468(2) 0.1566(1 N201 0.5621(1) 0.1274(1) 0.1238(1 C202 0.4861(2) 0.1387(2) 0.1359(1 N203 0.4605(1) 0.1712(1) 0.1804(1 C204 0.5159(2) 0.1993(1) 0.2150(1 C205 0.5886(1) 0.1909(1) 0.2062(1 C206 0.6190(1) 0.1561(1) 0.1641(1 N207 0.6229(1) 0.2263(1) 0.2536(1 C208 0.5719(2) 0.2560(1) 0.2804(1 N209 0.5028(1) 0.2393(1) 0.2614(1 N210 0.4425(1) 0.1049(1) 0.1005(1 0211 0.6832(1) 0.1438(1) 0.1500(1 C212 0.4313(2) 0.2500(2) 0.2856(1 0213 0.4304(1) 0.3266(1) 0.3038(1 C214 0.4161(2) 0.2040(2) 0.3368(1 0215 0.3398(1) 0.1921(1) 0.3424(1 C216 0.4475(2) 0.2544(2) 0.3824(1 Table 5.2 (continued) 0217 0.4146(1) 0.2298(1) 0.4309(1) C218 0.4217(2) 0.3352(2) 0.3590(1) C219 0.4615(2) 0.3952(2) 0.3819(1) 0220 0.5463(2) 0.3897(2) 0.3690(1) N1 0.7385(1) 0.3426(1) 0.2450(1) N2 0.8420(1) 0.2459(1) 0.2929(1) C l 0.8186(1) 0.3721(1) 0.2521(1) C2 0.8556(1) 0.3312(1) 0.3004(1) C3 0.8183(2) 0.3563(1) 0.3539(1) C4 0.8229(2) 0.4412(1) 0.3607(1) C5 0.7852(2) 0.4812(1) 0.3127(2) C6 0.8207(2) 0.4564(1) 0.2590(1) c r 0.7782(1) 0.3736(1) 0.2948(1) C2' 0.8245(1) 0.3163(1) 0.3251(1) C3' 0.7907(2) 0.2981(2) 0.3808(1) C4' 0.7886(3) 0.3674(2) 0.4171(1) C5' 0.7595(3) 0.4358(2) 0.3861(1) C6' 0.7221(2) 0.4128(2) 0.3328(1) CI1 0.5000(0) 0.0000(0) 0.2682(1) O 1 0.5204(2) 0.0553(2) 0.3000(2) 0 2 0.5598(2) -0.0207(3) 0.2533(2) CI2 0.5901(1) 0.4545(1) 0.2666(1) CI3 0.9562(1) 0.0874(1) 0.2697(1) 011 0.2799(2) 0.2782(2) 0.5746(2) 022 0.2784(2) 0.2825(2) 0.4609(1) 033 0.9822(3) 0.2863(3) 0.2399(2) Table 5.3: Anisotropic Tem perature Factors for Pt(ll)(cis-dach)(guanosine)2(CIO4)0 5CI., 5-3H20 Atom Un X103 u 22x io 3 U33X103 u 12x io 3 U 13X103 u 23x io 3 Pt 83(1) 84(1) 63(1) -30(1) -16(1) 22(1) N101 46(7) 55(6) 51(7) 2(6) 5(6) 1(6) C102 78(7) 97(7) 48(7) -29(7) 0(7) 6(7) IM103 78(7) 62(7) 68(7) -25(6) 10(7) -5(7) C l 04 60(7) 66(7) 52(7) 19(7) -4(7) 3(7) C105 41(7) 66(7) 57(7) 4(7) -21(6) -12(7) C106 41(7) 81(7) 53(7) 9(7) -13(7) 0(7) N107 44(6) 94(7) 68(7) -13(6) -4(6) 12(7) C108 88(7) 55(7) 56(7) 4(7) 12(7) -2(7) N109 39(6) 89(7) 40(7) 6(6) -5(6) -10(7) N110 87(7) 103(7) 75(7) -20(7) 0(7) 28(7) 0111 65(7) 91(7) 68(6) 4(6) -6(6) -11(6) C112 109(7) 64(7) 62(7) 9(7) -1(7) -21(7) 0113 56(6) 105(7) 92(7) -3(6) 28(6) -33(6) Cl 14 105(7) 131(7) 102(7) 4(7) 12(7) 29(7) 0115 114(7) 76(7) 93(7) -31(6) 25(7) -20(6) Cl 16 74(7) 127(7) 60(7) 10(7) -8(7) -37(7) 0117 105(7) 153(7) 108(7) -2(7) 12(7) -16(7) C118 127(7) 81(7) 95(7) -19(7) 48(7) 3(7) C119 101(7) 101(7) 66(7) -26(7) 34(7) 4(7) 0120 142(7) 135(7) 85(7) -35(7) 11(7) -13(7) N201 68(7) 86(7) 57(6) -1(6) 4(6) 9(6) C202 90(7) 81(7) 89(7) -8(7) 0(7) -8(7) N203 76(7) 66(6) 54(6) -6(6) 2(6) 25(6) C204 60(7) 64(7) 70(7) -30(6) -35(6) 24(6) C205 63(7) 67(7) 35(6) 7(6) -12(6) -2(6) C206 45(6) 53(7) 53(7) -10(6) -19(6) 3(6) N207 61(6) 59(6) 69(7) 8(6) 11(6) -10(6) C208 83(7) 51(6) 61(7) 10(6) -4(7) 14(6) IN 1209 72(6) 54(6) 42(6) 5(6) 2(6) -2(6) N210 80(7) 98(7) 51(6) -19(6) -33(6) -1(6) 0211 67(6) 90(7) 102(6) -13(6) 0(6) -25(6) C212 83(7) 81(7) 57(7) 10(7) -21(7) -13(7) 0213 123(7) 66(6) 73(d) 6(6) 14(6) -14(6) C214 106(7) 90(7) 48(7) 7(7) 13(7) 14(7) 0215 78(6) 95(6) 85(6) -15(6) 28(6) -12(6) C216 122(7) 54(7) 103(7) -5(7) -18(7) -38(7) 0217 117(7) 124(7) 46(6) -11(6) 12(6) 4(6) Table 5.3 (continued) C218 102(7} 108(7) 73(7) 3(7) 3(7) -47(7) C219 127(7) 85(7) 110(7) -20(7) 14(7) -18(7) 0220 165(7) 140(7) 116(7) -12(7) -24(7) -31(7) N 1 125(7) 99(7) 122(7) -50(6) -37(6) 47(6) N 2 120(7) 113(7) 117(7) -45(6) -26(6) 36(6) C 1 71(7) 72(7) 70(7) -4(7) 0(7) 3(7) C 2 100(7) 106(7) 103(7) -10(7) -1(7) 8(7) C 3 125(7) 97(7) 109(7) -28(7) -36(7) -33(7) C 4 108(7) 107(7) 105(7) -11(7) -5(7) 10(7) C 5 125(7) 102(7) 107(7) -17(7) -18(7) -15(7) C 6 129(7) 113(7) 83(7) -6(7) 6(7) 20(7) C V 145(7) 116(7) 136(7) -7(7) 16(7) 17(7) C 2' 168(7) 164(7) 151(7) 15(7) 8(7) -29(7) C 3' 136(7) 119(7) 96(7) -4(7) 11(7) -13(7) C 4' 142(7) 156(7) 141(7) 22(7) 28(7) 2(7) C 5' 145(7) 142(7) 145(7) -1(7) -2(7) -10(7) C 6' 130(7) 146(7) 125(7) -1(7) 25(7) - 17(7) Cl 1 66(5) 88(5) 119(5) -17(4) 0(0) 0(0) 0 1 249(7) 154(6) 321(7) - 86(6) -89(7) -79(7) 0 2 195(7) 346(7) 256(7) 66(7) -21(7) -171(7) C 12 277(6) 156(6) 107(5) 23(6) -44(6) -21(5) C 13 51(5) 151(6) 51(5) 1(5) -4(5) 6(6) O 11 188(7) 186(7) 175(7) -46(7) 57(7) -51(7) O 22 138(7) 193(7) 163(7) -36(6) 27(6) -48(6) O 33 326(7) 370(7) 344(7) -129(7) -22(7) -22(7) The complete temperature factor is exp[-27r2(U11h2a*2 + U22k2b*2 + U33l2c*2 + 2U12hka*b* + 2U 13h l a V + 2U23klb*c* ] 100 Table 5.4: Bond Distances(A) for Pt(ll){cis-dach)(guanosine)2(CIO4)05Clt 5 3H20 N107— Pt 2.01(2 N207— Pt 2.02(2 N 1 ----- Pt 2.07(1 N2 — Pt 2.07(1 C102----- N101 1.31(4 C106----- N101 1.31(4 IM103----- C102 1.36(4 N 110----- Cl 02 1.37(4 C104----- N103 1.41(4 C105----- C104 1.35(4 N109----- C104 1.32(3 C l 06----- C105 1.49(4 IN 1 107----- C105 1.40(4 0 1 1 1 ----- C106 1.31(4 C108----- N107 1.32(4 IM109----- C108 1.38(4 C l 12----- N109 1.50(4 0 1 1 3 ----- C112 1.49(4 C l 14----- C l 12 1.50(5 C l 18----- 0113 1.36(4 0 1 1 5 — C114 1.43(5 C l 16----- C114 1.53(5 0 1 1 7----- C116 1.52(4 C 118----- C 116 1.58(5 C 1 19----- C118 1.57(5 0 1 2 0 — -C 1 19 1.50(5 C202----- N201 1.41(4 C206----- N201 1.52(3 N203----- C202 1.33(4 IM210----- C202 1.33(4 C204----- N203 1.41(4 C205----- C204 1.33(4 N209----- C204 1.38(3 C206----- C205 1.33(3 N207----- C205 1.47(3 0 2 1 1 ----- C206 1.23(3 C208----- N207 1.25(3 N209----- C208 1.36(4 C212----- N209 1.43(4 Table 5.4 (continued) 0 2 1 3 — C212 1.45(3) C214----- C212 1.54(4) C218----- 0213 1.39(4) 0215----- C214 1.40(4) C216----- C214 1.56(4) 0 2 1 7----- C216 1.41(4) C218----- C216 1.63(5) C219----- C218 1.42(5) 0 2 2 0 — C219 1.56(5) C1 ----- N 1 1.55(3) C 1 '-----N .1 1.53(3) C 2 ----- N2 1.57(2) C 2 '----- N2 1.53(3) C 2 -----C1 1.55(3) C6 ----- C1 1.53(2) C 3 ----- C2 1.55(3) C 4 ----- C3 1.54(4) C 5 ----- C4 1.55(5) C6 ----- C5 1.54(5) C2' — c r 1.52(3) C6' — c r 1.55(4) C3' — C2' 1.54(4) C4' — C3' 1.54(5) C5' — C4' 1.54(5) C6' -----C5' 1.54(5) o i — c n 1.32(4) 0 2 ----- CI1 1.20(4) 102 Table 5.5: Bond Angles(deg) for Pt(ll)(cis-dach)(guanosine)2(CIO4)0 5CI1 5.3H20 N207-Pt — IM 107 86(1) N1 — Pt — N107 176(1) N1 — Pt — N207 93(1) N2 — Pt — N107 97(1) N2 — Pt — N207 174(1) N2 — Pt — IM 1 86(1) C106-N 101-C 102 130(2) N103-C102-N101 121(3) IM110-C102-N101 117(3) N 110-C 102-N 103 120(3) C 104-N 103-C 102 114(2) C105-C 104-N 103 124(3) N 109-C 104-N 103 125(3) N109-C 104-C 105 111 (2) C106-C 105-C 104 119(3) IM107-C105-C104 107(2) IM107-C105-C106 134(3) C105-C106-IM101 111(2) 0 1 1 1-C106-N101 129(2) 0 1 1 1-C 106-C 105 120(2) C105-IM107-Pt 130(2) C108-IM107-Pt 125(2) C 108-N 107-C 105 105(2) IM 109~C 108-IM107 112(2) C 108-IM 1 09 -C 104 105(2) C 112-N 109-C 104 126(2) C 112-N 109-C 108 129(2) 0 1 13-C112-IM109 102(2) C 114-C 112-N 109 111(3) C l1 4 - C 1 12-0113 105(3) C 1 1 8-0 1 13 -C 11 2 110(2) 0 1 1 5-C 1 1 4 -C 1 12 108(3) C116-C 114-C 112 104(3) C 1 1 6 -C 1 14-0115 112(3) 0 1 1 7-C 1 1 6 -C 1 14 112(3) C118-C 116-C 114 99(3) C 1 1 8 -C 1 16-0117 113(3) C l1 6 - C 1 1 8-0113 105(3) C l1 9 - C 1 1 8-0113 109(3) C119-C 118-C 116 115(3) Table 5.5 (co ntinu ed) 0 1 2 0 -C 1 1 9 -C 1 18 110(3 C206-N201-C202 118(2 N203-C2Q2-N201 125(3 N210-C202-N201 112(3 N210-C 202-N203 123(3 C 204-N 203-C202 115(3 C 205-C 204-N203 124(2 N209-C 204-N203 125(2 N 209-C 204-C205 111(2 C 206-C 205-C204 126(3 N207-C 205-C204 103(2 N 207-C 205-C206 131(2 C205-C206-N201 113(2 0 2 1 1-C206-N201 113(2 0211-C 206-C 205 134(3 C205-N 207-Pt 126(2 C208-N 207-Pt 126(2 C208-N 207-C205 107(2 N209-C 208-N207 113(2 C 208-N 209-C 204 104(2 C 212-N 209-C 204 125(2 C 212-N 209-C 208 130(2 O 213-C 212-N 209 106(2 C 214-C 212-N 209 116(2 C 2 14-C 212-0213 105(2 C 21 8 -0 2 1 3 -C 2 12 114(2 0 2 1 5 -C 2 14 -C 2 12 110(2 C216-C 214-C212 103(2 C 2 1 6 -C 2 14-0215 112(3 0217 -C 216-C 214 106(2 C 218-C 216-C 214 99(2) C 2 18-C 216-0217 118(3 C 216-C 218-0213 103(3 C 2 1 9 -C 2 18-0213 115(3 C 219-C 218-C 216 113(3 O 220-C 219-C 218 111(3 Cl — N1 --P t 110(1 C2 — N2 — Pt 107(1 C2 — C1 — N1 109(2 C6 — C1 — N1 112(2 C l — C2 — N2 108(2 C3 — C2 — N2 109(2 C3 — C2 — C1 110(2 C6 — C1 — C2 112(2 C4 — C3 — C2 111(2 Table 5.5 (co ntin u ed ) C5 — C4 — C3 111(2) C6 — C5 — C4 110(3) C5 — C6 — C1 112(2) C 1 --N 1 — Pt 98(1) C 2 - - N 2 — Pt 93(1) C 2 '~ C r — N1 114(2) C6'— C 1 '~ N 1 111(2) c r — C2'“ N2 115(2) C3'— C2'— N2 112(2) C6'— C V — C2' 111(2) C3'— C2'— C1' 112(2) C4'— C3'— C2' 111(3) C5'— C4'— C3' 111(2) C6'— C5'— C4' 111(3) C5'— C6'— c r 111(3) o 2— c n — o 1 100(3) 105 Table 6.1: Sum m ary of Crystal Data and Refinem ent Results for Pt<ll)(trans-d,l-dach)(9-m ethylguanine)2(C I0 4)2 molecular weight (g m ole-1) crystal dimensions (mm) space group molecules/ unit cell a=b (A) c (A) V (A3) calculated density (g cm -3) O wavelength (A) used for data collection Sin0/X limit (A-1) total number of reflections measured number of reflections used in structural analysis I > 3a(l) number of variable parameters final agreement factors 838.3 0.3 x 0.2 x 0.1 l^ /a c d (No.142) (tetragonal) 16 22.770(9) 22.844(6) 11843(9) 1.88 0.71069 0.5385 3369 954 (after averaging equivalent reflections) 132 R(F) = 0.0587 R(wF) = 0.0586 Table 6.2: Final Atomic