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DESIGN AND SYNTHESIS OF BISPHOSPHONATE ANALOGS AS
INHIBITORS OF FARNESYL PYROPHOSPHATE SYNTHASE
by
James Michael Hogan
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
August 2008
Copyright 2008 James Michael Hogan
Object Description
| Title | Design and synthesis of bisphosphonate analogs as inhibitors of farnesyl pyrophosphate synthase |
| Author | Hogan, James Michael |
| Author email | jameshogan@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemistry |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-05-13 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-07-23 |
| Advisor (committee chair) | McKenna, Charles |
| Advisor (committee member) |
Haworth, Ian Williams, Travis |
| Abstract | Molecular modeling and synthetic studies were carried out on several novel analogs of risedronate, a nitrogen-containing bisphosphonate (N-BP) drug that is widely used for