Coordinates for P t(ll)(trans-d,l-d ach )(9-m eth ylg u an in e)2(C I0 4)2 Atom X V z Cl -0 .0 4 10{ 4) 0.5692( 4) 0.0777( 4) 01 -0.0048( 8) 0.5376( 8) 0.1162( 8) 02 - 0.01 13(11) 0.6196( 7) 0.0584(10) 03 -0.0552( 9) 0.5339( 9) 0.0295( 7) 0 4 -0.0926( 7) 0.5857(11) 0.1069( 8) Pt1 0.1688( 1) 0.5000( 0) 0.2500( 0) IM 107 0.1054( 7) 0.4399( 7) 0.2409( 7) N109 Q.0375( 7) 0.3742( 8) 0.2588( 8) C105 0.0782( 9) 0.4244( 9) 0.1877( 8) C l 08 0.0798(10) 0.4087( 9) 0.2821( 9) C l 04 0.0380( 9) 0.3859(10) 0.2005(10) N101 0.0495( 8) 0.4171 ( 9) 0.0907( 8) 0110 0.1218( 7) 0.4812( 6) 0.1122( 7) C l 06 0.0872(11) 0.4437(10) 0.1309(10) N103 - 0.0002( 8) 0.3560( 9) 0.1615( 9) C l 12 - 0.0021(11) 0.3319(11) 0.2922(12) N 111 -0.0264( 9) 0.3566( 9) 0.0624( 9) C 102 0.0095(11) 0.3747(11) 0.1090(11) N 1 0.2352(13) 0.4424(15) 0.2380(20) C1 0.2901(16) 0.4691( 8) 0.2638(19) C2 0.3424(19) 0.4470(20) 0.2271(19) C3 0.3990(25) 0.4675{ 7) 0.2578(32) N1A 0.2336(15) 0.4394(16) 0.2509(25) C1A 0.2926(18) 0.4677( 8) 0.2402(24) C2A 0.3416(14) 0.4233(14) 0.2545(18) C3A 0.3901(34) 0.4680(19) 0.2393(33) 107 Table 6.3: Anisotropic Tem perature Factors for Pt(ll)(trans-d,l-dach){9-m ethylguanine)2(C I04)2 Atom un x io 3 U22X 103 U33X103 U12X103 U13X103 U23X103 Cl 169(5) 174(5) 100(4) 74(4) -31(4) -8(4) 0 1 196(6) 145(6) 1 84(6) 73(5) -83(5) -23(6) 0 2 765(6) 388(6) 244(6) -238(6) 176(6) 19(6) 0 3 198(6) 397(6) 102(5) -89(6) -41(5) -36(6) 0 4 208(6) 453(6) 270(6) 199(6) 76(6) 191(6) Pt 1 33(1) 74(1) 61(1) 0(0) 0(0) - 22(1) IM 107 60(4) N109 66(4) C105 53{4) C108 61(4) C104 61(4) N101 71(4) 0110 73(4) C l 06 68(4) IM103 71(4) C112 84(5) N 111 91(4) C102 73(5) N 1 62(5) C 1 84(5) C 2 74(5) C 3 97(5) N 1A 70(5) C 1A 79(5) C 2A 45(5) C 3A 101(6) The complete temperature factor is exp[-2tt2(U11h2a"2 + U22k2b*2 + U33l2c"2 + 2 U 12hka"b* + 2U 13hla*c” + 2U23klb*c* ] Table 6.4: Bond Distances(A) for P t(ll){trans-d,l-dach )(9-m ethylgu anin e)2(C I0 4)2 0 1 — Cl 1.403(2) 0 2 ----- Cl 1.403(2) 0 3 ----- Cl 1.402(2) 0 4 ----- Cl 1.403(2) N107-----Ptl 2.00(2) C102-----N101 1.39(3) C106-----N101 1.39(3) IM103----- C102 1.29(3) IM111-----Cl 02 1.40(3) C l 04----- N103 1.42(3) C105----- C104 1.30(3) N109----- C104 1.36(3) C106----- C105 1.39(3) N107----- C105 1.41(2) 0 1 1 0----- C106 1.24(2) C l 08----- N107 1.32(2) N109----- C108 1.35(2) C 1 12----- N109 1.52(3) N 1 ----- Pt1 2.02(1) C1 — N1 1.51(1) C2 — Cl 1.54(1) C1 — Cl 1.54(1) C3 — C2 1.54(1) C3 — C3 1.52(2) N 1 A ----- Pt1 2.02(1) C I A ----- N1A 1.51(1) C2A — C IA 1.54(1) C I A ----- C1A 1.54(1) C 3 A ----- C2A 1.54(1) C 3 A ----- C3A 1.54(4) Table 6.5: Bond Angles(deg) for P t(ll)(trans-d,l-d ach )(9-m eth ylg u an in e)2(C I0 4)2 0 2 — Cl— 01 109.5(2) 0 3 -----Cl------01 109.5(2) 0 4 -----Cl------01 109.4(2) 0 4 ----- Cl— 0 2 109.5(2) 0 4 ----- Cl— 03 109.5(2) IM 1 -Pt1 -N 107 94.7(5) N1A -Pt1 -N 107 93.5(5) C 106-N 101-C 102 120(2) N103-C 102-N101 128(2) IM111-C102-N101 111(2) N il1 -C 1 0 2 -N 1 0 3 121(2) C 104-N 103-C 102 109(2) C 105-C 104-N 103 128(2) N 109-C 104-N 103 121(2) N 109-C 104-C 105 111(2) C 106-C 105-C 104 122(2) N 107-C 105-C 104 107(2) N 107-C 105-C 106 132(2) C105-C 106-N101 113(2) 0 1 10-C106-N101 118(2) 0 1 10-C 106-C 105 130(2) C 105-N 107-Pt1 125(1) C 108-N 107-Pt1 128(1) C 108-N 107-C 105 107(2) N 1 0 9-C 108 -N 107 110(2) C 108-N 109-C 104 105(2) C 112-N 109-C 104 128(2) C 112-N 109-C 108 126(2) C1 -N1 -Pt1 108(2) C2 -C1 - N 1 107(3) C3 -C 2 - C l 108(4) C1A - N 1A -P tl 111(2) C2A -C 1A -N 1A 109(2) C3A -C 2A -C 1A 92(5) 110 CHAPTER 3 CRYSTALLOGRAPHIC STUDIES O N OCTAHEDRAL COMPLEXES OF Pt(IV)(1,2-DIAMINOCYCLOHEXANE) WITH NUCLEOBASES Introduction The reactions of Pt(IV) complexes with DNA are less w ell understood than those of square planar P t(II) complexes although some Pt{IV) complexes have been found to have anti-tumor a c tiv ity .*® *2^ I t has been suggested that Pt(IV) drugs become active only a fte r fn vivo reduction.^ However, there is s t i l l c o n flictin g evidence on such a p o s s ib ility .2®*2® Only recently, the structures of a few Pt(IV) nucleobase complexes have been described. However, they consist of either (i) a cis— P t(IV )(NH3)2C 13 fragment coordinated to only one nucleobase®® or ( i i ) a Pt(IV)(NH3) 2(0H)2 moiety coordinated to two OI nucleobases in a trans configuration. Since i t is strongly suspected that antitumor a c tiv ity mainly comes from the covalent binding of cis-Pt(NH3)2 to contiguous G-G pairs on the same DNA s t r a n d , t h e above compounds may not be optimum models for studying the interaction of octahedral Pt(IV) complexes with DNA. In order to assess how well an octahedrally-coordinated metal might interact with the guanine bases of a polynucleotide, the experiments described in this chapter were performed to demonstrate that the binding of cis - Pt(IV)(diamine) to two nucleobases, with the retention of the cis configuration, is in fact possible. Experimental Section A. [Pt(trans-d,l-dach)(9-m ethyl g u a n i n e ^ C l ( l ^ ^ ' l l ^ O ia) Preparation j Twenty m illigram s (0.05 mmoles) of P t(II)(tran s-d ,l-d ach )C l 2^2a (dach = cyclohexyldiamine) was mixed with 17.4 m g (0.10 mmoles) of 9-methyl guanine (9-MG) in 20 ml of d is t ille d water. The solution was stirred overnight at 37°C. After concentrating the colorless solution to about 2 ml, 0.1 mmoles of the mild oxidizing agent Fe(N03)3*9H20 was added. The solution was warmed up to about 40°C for about 60 minutes to speed up the reaction and le f t overnight at room temperature. After the addition of 0.10 mmoles of HC1, the solution became deep yellow. Yellow crystals came out in a week in the form of prisms. b) Data Collection and Structure Analysis A crystal of approximate dimensions 0.2 x 0.2 x 0.4 m m was chosen for structure analysis, and sealed in a glass c a p illa ry with one drop of mother liquor. The crystal was centered and unit c e ll parameters were determined as mentioned before. A summary of crystal data is shown in Table 7.1. The space group was found to be PT. Data were collected for h a lf of the d iffra c tio n sphere (+h, ±k, + 1) using the w scan technique with Mo 1 C radiation up to a 20 lim it of 45° at room 0( < temperature. Throughout data c o lle c tio n , three refle ctio n s were monitored p e rio d ic a lly (a fte r every 50 re fle ctio n s ). Their in ten sities dropped to about three-quarters at the end of the data co lle c tio n . The data were processed as mentioned before without any 1:1.2 decay corrections. Of 5775 unique refle ctio n s measured, 3170 reflectio ns with I > 3a(I) were retained fo r the ensuing structure analysis. The structure was solved by conventional heavy-atom methods using the SHELX-76^a system of computering programs and refined to fin a l agreement factors of R = 0.067 and R w = 0.064. (See Tables 7.2 through 7.5 for fin a l atomic coordinates, temperature factors, bond distances and bond angles.) (My colleague Ms. Sharon K.S. Huang helped in the solving of this structure.) c) Description of the Structure The platinum atom is in its expected octahedral arrangement, surrounded by two NH2 groups from the trans-dach molecule, two guanine rings in a cis configuration and two chloride ligands in a trans configuration (Figures 19, 20, 21). The 9-methyl guanine ligand binds in a monodentate fashion through its atom [Pt-N(107) = 2.07(1)A and O Pt-N(207) = 2.07(1) A]. Other distances and angles around platinum ° o are as fo l lows: Pt-C 1(1) = 2.32(1) A, P t-C l(2 ) = 2.30(1)A, P t-N (l) = 2.06(1)A, P t-N (2) = 2.02(1)A, C l(2 )-P t-C l (1) = 17 8(1 )°, N {2 )-P t-C 1(1) = 8 9 (1 )°, N (2 )-P t-C 1(2) = 9 0 (1 )°, N(207)-Pt-C 1 (1) = 9 2 (1 )°, N(207)— Pt— C1 (2) = 89(1)°, N (207)-Pt-N(2) = 17 8(1)°, N (l)-P t-C 1(1) = 9 1 (1)°, N ( l) - P t - C 1(2) = 8 8 (1 )°, N (l)-P t-N (2 ) = 8 5 (1 )°, N (2)-P t-N (207) = 9 3 (1 )°, N (107)-Pt-N (207) = 8 9 (1 )°, N (1 0 7 )-P t-N (l) = 178(1)°, N (107)-Pt-C 1(1) = 8 8 (1 )°, N (107)-Pt-C 1(2) = 93(1)°, N(107)-Pt-N(2) = 93(1)°. 113 Figure 19. Structure of the [(trans-d-dach)Pt(9-methyl - guanine)^! 2] 2+ cation. Note the small dihedral angle between the two purine rings. 114 Figure 20. A side view of the structure of [(trans-d-dach)Pt(9-methyT/guanine^Cl 2l 2+» showing the f l a t appearance of the trans-dach ligand. 116 NH ^ a - o d S 117 Figure 21. Another side view of the structure of [(trans-d-dach)Pt(9-methylguanine)2Cl 2^ +» showing the f l a t and tw ist-boat conformation of the trans-d-dach ligand. 118 c c c 119 The dihedral angle between the purine rings and the PtN^ plane of the P t(IV) complex is about 40°. The dihedral angle between the two purine rings is about 45° (Figure 19). Once again, the characteristical ly f 1 at appearance of the trans-dach ligand with its two equatorial NH£ groups was found (Figure 21). B. [Pt(cis-dach)(9-m ethylguanine^Cl2] C l^ 2 ^ 0 a) Preparation Twenty m illigram s (0.05 mmoles) of Pt(II)(cis-dach)C l was mixed with 17.4 m g (0.10 mmoles) of 9-methyl guanine in 20 ml of d is t ille d water. The solution was stirred overnight at 37°C. A fter concentrating the colorless solution to about 2 ml, 0.1 mmoles of H2O2 was added. The solution was warmed to about 40°C for about 30 minutes to remove unreacted H2O2, and l e f t overnight at room temperature. After the addition of 0.10 mmoles of HC1, the pale yellow solution became deep yellow . Yellow pi a te -lik e crystals appeared in about three days. b) Data Collection and Structure Analysis Crystals came out as clusters of plates or a p ile of thin plates stacked together. Thus, selecting a suitable single crystal from a l l the av a ila b le crys ta l-c lu ste rs was a n o n -triv ia l task. F in a lly , after a few days of screening of about 15 crystals, a crystal of approximate dimensions 0.4 x 0.4 x 0.1 m m was found to be s u ita b le fo r an x -ra y analysis. This crystal was sealed in a glass c a p illa ry with one drop 1 2 0 of mother liquor. I t was centered and unit c e ll parameters were determined as mentioned before. A summary of the crystal data is shown in Table 8.1. The space group was found to be PI. Data were collected for h a lf of the d iffra c tio n sphere (+h, ± k, ± 1) using the to scan technique up to a 20 lim it of 45° at room temperature. Throughout data c o lle c tio n , three reflectio ns were monitored p e rio d ic a lly (a fter every 50 reflectio ns) and no decay was observed. The data were processed as mentioned before. Of 5298 unique refle ctio n s measured, 2751 refle ctio n s with I >3o(I) were retained for the ensuing structure analysis. The structure was solved by conventional heavy-atom method using the SHELX-76 system of computing programs^®9 and refined to fin a l agreement factors of R = 0.0685 and Rw = 0.0657. (See Tables 8.2 through 8.5 fo r fin a l atomic coordinates, temperature factors, bond distances and bond angles.) c) Description of the Structure Molecular plots of [Pt(cis-dach)(9-methylguanine)2C l2^ + are given in Figures 22 through 24. The main difference between this structure determination and the previous one were (i) cis-dach was used in place of trans-d,l-dach, and ( i i ) a stronger oxidizing agent (H2O2) was used instead of F e (III). The whole structure is very sim ilar to its c lo s e ly -re la te d analog mentioned in Part A. The only difference is, in this compound, an L-shaped cis-dach ligand is used (Figure 22) in comparison to the f l a t trans-dach ligand used in Part A (Figure 21). I t appears that this difference does not affect the 121 Figure 22. A side view of the structure of [(cis-dach)- Pt(9-methyl guanine^Cl 2] 2+> showing the L-shaped configuration of the cis-dach ligand. 122 -1-2 3J Figure 23. Structure of the [(cis-dach)Pt(9-methyl- guanine)2Cl 2]^+ cation, showing v ir t u a lly the same orientation of the guanine rings as in the trans-dach complex, with the cis-dach ligand p a r t ia lly obscured by the upper chloride ligand. 124 & L Figure 24. Another side view of the structure of [(cis-dach)Pt(9-methyl guanine^lH cation, showing the L-shape of the cis-dach ligand. 126 vO Q o t y - 6 127 gross structure of [Pt(dach)(9-MG)^Cl2]^+-type complexes. For example, in [Pt(cis-dach)(9-MG)2Cl 2 ^ + the dihedral angle between the purine rings and the PtN4 plane (about 37°) and the dihedral angle between the two purine rings (about 46°) (Figure 23) are very sim ilar to corresponding values (page 120) in the c lo s e ly -re la te d trans-dach analog described in Part A (Figure 19). C. P t(cis-dach)(9-methylguanine)2(0H)2 C l2 a) Preparation In an attempt to make a mixed guanine/cytosine complex of P t(IV ), 20 m g (0.05 mmoles) of [Pt(II)(cis-dach)C l was mixed with 8.7 m g (0.05 mmoles) of 9-methyl guanine in 10 ml of d is t ille d water. The solution was stirred overnight at 37°C. Two peaks were observed on the HPLC chromatograph. The larger peak (about twice the area of the other) had a retention time of about h a lf of the sm aller one. The larger peak is presumed to be the mono-coordinated complex (i.e., [Pt(cis-dach)(9-MG)Cl]+) while the sm aller one is probably the bis-coordinated complex (i.e., [Pt(cis-dach)(9-MG)2 ] 2+)« A sample of 6.6 m g of 1-methyl cytosine was added and the colorless solution was stirred for several more days. Unreacted 1-methyl cytosine and two peaks with very close retention times were observed on the HPLC chromatograph. The s lig h tly larger peak with a smaller retention time is presumed to be the mixed guanine/cytosine complex of P t ( II) , while the other one is probably the bis-guanine complex of P t(II). (Refer to Appendix C for the working conditions of the HPLC.) The colorless 128 solution was concentrated to about 2 ml without further separation of those peaks and 0.10 mmoles of H2O2 was added. The solution was warmed up to about 40°c for about 20 minutes to decompose unreacted H202 and i t became pale yellow . Pale yellow le a f - lik e crystals appeared in about two weeks at room temperature from the mother liquor which gradually changed to a pale brown color. b) Data Collection and Structure Analysis A crystal of approximate dimensions 0.4 x 0.2 x 0.1 m m was chosen for the x-ray analysis and sealed in a glass c a p illa ry with one drop of mother liq u id . The crystal was centered and unit c e ll parameters J were determined as mentioned before. A summary of the crystal data is shown in Table 9.1. The space group was either C2/c or Cc (both monoclinic). One quadrant of data (+h, +k, +1) was collected using w scan techniques with Mo K a radiation up to a 20 lim it of 45° at room temperature. Throughout data c o lle c tio n , three refle ctio n s were monitored p e rio d ic a lly (a fte r every 50 refle ctio n s ) and no decay was j * 1 observed. The data were processed as mentioned before. Of 3575 unique reflectio n s measured, 1594 reflectio ns with I > 3a(I) were retained fo r the ensuing structure analysis, (i) I n i t i a l l y , the space group was assumed to be C2/c with the Pt atom situated on a 2-fold rotation axis. However, the carbon atoms of the cyclohexane ring of the cis-dach molecule could not be located (since the cis-dach molecule does not possess C2 symmetry), ( i i ) In order to break the symmetry, the space group was then assumed to be Cc. The Pt atom was 129 found by Patterson-search techniques using the SHELX-862^^ system of computing programs and the rest of the atoms were found by using SHELX-76.2^3 But the results of the refinement were s t i l l unsatisfactory, with many of the bond lengths and temperature factors having unreasonable values, ( i i i ) I t was then decided to transform the coordinates of the Pt atom, the whole cis-dach molecule, one of the oxygen atoms, one 9-methyl guanine ring and the 1-methyl cytosine ring back to the original space group, C2/c. The whole structure was then refined again, this time s a tis fa c to rily , to fin a l agreement fa c to rs of R = 0.070 and Rw = 0.069. (See Tables 9.2 through 9.5 fo r fin a l atomic coordinates, temperature factors, bond distances and bond angles.) c) Description of the Structure The compound turned out not to be a mixed guanine/cytosine complex of P t(IV ), but a bis(guanine) complex with two cytosine molecules of c ry s ta lliz a tio n . A d d itio n ally, unlike the f i r s t two compounds discussed in this chapter, this complex has two axial hydroxo ligands in place of two chloro ligands. B asically, the structure of th is compound is quite sim ilar to its dichloro analog mentioned in Part B, even though i t has two smaller axial hydroxo ° ligands [Pt-0 = 2.06(1)A] (Figure 25). The main difference is that j j the dihedral angle between the two purine rings is 57° in comparison j to a smaller angle of 46° in its dichloro analog. The dihedral angle between the purine rings and the PtN^ plane is about 40° (c.f. pages 130 Figure 25. Unit c e ll packing diagram of the [(cis-dach)Pt(9-methyl g u a n in e )O H )2] 2+*2(1-methyl cytosine) cation, showing the intermolecular Watson-Crick type hydrogen bonding between platinated guanine and non coordinated cytosine (dotted lines). 131 132 120 and 128). Probably the most notable factor is the intermolecular Watson-Crick type hydrogen bonding between uncoordinated cytosine and platinated guanine which was found to take place in the crystal l a t t i c e N(101)-N{203) = 2.956 A, N(111)-0(208) = 2.856 A and 0(110)- O N(209) = 2.882 A]. Moreover, these G-C base pairs from adjacent molecules were found to be laid out in p a ra lle l sheets (Figure 25). General Discussion The existence of [ Pt(cis-dach)(9-methylguanine^Cl2] ^+> together with its c lo s e ly-re la ted analog [(Pt(trans-dach)(9-methyl- guanine^Cl £ ]2+ (prepared under mi Ider oxidation conditions), shows that i t is possible to accommodate two purine bases and four other 1iqands around a _ Pt(IV) atom in cis configuration. Perhaps more s ig n ific a n tly , however, is the striking contrast between the small dihedral angle between the purine rings and the PtN4 plane of the Pt(IV) complex (about 37-40° in both cases) as opposed to the much larger angle (about 75-85°) in the corresponding P t(II) complexes discussed in Chapter 2. To put i t in another way, the purine rings are somewhat " p a ra lle l" to the PtN^ plane in the Pt(IV) complexes whereas they are decidedly "perpendicular" to the PtN^ plane in the P t ( I I ) complexes.^ 2 As mentioned in the experimental section, the th ird compound in this chapter, [Pt(cis-dach)(9-methyl g u a n in e ^ O ^ ]2* , resulted from an attempt to make a P t(IV) complex with both 9-methyl guanine and 1-methyl cytosine as ligands. Instead, the compound turned out to . m contain two 9-methyl guanine ligands just as in the two previous structures. Features that are p a rtic u la rly notable about this compound are (i) the presence of hydroxo ligands and ( i i ) the fact that 1-methyl cytosine co-crystal 1izes with the complex in an intriguing manner. Intermolecu! ar Watson-Crick type hydrogen bonding between uncoordinated cytosine and platinated guanine was found to take place in the crystal la ttic e . Conclusion The main conclusion from these resu lts, apart from showing that octahedral Pt(IV) complexes with two cis guanine bases can exist, is the peculiar orientations of the purine rings. One can speculate that the bulk of the axial ligands, either chloro or hydroxo, forces the purines towards a more " p a ra lle l" configuration with respect tothePtN^ plane. One might then expect that an octahedral Pt(IV)(dach)- (dinucleotide)X2 complex ( i f i t can be made, c ry s ta lliz e d and s tru c tu ra lly characterized) could have significant departures from the known geometries of square planar P t(II)/d in u c le o tid e s ^ a and P t(II)/tr in u c le o tid e ^ b comp 1 exes. 134 Table 7.1: Summary of Crystal Data and Refinement Results f< [Pt(IV)(trans-d,l-dach)(9-m ethylguanine)2CI2](N 0 3)2.11H20 molecular weight (g m o le '1) 1032 crystal dimensions (mm) 0.2 x 0.2 x 0.4 space group pT (No.2) (triclinic) molecules/ unit cell 2 a (A) 7.883(3) b (A) 13.463(8) c (A) 18.968(12) a (deg) 92.40(5) 8 (deg) 98.14(4) Y (deg) 72.87(4) V (A3) 1906(2) calculated density (g cm -3) 1.80 O wavelength (A) used for data collection 0.71069 Sin0/X limit (A '1) 0.5385 total number of reflections measured 5775 number of reflections used in structural analysis I > 3o(l) 3170 number of variable parameters 492 final agreement factors R(F) = 0.0667 R(wF) = 0.0637 Table 7.2: Final Atom ic Coordinates for [P t(IV )(trans-d,l-dach){9-m ethylguanine)2CI2](N 0 3)2.11H20 Atom X y 2 Pt 1 0.1660(1) 0.1681(1) 0.2501(1 Cl 1 0.4474(1) 0.1704(1) 0.2288(1 Cl 2 -0.1165(1) 0.1715(1) 0.2706(1 IM101 0.1663(2) 0.0633(1) 0.5090(1 C102 0.2733(3) -0.0333(1) 0.5265(1 N 103 0.3807(2) -0.0959(1) 0.4856(1 C104 0.3663(2) -0.0517(1) 0.4198(1 Cl 05 0.2588(2) 0.0457(1) 0.3948(1 C 106 0.1513(3) 0.1129(1) 0.4422(1 M107 0.2922(2) 0.0526(1) 0.3252(1 C108 0.4117(2) -0.0314(1) 0.3103(1 IM109 0.4647(2) -0.0971(1) 0.3677(1 N 110 0.2676(2) -0.0665(1) 0.5941(1 0111 0.0584(2) 0.2042(1) 0.4336(1 C l 12 0.5931(3) -0.2026(1) 0.3687(1 IM201 0.2731(2) 0.0628(1) -0.0084(1 C202 0.2629(2) -0.0343(2) -0.0280(1 N203 0.2124(2) -0.0945(1) 0.0140(1 C204 0.1848(2) -0.0521(1) 0.0801(1 C205 0.1950(3) 0.0448(1) 0.1045(1 C206 0.2391(2) 0.1102(1) 0.0570(1 N207 0.1575(2) 0.0536(1) 0.1742(1 C208 0.1137(2) -0.0330(1) 0.1899(1 N209 0.1296(2) -0.0965(1) 0.1322(1 N210 0.2920(2) -0.0662(1) -0.0936(1 0211 0.2391(2) 0.2045(1) 0.0664(1 C212 0.1020(3) - 0.2002(2) 0.1304(1 N 1 0.0465(2) 0.2862(1) 0.1774(1 N 2 0.1652(2) 0.2845(1) 0.3216(1 C 1 0.0857(3) 0.3878(1) 0.2100(1 C 2 0.0441(2) 0.3905(1) 0.2852(1 C 3 0.0858(2) 0.4805(1) 0.3287(1 C 4 0.0005(3) 0.5819(1) 0.2856(1 C 5 -0.1338(2) 0.5627(1) 0.2241(1 C 6 -0.0456(2) 0.4828(1) 0.1716(1 IM 3 0.3995(2) 0.1587(1) 0.8479(1 0 31 0.3598(3) 0.1989(2) -0.0962(1 O 32 0.3746(3) 0.0893(2) -0.1753(1 136 Table 7.2 (continued) O 33 IS I 4 O 41 O 42 O 43 O 1 O 2 O 3 O 4 O 5 O 6 O 7 O 8 O 9 O 10 O 11 0.4613(3) 0.9483(2) 0.9459(2) 1.0387(3) 0.8161(3) 0.4797(3) 0.7294(3) 0.8898(3) 0.6474(3) 0.4762(3) 0.5463(3) 0.2087(3) 0.4010(3) 0.4407(3) 0.2503(3) 0.8164(3) 0.2153(2) 0.1583(1) 0.1957(2) 0.0893(2) 0.2151(2) 0.2856(2) 0.2860(2) 0.3963(3) 0.3736(2) 0.3717(3) 0.4326(3) 0.3984(3) 0.5265(3) 0.4739(3) 0.4358(2) 0.4423(2) -0.1881(1 0.6504(1 0.5950(1 0.6764(1 0.6850(1 0.4173(1 0.0841(1 0.4895(2 0.5636(2 0.9332(2 0.2561(2 0.0115(2 0.6222(2 0.1252(2 0.5193(2 0.9678(2 137 Table 7.3: Anisotropic Tem perature Factors for [P t(IV )(trans-d,l-dach )(9-m eth ylg u an in e)2CI2](N 0 3)2.11 HzO Atom Un X103 u 22x i o 3 U33X103 u 12x i o 3 U13X103 u 23x i o 3 Pt 1 57(1) 32(1) 28(1) -7(1) 5(1) 1(1) Cl 1 64(3) 64(3) 56(2) -17(2) 17(2) -3(2) Cl 2 77(3) 56(2) 52(2) -13(2) 8(2) 0(2) N 101 79(4) 52(4) 32(4) -16(4) 2(4) 7(4) C102 85(4) 46(4) 42(4) -17(4) -11(4) 5(4) N 103 84(4) 52(4) 49(4) -21(4) -8(4) 15(4) C104 58(4) 36(4) 54(4) -9(4) -14(4) 6(4) C l 05 48(4) 35(4) 37(4) -8(4) -2(4) 6(4) C106 121(4) 58(4) 26(4) -43(4) 27(4) 0(4) N 107 71(4) 33(4) 43(4) -10(4) 3(4) 11(3) C108 52(4) 32(4) 51(4) 5(4) 23(4) -4(4) N 109 65(4) 32(4) 44(4) -5(4) -1(4) 0(3) N 110 95(4) 93(4) 34(4) -26(4) -1(4) 28(4) 0111 108(4) 43(4) 41(3) -12(4) 25(4) 1(3) C112 95(4) 32(4) 87(4) -3(4) 6(4) -1(4) N201 81(4) 61(4) 39(4) -18(4) 10(4) -7(4) C202 66(4) 55(4) 55(4) -13(4) 1(4) -2(4) N203 60(4) 54(4) 49(4) -8(4) 7(4) -15(4) C204 59(4) 34(4) 49(4) -6(4) -11(4) 1(4) C205 97(4) 31(4) 39(4) -5(4) 9(4) 3(4) C206 55(4) 45(4) 46(4) -1(4) -13(4) -13(4) N207 83(4) 29(4) 33(4) -12(4) 4(4) -13(3) C208 67(4) 36(4) 51(4) -18(4) 5(4) -12(4) N209 84(4) 33(4) 51(4) -6(4) 0(4) 4(4) N210 68(4) 60(4) 23(4) 7(4) 10(4) -20(4) 0211 114(4) 49(4) 39(4) -18(4) 14(4) 0(3) C212 82(4) 52(4) 85(4) -33(4) 4(4) -2(4) N 1 146(4) 30(4) 27(4) -17(4) 6(4) 6(3) N 2 67(4) 47(4) 38(4) -10(4) 10(4) 10(3) C 1 218(4) 94(4) 125(4) 17(4) -21(4) -16(4) C 2 179(4) 38(4) 64(4) 0(4) 34(4) -2(4) C 3 129(4) 36(4) 78(4) -3(4) 0(4) -8(4) C 4 136(4) 39(4) 138(4) -7(4) -9(4) -2(4) C 5 224(4) 160(4) 190(4) 30(4) -10(4) -1(4) C 6 93(4) 35(4) 68(4) -2(4) -4(4) 9(4) N 3 70(4) 64(4) 19(3) 1(4) 15(3) -5(3) O 31 151(4) 143(4) 116(4) -12(4) 41(4) 29(4) 0 32 208(4) 128(4) 99(4) -45(4) 39(4) -20(4) T ab le 7 .3 (c o n tin u e d ) 0 33 168(4) 121(4) 97(4) -22(4) 30(4) 9(4) N 4 83(4) 62(4) 30(4) -24(4) 14(4) 2(3) 0 41 145(4) 128(4) 78(4) -20(4) 4(4) 15(4) 0 42 201(4) 115(4) 107(4) -10(4) 59(4) 15(4) 0 43 183(4) 124(4) 105(4) -79(4) 13(4) 14(4) 0 1 170(4) 123(4) . 185(4) -17(4) -68(4) -21(4) 0 2 188(4) 136(4) 180(4) -60(4) -91(4) 20(4) 0 3 352(4) 331(4) 322(4) -61(4) 56(4) -6(4) 0 4 267(4) 246(4) 290(4) -71(4) 30(4) 15(4) 0 5 271(4) 255(4) 295(4) -82(4) 17(4) -18(4) 0 6 352(4) 360(4) 379(4) -114(4) 57(4) 9(4) 0 7 363(4) 314(4) 319(4) -110(4) 45(4) 8(4) 0 8 265(4) 273(4) 286(4) -74(4) 47(4) -2(4) 0 9 265(4) 273(4) 279(4) -60(4) 22(4) 3(4) 0 10 248(4) 235(4) 232(4) -22(4) 10(4) -5(4) 0 11 248(4) 228(4) 238(4) -44(4) 14(4) -1(4) The complete temperature factor is exp[-2iT2(U11h2a 2 + U22k2b*2 + U33I V 2 + 2U12hka*b* + 2U13h l a V + 2U23k lb V ] 139 Table 7.4: Bond Oistances(A) for [P t(IV )(trans-d,l-dach)(9-nieth ylgu anine)2CI2](IM03)2.11H20 CL 1— Pt 1 2.32(1) CL 2----- Pt 1 2.30(1) N 2— Pt 1 2.02(2) N207----- Pt 1 2.07(1) N 1----- Pt 1 2.06(1) IM107— Pt 1 2.07(1) C106----- 0111 1.23(2) C 2— N 2 1.58(2) C208— N207 1.36(3) C205----- N207 1.39(2) C206— 0211 1.27(2) C 1— N 1 1.57(3) C105----- N107 1.39(2) C108----- IM107 1.29(2) C204----- N209 1.36(3) C208----- N209 1.36(2) C212----- N209 1.47(3) C206----- N201 1.39(2) C202----- N201 1.36(3) C205----- C206 1.43(3) C104----- IM 109 1.36(2) C108----- N109 1.37(2) Cl 12— -N109 1.48(2) C106----- N101 1.43(2) C102----- IM101 1.35(2) C105----- C l 06 1.43(2) C204----- N203 1.37(3) C202----- N203 1.34(3) C205----- C204 1.38(3) C104----- C105 1.39(2) C102----- IM110 1.38(3) N 103----- C104 1.38(3) C102----- N103 1.32(2) N210----- C202 1.33(3) C 2 — C 3 1.52(2) C 4----- C 3 1.54(2) C 1— C 2 1.50(3) C 6— C 1 1.52(2) C 5— C 4 1.52(3) Table 7.4 (continued) C 6 C 5 1.51(2) O 31— N 3 1.21(3) O 32 (M 3 1.07(3) O 33— N 3 1.28(3) O 41 — N 4 1.18(3) O 42 IN I 4 1.08(2) O 43— IM 4 1.34(3) 141 Table 7.5: Bond Angles(deg) for [P t(IV )(trans-d,l-dach)(9-m eth ylg uanine)2CI2](N 0 3)2.11 HzO CL 2-Pt 1-CL 1 178(1) IN I 2-Pt 1-CL 1 89(1) N 2-Pt 1-CL 2 90(1) N207-Pt 1-CL 1 92(1) N207-Pt 1-CL 2 89(1) N207-Pt 1-N 2 178(1) N 1-Pt 1-CL 1 91(1) N 1-Pt 1-CL 2 88(1) N 1-Pt 1-N 2 85(1) N 1-Pt 1-N207 93(1) N 107-Pt 1-CL 1 88(1) N107-Pt 1-CL 2 93(1) N107-Pt 1-N 2 93(1) N107-Pt 1-N207 89(1) N107-Pt 1-N 1 178(1) C 2-N 2-Pt 1 108(1) C 208-N 207-Pt 1 121(1) C 205-N 207-P t 1 131(1) C 205-N 207-C 208 108(2) C 1-N 1-Pt 1 108(1) C 105-N 107-Pt 1 129(1) C 108-N 107-P t 1 122(1) C108-N 107-C 105 109(1) C 208-N 209-C 204 110(2) C 212-N 209-C 204 127(2) C 212-N 209-C 208 124(2) C202-N 201-C 206 126(2) N201 C 2 0 6 -O 2 1 1 119(2) C 2 0 5 -C 2 0 6 -0 2 1 1 128(2) C 205-C 206-N201 113(2) C 108-N 109-C 104 108(1) C 112-N 109-C 104 127(2) C 112-N 109-C 108 125(2) C102-N 101-C 106 125(2) N 1 0 1-C 1 0 6 -O 11 1 119(2) C 1 0 5 -C 1 0 6 -0 1 1 1 129(2) C105-C106-N101 112(1) C 202-N 203-C 204 113(2) N203-C 204-N 209 125(2) C205-C 204-N 209 107(2) Table 7.5 (continued) C205-C 204-N203 127(2) N 209-C 208-N 207 108(2) C206-C 205-N207 135(2) C204-C 205-N207 107(2) C 204-C 205-C206 118(2) C106-C 105-N107 136(2) C 1 0 4-C 10 5 -N 107 106(1) C 104-C 105-C106 118(2) C 105-C 104-N 109 107(2) N 10 3 -C 10 4 -N 109 124(1) N 10 3 -C 1 0 4 -C 105 128(2) C 1 0 2-N 10 3 -C 104 111(2) N 109-C 108-N 107 110(2) N110-C102-N101 115(2) N103-C102-N101 126(2) N 103-C 102-N 110 119(2) N203-C202-N201 123(2) N210-C202-N201 118(2) N210-C 202-N 203 119(2) C 4 -C 3 -C 2 109(1) C 3 -C 2-N 2 109(1) C 1-C 2-N 2 107(1) C 1-C 2-C 3 113(2) C 2-C 1-N 1 104(2) C 6-C 1-N 1 110(1) C 6-C 1-C 2 107(1) C 5-C 4-C 3 109(1) C 6-C 5-C 4 112(1) C 5-C 6-C 1 111(1) 0 32-N 3 - 0 31 128(2) O 33-N 3 - 0 31 112(2) 0 33-N 3 - 0 32 120(2) O 42-N 4 - 0 41 131(2) 0 43-N 4 - 0 41 112(2) 0 43-N 4 - 0 42 118(2) Table 8.1: Summ ary of Crystal Data and Refinem ent Results for [Pt(IV)(cis-dach)(9-m ethylguanine)2CI2JCI2*2H20 molecular weight (g mole-1) crystal dimensions (mm) space group molecules/ unit cell a (A) b (A) c (A) a (deg) 3 (deg) Y (deg) O « V (A3) calculated density (g cm -3) O wavelength (A) used for data collection Sin9/X limit (A-1) total number of reflections measured number of reflections used in structural analysis I > 3o(l) number of variable parameters final agreement factors 817.0 0.5 x 0.5 x 0.3 pT (No.2) (triclinic) 2 18.411(6) 7.834(3) 13.146(11) 96.73(5) 100.49(5) 96.30(3) 1835(2) 1.48 0.71069 0.5385 5298 2751 254 R(F) = 0.0685 R(wF) = 0.0657 144 Table 8.2: Final Atom ic Coordinates for [Pt(IV)(cis-dach)(9-m ethylguanine)2CI2]CI2‘ 2H20 Atom Pt 0.7745(1) 0.7895(1) 0.6736(1 Cl 1 0.7934(1) 0.5022(1) 0.6725(1 Cl 2 0.7551(1) 1.0735(1) 0.6713(1 N 11 1.0277(1) 0.7009(2) 0.5738(1 C 12 1.0347(1) 0.7429(2) 0.4756(2 N 13 0.9812(1) 0.8055(2) 0.4141(1 C 14 0.9158(1) 0.8191(2) 0.4568(1 C 15 0.9068(1) 0.7813(2) 0.5509(1 C 16 0.9657(1) 0.7257(2) 0.6252(1 N 17 0.8354(1) 0.8197(2) 0.5592(1 C 18 0.8086(1) 0.8801(2) 0.4703(1 N 19 0.8577(1) 0.8870(2) 0.4064(1 IN I 10 1.0981(1) 0.7184(2) 0.4420(1 O 10 0.9707(1) 0.7008(1) 0.7145(1 C 10 0.8449(1) 0.9316(2) 0.3058(2 N 21 0.4916(1) 0.8301(2) 0.5705(1 C 22 0.4608(1) 0.7512(2) 0.4767(1 N 23 0.4951(1) 0.6549(2) 0.4105(1 C 24 0.5715(1) 0.6587(2) 0.4570(1 C 25 0.6073(1) 0.7403(2) 0.5500(1 C 26 0.5674(1) 0.8278(2) 0.6171(2 N 27 0.6816(1) 0.7071(2) 0.5593(1 C 28 0.6838(1) 0.6066(2) 0.4712(2 N 29 0.6163(1) 0.5768(2) 0.4060(1 C 20 0.6025(1) 0.4782(2) 0.3091(2 N 20 0.3874(1) 0.7590(2) 0.4476(1 O 20 0.5908(1) 0.9055(2) 0.7088(1 N 1 0.7184(1) 0.7648(2) 0.7932(1 N 2 0.8648(1) 0.8653(2) 0.7927(1 C 1 0.7685(1) 0.8236(2) 0.8978(1 C 2 0.8456(1) 0.7960(2) 0.8897(2 C 3 0.9030(1) 0.8667(2) 0.9893(2 C 4 0.8981(1) 1.0533(2) 1.0280(2 C 5 0.8161(1) 1.0722(2) 1.0432(2 C 6 0.7635(1) 1.0140(2) 0.9319(2 Cl 3 0.8208(1) 1.4301(1) 0.3431(1 Cl 4 0.6367(1) 0.9947(1) 0.3492(1 0 1 0.9541(1) 0.1820(2) 0.7816(1 Table 8.2 (continued) 0.6205(1) 0.4462(2) 0.7788(2) 146 Table 8.3: Anisotropic Tem perature Factors for [Pt(IV)(cis-dach)(9-m ethylguanine)2CI2]C I2*2H20 Atom U n X103 u 22x i o 3 U33X103 u 12x io 3 U13X 103 u 23x i o 3 Pt 28(1) 42(1) 50(1) 6(1) 10(1) 2(1) Cl 1 59(2) 47(2) 85(2) 16(2) 18(2) 7(2) Cl 2 54(2) 46(2) 69(2) 16(2) 10(2) 5(2) N 11 46(2) 57(2) 62(2) 2(2) 19(2) 8(2) C 12 57(2) 53(2) 67(2) 12(2) 14(2) -8(2) N 13 55(2) 57(2) 51(2) 3(2) 10(2) -8(2) C 14 51(2) 42(2) 46(2) 0(2) 10(2) -7(2) C 15 49(2) 42(2) 49(2) 10(2) 17(2) 12(2) C 16 49(2) 53(2) 54(2) -7(2) 8(2) 7(2) N 17 29(2) 51(2) 43(2) 7(2) 12(2) 6(2) C 18 51(2) 44(2) 43(2) -1(2) 12(2) 7(2) N 19 49(2) 45(2) 40(2) 9(2) 11(2) -2(2) N 10 60(2) 84(2) 82(2) 15(2) 34(2) -5(2) 0 10 39(2) 60(2) 53(2) 7(2) 12(2) 12(2) C 10 76(2) 63(2) 64(2) 10(2) 17(2) 15(2) N 21 45(2) 56(2) 57(2) 6(2) 11(2) 1(2) C 22 59(2) 54(2) 61(2) 10(2) 13(2) 20(2) IM 23 64(2) 63(2) 75(2) 0(2) 3(2) 23(2) C 24 47(2) 49(2) 50(2) 3(2) -1(2) 19(2) C 25 49(2) 56(2) 58(2) 12(2) 11(2) 5(2) C 26 65(2) 61(2) 67(2) 10(2) 16(2) 13(2) N 27 28(2) 48(2) 48(2) 6(2) 3(2) 4(2) C 28 67(2) 72(2) 65(2) 1(2) 13(2) 11(2) N 29 47(2) 57(2) 47(2) 13(2) 7(2) -2(2) C 20 86(2) 94(2) 87(2) 13(2) 12(2) -1(2) N 20 60(2) 78(2) 85(2) 12(2) 1(2) 24(2) 0 20 53(2) 78(2) 83(2) 25(2) 15(2) -3(2) N 3 52(2) 67(2) 61(2) 16(2) 10(2) 7(2) N 4 56(2) 64(2) 62(2) 15(2) 13(2) 8(2) C 1 62(2) 68(2) 63(2) 18(2) 16(2) 4(2) C 2 67(2) 90(2) 70(1) 12(2) 10(2) 2(2) C 3 81(2) 80(2) 76(2) 4(2) 7(2) -2(2) C 4 80(2) 91(2) 88(2) 4(2) 7(2) 11(2) C 5 86(2) 92(2) 83(2) 2(2) -2(2) 0(2) C 6 77(2) 83(2) 65(2) 2(2) -9(2) 5(2) Cl 3 68(2) 92(2) 130(2) 21(2) 13(2) -6(2) Cl 4 94(2) 127(2) 185(2) 43(2) 51(2) 70(2) 0 1 157(2) 145(2) 123(2) -84(2) -35(2) 42(2) 147 Table 8.3 (continued) O 2 230(2) 188(2) 217(2) -122(2) 70(2) 5(2) 0 9 *9 The complete temperature factor is exp[-2ir a + U22k2b*2 + U33l V 2 + 2U12hka*b* + 2U13h la V + 2U23k lb V ] 148 Table 8.4: Bond Oistances(A) for [Pt(IV)(cis-dach)<9-m ethylguanine)2CI2]CI2*2H20 Cl 1— Pt 2.314(6) Cl 2----- Pt 2.294(6) N 17----- Pt 2.05(2) N 27— Pt 2.05(1) N 3----- Pt 2.05(2) N 4----- Pt 2.05(2) C 12----- N 11 1.39(2) C 16----- N 11 1.45(2) N 13----- C 12 1.33(2) N 10— C 12 1.35(3) C 14----- N 13 1.43(2) C 15----- C 14 1.34(2) N 19----- C 14 1.35(2) C 16----- C 15 1.46(3) N 17— C 15 1.40(2) 0 10----- C 16 1.20(2) C 18----- N 17 1.34(2) N 19----- C 18 1.34(2) C 10----- N 19 1.39(2) C 22-----N 21 1.31(2) C 26----- IN I 21 1.42(2) N 23----- C 22 1.37(2) IN I 20-----C 22 1.35(3) C 24— N 23 1.42(2) C 25— C 24 1.33(2) N 29— C 24 1.33(2) C 26— C 25 1.41(3) N 27-----C 25 1.41(2) O 20-----C 26 1.26(2) C 28— N 27 1.33(2) l\l 29----- C 28 1.36(2) C 20— N 29 1.38(2) C 1----- N 3 1.50(2) C 2-----N 4 1.53(2) C 2-----C 1 1.48(3) C 6----- C 1 1.52(2) C 3— C 2 1.53(3) C 4 — C 3 1.51(2) C 5— C 4 1.58(3) 149 Table 8.4 (continued) C 6 C 5 1.59(3) 150 Table 8.5: Bond Angles(deg) for [Pt(IV)(cis-dach)(9-m ethylguanine)2CI2]CI2-2H20 Cl 2-Pt -C l 1 179.0(3) N 17-Pt -C l 1 91.8(4) N 17-Pt -Cl 2 87.5(4) N 27-Pt -C l 1 87.9(4) N 27-Pt -C l 2 91.4(4) N 27-Pt -N 17 88.9(6) N 3-Pt -C l 1 88.6(4) N 3-Pt -C l 2 92.2(4) N 3-Pt -N 17 177.1(7) N 3-Pt -N 27 94.0(6) N 4-Pt -C l 1 90.9(4) N 4-Pt -C l 2 89.9(4) N 4-Pt -N 17 93.7(6) N 4-Pt -N 27 177.1(7) N 4-Pt -N 3 83.4(7) C 16-N 11-C 12 127(2) N 13-C 12-N 11 123(2) N 10-C 12 -N 11 118(2) N 10-C 12-N 13 119(2) C 14-N 13-C 12 114(2) C 15-C 14-N 13 126(2) IM 19-C 14-N 13 121(2) N 19-C 14-C 15 113(2) C 16-C 15-C 14 123(2) N 17-C 15-C 14 105(2) N 17-C 15-C 16 132(2) C 15-C 16-N 11 108(2) 0 10-C 16-N 11 119(2) 0 10-C 16-C 15 133(2) C 15-N 17-Pt 131(1) C 18-N 17-Pt 123(1) C 18-IM 17-C 15 106(2) N 19-C 18-N 17 113(2) C 18-N 19-C 14 104(2) C 10-N 19-C 14 130(2) C 10-N 19-C 18 126(2) C 26-N 2 1-C 22 123(2) N 23-C 22-N 21 126(2) N 20-C 2 2-N 21 115(2) N 20-C 22-N 23 119(2) Table 8.5 (continued) c 24-N 23-C 22 110(2) C 25-C 24-N 23 128(2) N 29-C 24-N 23 120(2) N 29-C 24-C 25 112(2) C 26-C 25-C 24 120(2) N 27-C 25-C 24 106(2) N 27-C 25-C 26 134(2) C 25-C 26-N 21 113(2) 0 20-C 26-N 21 118(2) O 20-C 26-C 25 129(2) C 25-N 27-Pt 132(1) C 28-N 27-Pt 122(1) C 28-N 27-C 25 106(2) N 29-C 28-N 27 111(2) C 28-N 29-C 24 105(2) C 20-N 29-C 24 131(2) C 20-N 29-C 28 124(2) C 1-N 3-Pt 112(1) C 2 -N 4-Pt 107(1) C 2-C 1-N 3 109(2) C 6-C 1-N 3 109(1) C 6-C 1-C 2 111(2) C 1-C 2-N 4 110(2) C 3 -C 2-N 4 113(2) C 3-C 2-C 1 114(2) C 4 -C 3-C 2 113(2) C 5-C 4-C 3 110(2) C 6-C 5-C 4 106(2) C 5-C 6-C 1 108(1) Table 9.1: Summary of Crystal Data and Refinement Results for [Pt(IV){cis-dach)(9-methylguanine)2{OH)2]CI2,i2(1-methylcytosine) molecular weight (g mole-1) 994.0 crystal dimensions (mm) 0.4 x 0.2 x 0.1 space group C2/c (No.15) (monoclinic) molecules/ unit cell 4 a (A) 8.325(2) b (A) 23.964(10) c (A) 23.187(10) 8 (deg) 93.17(3) V (A3) 4610(3) calculated density (g cm -3) 1.43 O wavelength (A) used for data collection 0.71069 S in 0 /\ limit (A-1) 0.5947 total number of reflections measured 3575 number of independent reflections 3575 number of reflections used in structural analysis 1 > 3a(l) 1549 number of variable parameters 335 final agreement factors R(F) = 0.0704 R(wF) = 0.0691 153 Table 9.2: Final Atom ic Coordinates for [P t(IV)(cis-dach)(9-m ethylguanine)2(OH)2]C I2*2(1-m ethylcytosine) Atom X V z Pt 1 0.0000(0) 0.5039(1) 0.2500(0) N101 -0.1107(2) 0.4522(1) 0.4543(1) C102 -0.0500(2) 0.4042(1) 0.4732(1) N103 0.0394(2) 0.3708(1) 0.4437(1) Cl 04 0.0584(2) 0.3913(1) 0.3893(1) C105 -0.0036(2) 0.4394(1) 0.3673(1) C106 -0.0954(2) 0.4733(1) 0.3992(1) N107 0.0464(2) 0.4398(1) 0.3087(1) C108 0.1299(3) 0.3963(1) 0.3000(1) N109 0.1434(2) 0.3640(1) 0.3488(1) 0110 -0.1614(2) 0.5187(1) 0.3857(1) N 111 -0.0815(2) 0.3890(1) 0.5276(1) C112 0.2166(3) 0.3100(1) 0.3525(1) N201 0.5605(2) 0.4715(1) 0.1176(1) C202 0.6618(2) 0.4997(2) 0.0814(1) N203 0.6877(2) 0.4799(1) 0.0285(1) C204 0.6173(2) 0.4349(1) 0.0123(1) C205 0.5120(2) 0.4036(1) 0.0476(1) C206 0.4927(3) 0.4252(1) 0.1002(1) C207 0.5314(2) 0.5003(2) 0.1751(1) 0208 0.7265(2) 0.5452(1) 0:0991(1) N209 0.6433(2) 0.4146(1) -0.0415(1) N 1 0.0151(15) 0.5621(4) 0.3153(4) IN I 2 -0.0618(12) 0.5647(4) 0.1909(4) C 1 0.0524(12) 0.6179(5) 0.2807(4) C 2 -0.0758(14) 0.6217(5) 0.2275(4) C 3 -0.2541(12) 0.6195(12) 0.2515(9) C 4 -0.2762(15) 0.6720(11) 0.2927(7) C 5 -0.1497(15) 0.6641(11) 0.3467(5) C 6 0.0258(14) 0.6699(6) 0.3223(7) 0 1 0.2387(10) 0.5178(5) 0.2359(6) Cl 1 -0.4445(3) 0.3646(2) 0.2605(2) Cl 2 0.9748(3) 0.1880(2) 0.4245(2) Cl 3 -0.2714(3) 0.3360(2) 0.3204(2) Cl 4 -0.1930(3) 0.3099(2) 0.3145(2) Cl 5 -0.7465(3) 0.2882(2) 0.1496(2) Table 9.2 (continued) Cl 6 -0.8576(3) 0.2699(2) 0.4954(2) 155 Table 9.3: Anisotropic Tem perature Factors for [Pt(IV)(cis-dach)(9-m ethylguanine)2(OH)2]CI2*2(1-m ethylcytosine) Atom U n X103 u 22x io 3 U33X103 U 12X103 u 13x i o 3 u 23x io 3 I Pt 1 62(1) 44(1) 33(1) 0(0) 14(3) 0(0) I N101 53(3) 59(3) 45(3) 0(3) 7(3) 6(3) C102 50(3) 52(3) 46(3) -5(3) 6(3) -3(3) IN 1 103 59(3) 61(3) 59(3) -6(3) 0(3) 3(3) Cl 04 56(3) 44(3) 49(3) 1(3) 0(3) 0(3) C105 45(3) 38(3) 33(3) 2(3) 5(3) -1(3) C l 06 48(3) 50(3) 49(3) -4(3) 0(3) 1(3) N107 86(3) 89(3) 70(3) 6(3) 6(3) 10(3) C l 08 73(3) 69(3) 73(3) 2(3) 2(3) 5(3) N109 51(3) 52(3) 48(3) 6(3) 6(3) 1(3) 0110 67(3) 68(3) 58(3) 12(3) 9(3) 4(3) N 111 76(3) 78(3) 63(3) 5(3) 6(3) 3(3) C112 79(3) 70(3) 75(3) 9(3) 3(3) -1(3) N201 59(3) 79(3) 60(3) 1(3) 3(3) 3(3) C202 55(3) 67(3) 64(3) 3(3) 1(3) 5(3) N203 48(3) 56(3) 41(3) 2(3) -2(3) 2(3) C204 58(3) 60(3) 57(3) 8(3) 3(3) 1(3) C205 58(3) 63(3) 60(3) 2(3) 2(3) 5(3) C206 67(3) 68(3) 68(3) 6(3) 8(3) 4(3) C207 86(3) 96(3) 75(3) 1(3) 18(3) -1(3) 0208 75(3) 77(3) 59(3) -1(3) 2(3) 3(3) N209 69(3) 74(3) 63(3) 4(3) 6(3) 2(3) N 1 75(3) 70(3) 72(3) -2(3) -2(3) 2(3) N 2 54(3) 50(3) 46(3) 4(3) 13(3) 2(3) C 1 59(3) 55(3) 54(3) -1(3) -1(3) -7(3) C 2 92(3) 85(3) 86(3) 1(3) 2(3) 4(3) C 3 90(3) 86(3) 87(3) 0(3) 3(3) 1(3) C 4 88(3) 84(3) 85(3) 5(3) 2(3) -4(3) C 5 91(3) 91(3) 88(3) 6(3) 2(3) -1(3) C 6 90(3) 90(3) 89(3) 1(3) 3(3) -2(3) O 1 123(3) 115(3) 124(3) 0(3) 4(3) 1(3) Cl 1 457(3) 182(3) 614(3) -261(3) 525(3) -282(3) Cl 2 122(3) 146(3) 293(3) 97(3) 39(3) 124(3) Cl 3 69(3) 108(3) 152(3) 43(3) -59(3) 13(3) Cl 4 100(3) 154(3) 208(3) 54(3) -69(3) 55(3) Cl 5 404(3) 203(3) 229(3) 220(3) -239(3) -113(3) Table 9.3 (continued) Cl 6 354(3) 84(3) 123(3) 60(3) 60(3) 2 2 *2 The complete temperature factor is exp[-2 T T (Un h a + U22k2b*2 + U33l V 2 + 2U12h k a V + 2U13h la V + 2U23k lb V ] 58(3) Table 9.4: Bond Distances(A) for [Pt(IV)(cis-dach)(9-m ethylguanine)2(OH)2JCI2*2(1-m ethylcytosine) N107 Pt1 2.07(2) N 1 — Pt1 2.06(1) N2 — Pt1 2.05(1) 0 1 -----Pt1 2^06(1) C l 05----N107 1.44(3) C108----N 107 1.27(3) C102----N103 1.31(3) C104----N103 1.37(3) N1G1----C l 06 1.39(3) 0 1 1 0 ----C106 1.25(3) C l 05---- Cl 06 1.36(3) C l 02— IN 1 101 1.32(3) Cl 04---- N 109 1.37(3) C108 l\l 109 1.37(4) C 1 12---- N109 1.43(3) N111---- C102 1.35(3) C 104---- C105 1.35(3) 0 2 0 8 ----C202 1.27(4) N203— C202 1.34(3) IM201---- C202 1.40(3) C204-----N209 1.37(3) IM201---- C207 1.53(4) C206-----IM201 1.30(4) C206-----C205 1.34(4) C204-----C205 1.44(4) C1 N1 1.60(2) C2 — N2 1.62(1) C 6 C5 1.60(2) C 4 C5 1.60(2) C l — C6 1.60(2) C 2 Cl 1.60(1) C3 — C2 1.59(2) C3 — C4 1.59(3) 158 Table 9.5: Bond Angles(deg) for [Pt(IV)(cis-dach)(9-m ethylguanine)2(OH)2]CI2«2(1-m ethylcytosine) N1 -Pt1 -N 107 90.9(5) N2 -P tl -N107 175.9(5) N2 -P tl -N1 90.8(4) 01 -Pt1 -N 107 94.5(5) 01 -P tl -N1 89.3(5) 01 -Pt1 -N 2 89.3(4) C105-N107-Pt1 124.7(3) C108-N107-Pt1 125.7(7) C 108-N 107-C 105 110(2) C 104-N 103-C 102 111(2) 0 1 10-C106-N101 119(2) C105-C106-N101 112(2) C 1 0 5 -C 1 0 6 -0 1 10 130(2) C 102-N 101-C 106 125(2) C 108-N 109-C 104 106(2) C 112-N 109-C 104 129(2) C 112 -N 10 9 -C 108 125(2) N 101-C 102-N 103 121(2) N il1 -C 1 0 2 -N 1 0 3 118(2) IM111-C102-N101 117(2) C 106-C 105-N 107 135(2) C 104-C 105-N 107 104(2) C 10 4 -C 10 5 -C 106 121(2) IN 1 109-C 1 0 4 -N 103 123(2) C 10 5 -C 1 0 4 -N 103 126(2) C l0 5 -C 1 0 4 -N 109 110(2) N 109-C 108-N 107 111(2) N 20 3-C 20 2 -0 20 8 121(2) N2Q1-C2Q2-O208 119(2) N 201-C 202-N 203 121(3) C 204-N 203-C 202 118(2) C 207-N 201-C 202 116(2) C 206-N 201-C 202 119(2) C 206-N 201-C 207 125(2) C 204-C 205-C 206 115(2) C205-C 206-N201 123(3) N 209-C 204-N 203 118(2) C 205-C 204-N 203 124(2) 159 Table 9.5 (continued) C205-C 204-N209 118(2) C1 -N1 -Pt1 101.6(6) C2 -N 2 -Pt1 105.9(6) C4 -C5 -C6 107(1) C1 -C6 -C 5 108(1) C6 -C1 -IM1 108.1(9) C2 -C1 -IM1 106.9(8) C2 -C l -C6 108.1(9) C1 -C2 -N 2 106.4(8) C3 -C 2 -N 2 105(1) C3 -C 2 -C1 109(1) C3 -C 4 -C 5 107(2) C4 -C 3 -C 2 109(1) APPENDIX A SYNTHESIS AND CRYSTALLIZATION OF cis-[Pt(NH 3) 2(DINUCLE0TIDE)] COMPLEXES Much has been written about the discovery, mechanism of action and effectiveness of platinum anti-tumor drugs, 33 to the point where i t would be redundant to repeat this discussion here. Suffice i t to say that cis-Pt(NH3)Cl 2 (cis-DDP, CISPLATIN or PLATINOL) is now one of the most widely-used drugs in chemotherapy, usually applied in combination with bleomycin and vin blastin , or in combination with adriamycin. 34 I t appears to be p a rtic u la rly e ffe c tiv e against bladder, ovarian and te s tic u la r cancers.33,1,1 The compound is now (a fter some debate) widely acknowledged to act by binding DNA. Our group,35-37 and other investigators33 have already published a considerable number of papers about the X-ray analysis of the piatium-nucleoside and piatinum-nucleotide complexes to id en tify the most probable site of this attack. The overwhelming accumulation of eidence points to N(7) of guanine as the Pt-binding site. The natural extension of this research e ffo rt, then, is to study the structures of platinum complexes of larger building blocks of nucleic acids...specifical ly , the dinucleoside monophosphates (i.e., molecules of the type NpN, where N is a nucleoside), the dinucleotides (i.e., molecules of the type pNpN), and th e ir deoxy analogs.3^ Such molecules would be larger (and presumably better) 161 models with which to study the d e tails of Pt-DNA and Pt-RNA interactions at the molecular le v e l. Since our group was at that time p a rtic u la rly interested in the three-dimensional structures of Pt-dinucleotide complexes containing G and C (i.e. GpG, GpC, CpG and CpC; especially the former), the early part of my research project (Summer 1984-Fall 1985) mainly involved the preparation and c ry s ta lliz a tio n of various Pt-dinucleotide complexes. One reason we used GpG, GpC, CpG and CpC instead of th e ir deoxy analogs was because they were commercially a v a ila b le . The Pt-dinucleotide complexes were usually synthesized using 1.5 m g of cis-Pt(NH3)2Cl 2 and a stoichiometric amount (1:1 ra tio ) of the corresponding dinucleotide, dissolved in 50 ml of d is t ille d water and stirred for about three to six days at room temperature in the dark. cis-Pt(NH3)2Cl 2 + NpN --------------[(Pt(NH3) 2NpN)Cl] The pH of the above reaction took place at a value that varied between 6 and 7. Crystal 1ization by vapor-diffusion or by adding bulky anions (e.g. [Ph3BCN]- , [BPh^]- , [B (p -to ly l^ l" ) was found to be not very successful. W e could only get microcrystals (0.15 x 0.05 x 0.02 m m ) and the results were not very reproducible. Later, we shifted our c ry s ta lliz a tio n attempts to the "spot-plate" method: this technique involves placing a small amount of [Pt(NH3) 2GpG](C.l) or [Pt(NH3)2CpC](Cl) solution (approximately 4.5 m g of complex dissolved in 2 ml of H20) into a depression of a siliconized spot-plate and vapor-diffusing this solution against 80% dioxane (24 ml dioxane: 6 ml 162 H20). Using this method, colorless, long needle-shaped crystals (3.0 x 0.1 x 0.02 m m ) would appear reproducibly in about a week. However, they were not thick enough to produce any diffractio n pattern with a normal x-ray beam. Unfortunately, at about the same time, Lippard and co-workers published the x-ray analysis of cis- [Pt (NH3) 2 {d(pGpG) } ] ; ^ 3 and after a year, Reedijk and co-workers published x-ray studies on cis-CPt(NH3)2 {d(CpGpG)}].^k Both structures showed, at atomic resolution, an N(7)-Pt-N(7) intrastrand chelate involving two adjacent guanines in a head-to-head conformation. Thus, we decided to de-emphasize our efforts on the square planar Pt(II)/cis-DDP system. To fin ish o ff the project, one of the remaining tasks was to examine single crystals of [Pt(NH3)2GpG]+ to explore the effect of the extra 2'-0H groups and to examine the con formational changes ( i f any) in the phosphate-sugar backbone When G- Pt-G chelation takes place (as compared to Lippard's deoxy a n a lo g )^ 3. Although once again the crystals obtained were not large enough for crystal lographic analysis using a normal X-ray beam, they did d iffra c t when the high intensity X-ray beam from a synchrotron source was employed (Figure 26). I t is hoped, therefore, that some day in the near future when single-crystal x-ray diffractometers are successfully implemented on dedicated synchrotron x-ray sources (as is currently happening at Brookhaven National Laboratory), someone else from our group would be able to c o lle c t data on these u ltra -s m a ll crystals. 163 Figure 26. Rotation photograph (20 minute exposure) of [Pt(NH3) 2(GpG)]+C1~ showing strong diffractio n spots (up to the outer lim its of the photograph) on an ultra-sm all crystal using synchrotron radiation. (This particular photograph was taken at the Daresbury Synchrotron Laboratory in Warrington, England). The large black object in the center of the photograph is simply over-exposure from the intense X-ray source. 164 One fin a l comment: c ry s ta lliz a tio n of cis-[Pt(NH3) 2{d(pCpG)J] was tried using the c ry s ta lliz a tio n method described by Lippard et a l . 1-^3 in an attempt to see i f this published procedure (a) would be more reproducible and (b) i f larger crystals could be grown. In this method, a mixture of (i) 80 PI of the Pt-dinucleotide solution (5 mg/1.1 ml H2O), ( i i ) 10 pi of 2-methyl-2 ,4-pentanediol, ( i i i ) 5 yl of glycine-HCl buffer solution (660 mM; pH = 3.5) and (iv ) 5 y l of MgC^ solution (660 mM) is f i r s t prepared. This mixture was then placed into a depression of a siliconized spot-plate and vapor-diffused against 90% 2-methyl-2 ,4-pentanediol (45 ml MPD: 5 ml H2O). W e found that colorless crystals came out as small needles and plates in several months. I t appears, therefore, that the method described by j 1 " 3 s I Lippard et a l. a is indeed quite reproducible. Perhaps i t would be worthwhile in the future to spend more e ffo rt in finding better c ry s ta lliz a tio n conditions to get larger crystals of cis- [Pt(NH3) 2{d(pCpG)>] fo r conventional x-ray analysis. 165 APPENDIX B THE DEFINITION O F VARIOUS DNA AND RNA CONSTITUENTS Mononucleotides serve as the building blocks of the nucleic acids DNA and RNA. Each mononucleotide contains three characteristic components: (1) a nitrogenous bases, (2) a pentose sugar, and (3) a phosphate group. For convenience, the structures and numbering schemes of the com m on bases and th e ir corresponding nuclesides are given in Chart I. The numbering of the pentose ring is indicated in Chart I I ; the phosphate group ( i f present) is usually attached to the 5' position. F in a lly , Table B lis ts the names and relationships between the molecules commonly referenced in this a rtic le . I t should be noted that at neutral pH the mononucleotides are usually found in the dinegative form. Chart I purines 0 0 R adenine, R ■ H adenosine, R » ribose " R guanine, R * H hypa&anthine , R * H guanosine, R = ribose inosine, R > ribose pyrimidines " ~ T N H * 0 0 R R cytosine , R> H uracil, R ■ H cytidine, R * ribose uridine. R s ribose R thymine, R ■ H thymidine. R 3 2'-deoxyribose 166 Chart I I ribose H O fvV? $LM S & J p l d l H H U h 2*- dsoxyriboM Table B Relationships Between the Com m on Bases, Nucleosides, and Nucleotides Base Nucleoside Nucleotide Purines Adenine Adenosine Adenylic acid, adenosine monophosphate (AMP) Guanine Guanosine Guanylic acid, guanosine monophosphate (GMP) Hypoxanthi ne Inosine Inosinic acid, inosine monophosphate (IMP) Pyrimidines Cytosine Cytidine Cytidylic acid, cytidine monophosphate (CMP) Uracil Uridine U ridylic 'acid, uridine monophosphate (UMP) Thymine Thymidine Thymidylic acid, thymidine monophosphate (TMP) 167 APPENDIX C W ORKING CONDITIONS O F THE HIGH PERFORMANCE (PRESSURE) LIQUID CHROMATOGRAPHIC (HPLC) APPARATUS The chromatographic separations were carried out using a Perkin- Elmer HPLC instrument (Series 3B), equipped with a dual pump system and a variable UV LC-75 spectrophotometric detector, which was set to &=254 nm for a ll compounds. Two columns were used for the separation of reaction products: (i) a Perkin-Elmer analytical reverse phase column containing a support called "octyl (RP-C8)", with p a rtic le size 10 ym, and ( i i ) a preparative column containing exactly the same support m aterial. The diameters of the analytical and preparative columns were 4.6 and 21.5 m m respectively, and the column lengths of both of them were 25.0 cm. O rig in a lly , we had hoped that working out the proper conditions with the analytical column would enable us to . switch to a preparative column read ily in order to do preparative HPLC: As both columns have the same packing m aterial, i t would have been very simple to switch from the analytical to the preparative column. The ra tio of column volumes is 22, which meant that the optimum flow rate for analytical separations would have had to be m ultiplied by this factor when the preparative column was put in place. However, we la te r found that the synthetic techniques reported by Chottard et a l . ^ for the preparation of [(Pt(NH3)2GpG]+ and [Pt(NH3)^CpC3+ gave only one major product in both i 168 cases. W e confirmed that these reactions could be carried out to about 98% completion, thereby rendering the use of preparative HPLC unnecessary. From that point onwards, the product was used without any further pu rification in a ll our subsequent c ry s ta lliz a tio n attempts. The conditions we used in our HPLC work were as fo l lows: an aqueous ammonium acetate solution (10“^ M, pH = 7.76) was used as eluant B whereas a less polar solution (1:1 H2O/CH3OH) of ammonium acetate (10- 2M, pH = 6.99) was used as eluant A. Usually 10% A/90% B was used as the eluant and the flow rate was normally set at 1.0 ml/min. Satisfactory resolution between the starting material and product was found under these conditions. The ammonium acetate s a lt can be removed quite ea sily after a preparative separation under in vacuo (ammonium acetate ^ammonia + acetic acid). However, in contrast to the PtfNHj^-systems, this solvent system did not work e ffic ie n tly fo r the Pt(dach)(nucleobase) and Pt(dach)(nucleoside) I complexes. i For the analytical separation of Pt(dach)(nucleobase), Pt(dach)(nucleoside) and Pt(dach)(nucleotide) complexes, methanol was used as eluant A and aqueous t r i f 1 uoroacetic acid (TFA, 0.2%) was used j as eluant B. Usually, 15% A/90% B was used as the eluant and the flow rate was again 1.0 ml/min. T r i f 1uoroacetic acid was used for three reasons: f ir s t , i t is a buffer which serves as an e ffic ie n t ion- pairing agent, leading to differen t retention times for a l l cationic Pt-species and produces good separations. Second, i t is a very 169 e ffe c tiv e eluant for Pt(dach) complexes. Satisfactory resolutions between starting m aterials and products were found with a very reasonable elution period (less than 30 minutes) fo r every analytical separation. Third, i t can eas ily be removed in vacuo because of its v o l a t i l i t y afte r a preparative separation. The disadvantage of using TFA is its low pH value (about 2.Z-Z.6) which may cause the decomposition of dinucleotides in a preparative separation of Pt(dinucleotides) complexes. 170 APPENDIX D CRYSTALLOGRAPHIC STUDIES O N Pt(TRANS-&-DACH) ( GUANOSINE) £ 11# g(C104)Q #5 * 2H £0 In order to convince ourselves that the same P t(II) square planar complex could be obtained starting with a known P t(II) source [as compared with the P t(II) complexes prepared unexpectedly from a Pt(IV) source (Chapter 2)], we decided to synthesize [Pt(trans-1 -dach)- (guanosine)]^+ independently using a d ifferen t method. Thus, the follow ing project was carried out by Ms. Thizar Tintut (an undergraduate researcher in our lab) and myself. In 10 ml of d is tille d water at 37°C, 10.0 m g of P t(II)(tran s-l-dach)C l was mixed with 15.9 m g of guanosine (two equivalents). The solution was stirred overnight and concentrated to about 1 ml. A stiochiometric amount of NaClO^ was added and the colorless solution was vapor- diffused against isopropanol. Colorless diamond-like crystals formed in about two weeks. A crystal of approximate dimensions 0.4 x 0.4 x 0.4 m m was chosen for structure analysis, and sealed in a glass c a p illa ry with one drop of mother liquor. The crystal was centered and unit c e ll parameters were determined as mentioned before. A summary of the crystal data is shown in Table 10.1. The data were processed as described in previous chapters. Of 3282 unique reflections measured, 1838 reflections with I > 3a(I) were retained for the ensuing structure analysis. The 171. structure was solved by standard heavy-atom techniques and refined to a fin a l agreement factors of R = 0.065 and Rw = 0.064. (See Tables 10.2 through 10.5 fo r fin a l atomic coordinates, temperature factors, bond distances and bond angles.) Figures 27, 28 and 29 shows the results of this study. The significance of this work is probably best appreciated by a comparison of three structure determinations: (a) [P t(II)(cis-d ach)(guanosine)2] 2+ (Chapter 2) (b) [P t(II)(tra n s -d ,l-d a c h )( 9-methylguanine)2] 2+ (Chapter 2) (c) [ P t ( I I ) ( t r a n s - 1-dach)(guanosine)2] 2+ (Appendix D). The main conclusion of this investigation is that which was stated at the beginning of this appendix: namely, that Pt(II)(dach) complexes prepared from a P t(II) starting material (compound £) has a gross geometry which is es sen tia lly identical with Pt(II)(dach) complexes prepared from a Pt(IV) source (compounds a _ and b). A secondary conclusion can be derived by comparing the structures of compounds a and _ c : the fact that steric encumberance is more pronounced in complexes of the L-shaped cis-dach ligand than in complexes of trans-dach (see Chapter 2, Figure 18). 1 7 2 Figure 27. Structure of the [(trans-1-dach)- Pt(guanosine)2] 2+ cation (View #1). 173 174 Figure 28. Structure of the [ (trans-1-dach)- Pt(guanosine)2] 2+ cation (View #2). I Figure 29. Structure of the [(trans-1-dach)- Pt(guanosine)2] 2+ cation (View #3). 177 o Table 10.1: Summary of Crystal Data and Refinement Results for Pt(ll){trans-l-dach)(guanosine)2(CIO4)0 5.2H20 molecular weight (g mole-1) 1085.5 crystal dimensions (mm) 0.4 X 0.4 x 0.4 space group I4t (No.80) (tetragonal) molecules/ unit cell 8 a=b (A) 18.141(3) c (A) 25.062(4) V (A3) 8248(4) calculated density (g cm -3) 1.75 O wavelength (A) used for data collection 0.71069 Sin9/X limit (A-1) 0.5385 total number of reflections measured 3282 number of reflections used in structural analysis I > 3a(l) 1838 number of variable parameters 504 final agreement factors R(F) = 0.0654 R(wF) = 0.0641 179 Table 10.2. Final Atom ic Coordinates for Pt(trans-l-dach)G uo2(CIO4)0 5(Cl)1 5?2H20 Atom X Y Z Pt 1 0.2737(1) 0.7739(1) 0.0030(1 N 101 0.3731(1) 0.9415(1) 0.1449(1 C l 02 0.3631(2) 1.0190(2) 0.1329(1 Cl 03 0.3286(2) 1.0444(2) 0.0914(1 Cl 04 0.3034(2) 0.9925(2) 0.0576(1 C105 0.3120(2) 0.9173(2) 0.0640(1 C106 0.3450(2) 0.8874(2) 0.1120(1 N107 0.2779(1) 0.8829(1) 0.0178(1 C l 08 0.2510(2) 0.9351(2) -0.0061(1 N109 0.2686(1) 1.0027(1) 0.0127(1 N110 0.3956(2) 1.0611(2) 0.1693(1 0111 0.3552(1) 0.8212(1) 0.1222(1 C 11 0.2514(2) 1.0763(2) -0.0123(1 C 12 0.2970(2) 1.0849(2) -0.0629(2 O 12 0.3086(1) 1.1616(1) -0.0713(1 C 13 0.2480(2) 1.0577(2) -0.1082(1 O 13 0.2639(1) 1.0830(1) -0.1582(1 C 14 0.1646(2) 1.0788(2) -0.0892(1 C 15 0.1046(2) 1.0413(3) -0.1079(2 O 15 0.1156(2) 0.9557(2) -0.0946(2 O 16 0.1746(1) 1.0712(1) -0.0304(1 N201 0.4472(1) 0.8720(2) -0.1374(1 C202 0.5178(2) 0.8627(2) -0.1255(2 C203 0.5443(2) 0.8284(2) -0.0871(1 C204 0.4932(2) 0.7979(2) -0.0544(2 C205 0.4146(2) 0.8095(2) -0.0597(1 C206 0.3882(2) 0.8421(2) -0.1027(1 N207 0.3821(2) 0.7783(2) -0.0142(1 C208 0.4342(2) 0.7481(2) 0.0167(1 IM209 0.5012(1) 0.7670(1) -0.0071(1 N210 0.5611(2) 0.8941(2) -0.1651(1 0211 0.3221(1) 0.8579(2) -0.1141(1 C311 0.5729(2) 0.7503(2) 0.0187(1 C312 0.5849(2) 0.7937(2) 0.0695(1 0312 0.6629(1) 0.8078(1) 0.0758(1 C313 0.5573(2) 0.7454(2) 0.1140(1 Table 10.2 (continued) 0313 0.5841(2) 0.7633(1) 0.1642(1) C314 0.5800(2) 0.6654(2) 0.0931(1) C315 0.5375(2) 0.6043(2) 0.1134(2) 0315 0.4600(2) 0.6155(2) 0.1026(1) 0316 0.5709(1) 0.6760(1) 0.0384(1) N 1 0.1614(1) 0.7710(1) 0.0245(1) N 2 0.2660(1) 0.6614(1) -0.0157(1) C 1 0.1345(1) 0.6987(1) - 0.0012(1) C 2 0.1923(1) 0.6378(1) 0.0093(1) C 3 0.1660(1) 0.5652(1) -0.0161(1) C 4 0.0918(1) 0.5427(1) 0.0093(2) C 5 0.0341(1) 0.6028(1) -0.0008(2) C 6 0.0597(1) 0.6767(1) 0.0228(1) C! 1 1.0000(0) 0.5000(0) 0.5039(1) 0 1 1.0676(3) 0.5025(3) 0.4722(2) 0 2 0.9963(3) 0.4299(3) 0.5321(2) Cl 2 0.5455(1) 0.4059(1) 0.5071(1) 0 3 0.2783(2) 0.2123(2) 0.5600(2) 0 4 0.2776(2) 0.2900(2) 0.1956(2) Cl 3 0.5956(1) 0.4541(1) 0.0009(1) 1 8 1 Table 10.3. Anisotropic Tem perature Factors for P t(trans-l-d ach)G u o2CIO4)0 5(CI)1 5*2H20 Atom U n X103 u 22x io 3 U 33XIO 3 u 12x io 3 u 13x i o 3 u 23x io 3 Pt 1 49(1) 47(1) 53(1) -11(1) 1(1) 0(1 N101 53(8) 50(8) 37(8) -1(8) -5(8) -15(8 C102 31(8) 56(8) 59(9) 0(9) 14(8) -26(9 Cl 03 32(8) 34(8) 43(9) 10(8) 6(8) -6(8 C104 32(8) 53(9) 57(9) -4(8) 6(8) 3(9 Cl 05 45(8) 58(9) 53(9) 10(8) -21(8) 4(9 Cl 06 48(9) 64(9) 59(9) 13(9) -10(9) 10(9 IM 107 76(8) 42(8) 57(9) -18(8) 23(8) 1(8 C108 46(8) 55(9) 43(9) 4(8) 0(8) 10(9 IM 109 76(8) 48(8) 29(8) -4(8) 3(8) 0(8 N 110 79(9) 75(9) 42(8) -2(8) -14(8) -26(8 0111 50(8) 76(8) 69(8) 16(8) -24(8) 2(8 C 11 71(9) 44(9) 68(9) 29(9) -19(9) 6(8 C 12 71(9) 58(9) 68(9) -34(9) -2(9) 3(9 0 12 67(8) 58(8) 88(9) -21(8) -11(8) 11(8 C 13 36(8) 55(9) 45(9) 6(8) 10(8) 34(8 0 13 81(8) 75(8) 71(8) -12(8) 7(8) -5(8 C 14 62(9) 61(9) 29(8) 4(9) -25(8) 7(8 C 15 77(9) 89(9) 89(9) -25(9) -42(9) 6(9 0 15 90(9) 129(9) 153(9) -47(9) -7(9) -42(9 0 16 56(8) 58(8) 78(8) -1(8) -5(8) 2(8 N201 50(8) 56(8) 68(9) 3(8) -1(8) 0(8 C202 79(9) 52(9) 51(9) -11(9) -3(9) -11(8 C203 44(8) 36(8) 34(9) 17(8) 7(8) 7(8 C204 56(9) 67(9) 67(9) -27(9) -4(9) -9(9 C205 61(9) 31(8) 31(8) 8(8) 4(8) 20(8 C206 34(8) 26(8) 60(9) -1(8) -3(8) -10(8 N207 52(8) 91(9) 82(9) -10(8) -11(8) 20(8 C208 44(8) 51(8) 45(9) 12(8) -21(8) -42(8 N209 50(8) 44(8) 36(8) 3(8) -10(8) 32(8 N210 84(9) 73(9) 69(9) -2(9) 3(9) 11(9 0211 77(8) 66(9) 79(8) -10(8) -6(8) 10(8 C311 77(9) 51(9) 55(9) -6(9) 7(9) 13(8 C312 56(9) 62(9) 48(9) -6(8) -30(8) -3(8 0312 70(8) 52(8) 98(9) -5(8) -29(8) 14(8 C313 60(9) 63(9) 58(9) -10(9) -28(9) 6(8 0313 104(9) 71(8) 77(9) 5(8) 8(8) -25(8 C314 89(9) 70(9) 26(8) -7(9) 13(9) -7(8 182 Table 10.3 (continued) C315 88(9) 67(9) 66(9) 4(9) -12(9) 7(9) 0315 113(9) 75(8) 120(9) -35(8) 26(9) 3(8) 0316 69(8) 59(8) 72(8) 15(8) 1(8) 13(8) N 1 51(8) 98(9) 88(9) - 10(8) 27(8) - 6(8) N 2 103(9) 63(8) 79(9) -19(8) 24(8) -15(8) C 1 73(9) 98(9) 111(9) -50(8) 31(9) 5(9) C 2 93(9) 77(9) 106(9) -65(8) 9(9) -17(9) C 3 110(9) 103(9) 102(9) -41(9) 36(9) -11(9) C 4 108(9) 105(9) 110(9) -71(9) -3(9) 0(9) C 5 107(9) 115(9) 110(9) -54(9) 21(9) -26(9) C 6 109(9) 107(9) 72(9) -53(9) 32(9) -52(9) Cl 1 52(5) 68(6) 141(8) 13(5) 0(0) 0(0) 0 1 276(9) 213(9) 248(9) -11(9) -42(9) -68(9) 0 2 179(9) 227(9) 208(9) -4(9) 61(9) 65(9) Cl 2 45(6) 88(7) 23(6) 9(6) -3(6) -15(7) 0 3 101(9) 163(9) 123(9) 0(9) -5(9) -19(9) 0 4 Cl 3 97(9) 14(5) 158(9) 111(9) 0(9) 9(9) 15(9) 2 2 2 The complete temperature factor is exp[-2tr (U ^ h a + U22k2b*2 + U33l V 2 + 2U 12hka*b* + 2U13h la V + 2U23k lb V 183 Table 10.4. Bond Distances for P t(trans-l-dach)G uo2(CIO4)0 ..(Cl), 5-2H2Q l\l 107----- Pt 1 2.01(3 N207----- Pt 1 2.01(3 N 1— Pt 1 2.11(2 l\l 2----- Pt 1 2.10(3 C102----- N101 1.45(4 C106----- N101 1.38(4 C103----- C102 1.30(5 IM110— C102 1.33(5 Cl 04-----C103 1.35(5 C105----- C104 1.38(5 N109-----C104 1.30(4 C106----- C105 1.45(5 N107----- C105 1.45(4 0 1 1 1 — C106 1.24(4 C l 08----- N107 1.22(4 ISI109----- C108 1.35(4 C 11----- N109 1.51(4 C 12----- C 11 1.52(5 0 16----- C 11 1.47(4 0 12----- C 12 1.42(4 C 13----- C 12 1.52(5 0 13— C 13 1.37(4 C 14----- C 13 1.63(4 C 15— C 14 1.37(5 0 16— C 14 1.49(4 0 15— C 15 1.60(6 C202-----IN1201 1.33(5 C206----- N201 1.48(4 C203----- C202 1.24(5 N 2 10----- C202 1.39(5 C204----- C203 1.36(5 C205----- C204 1.45(5 N209-----C204 1.32(5 C206-----C205 1.32(4 IM207----- C205 1.40(4 0 2 1 1 — C206 1.27(4 C208----- N207 1.34(4 N209----- C208 1.40(4 C 311----- N209 1.48(4 C312----- C311 1.51(5 Table 10.4 (continued) 0 3 1 2----- C312 1.45(4) C313----- C312 1.50(5) 0 3 1 3 — C313 1.39(5) C314----- C313 1.60(5) C315----- C314 1.44(5) 0 3 1 6----- C314 1.40(4) 0 3 1 5 — C315 1.45(5) C 1— N 1 1.54(3) C 2— N 2 1.54(3) C 2 — C 1 1.55(3) C 6— C 1 1.54(3) C 3— C 2 1.54(3) C 4 — C 3 1.55(4) C 5— C 4 1.53(3) C 6— C 5 1.54(4) 0 1— Cl 1 1.46(6) O 2— Cl 1 1.46(5) 185- Table 10.5. Bond Angles (deg) for Pt(trans-l-dach)G uo2(CIO4)05(CI)1 5*2H20 N207-Pt 1-N107 88 (1) N 1-Pt 1-N107 91 (1) N 1-Pt 1-N207 177(1) N 2-Pt 1-N107 177(1) N 2-Pt 1-N207 93 (1) N 2-Pt 1-N 1 88 (1) C106-N101-C102 121(3) C103-C102-N101 125(3) N110-C102-N101 111(3) N110-C102-C103 124(3) C104-C103-C102 115(3) C105-C104-C103 125(3) N109-C104-C103 128(3) N109-C104-C105 107(3) C106-C105-C104 121(3) N107-C105-C104 107(3) N107-C105-C106 133(3) C105-C106-IM101 113(3) 0111-C 106-N 101 121(3) 0111-C 106-C 105 127(3) C105-IM1Q7-Pt 1 126(2) C108-N 107-Pt 1 131(3) C108-N107-C105 103(3) I\I109-C108-IM107 116(3) C108-N109-C104 107(3) C 11-N109-C104 126(3) C 11-N109-C108 128(3) C 12-C 11-N109 109(3) 0 16-C 11-N109 106(3) 0 16-C 11-C 12 105(3) 0 12-C 12-C 11 108(3) C 13-C 12-C 11 106(3) C 13-C 1 2 -0 12 107(3) 0 13-C 13-C 12 117(3) C 14-C 13-C 12 104(3) C 14-C 1 3 -0 13 113(3) C 15-C 14-C 13 122(3) 0 16-C 14-C 13 99 (2) 0 16-C 14-C 15 113(3) 186 Table 10.5 (continued) O 15-C 15-C 14 108(3 C 1 4 -0 16-C 11 115(3 C 206-N 201-C202 121(3 C203-C2G2-N201 128(4 N210-C202-N201 109(3 N210-C202-C203 123(3 C204-C203-C202 114(3 C205-C204-C203 124(3 N209-C204-C203 130(3 N209-C204-C205 105(3 C206-C 205-C204 120(3 N207-C 205-C204 106(3 N 207-C 205-C206 134(3 C 2 05-C 206 -N 2 01 112(3 0 2 1 1-C206-N201 118(3 0 2 1 1-C206-C 205 129(3 C205-N 207-Pt 1 127(2 C208-N 207-Pt 1 123(2 C208-N 207-C205 110(3 N209-C 208-N207 106(3 C208-N 209-C204 113(3 C311-N 209-C204 125(3 C 311-N 209-C 208 122(3 C312-C 311-N209 113(3 0316-C 311-N 209 109(3 0316-C 311-C 312 102(3 0 3 1 2 -C 3 1 2 -C 3 1 1 109(3 C313-C312-C311 106(3 C 313-C 31 2-0 312 110(3 0313-C 313-C 312 115(3 C314-C 313-C312 102(3 C 314-C 313-031 3 115(3 C315-C 314-C313 116(3 0316-C 314-C 313 100(3 0 3 1 6 -C 3 14 -C 3 15 113(3 0315 -C 315 -C 314 110(3 C 314-0316-C 311 118(3 C 1-N 1-Pt 1 103(1 C 2-N 2-Pt 1 104(1 C 2-C 1-N 1 109(2 C 6-C 1-N 1 110(2 C 6-C 1-C 2 110(2 C 1-C 2-N 2 109(2 C 3 -C 2-N 2 110(2 C 3 -C 2-C 1 109(2 Table 10.5 C 4 -C 3-C 2 C 5-C 4-C 3 C 6-C 5-C 4 C 5-C 6-C 1 O 2-CI 1 -0 1 (continued) 109(2) 110(2) 111 (2 ) 110(2) 109(3) 188 REFERENCES | 1. 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Asset Metadata

Creator Choi, Hok-Kin (author)

Core Title Crystallographic studies on new Pt(IV) anti-cancer agents and their reaction products

Contributor Digitized by ProQuest (provenance)

Degree Doctor of Philosophy

Degree Program Chemistry

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag chemistry, organic,OAI-PMH Harvest

Language English

Advisor Bau, Robert (committee chair), [illegible] (committee member), Yang, P.Y. (committee member)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c17-650068

Unique identifier UC11344170

Identifier DP21966.pdf (filename),usctheses-c17-650068 (legacy record id)

Legacy Identifier DP21966.pdf

Dmrecord 650068

Document Type Dissertation

Rights Choi, Hok-Kin

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA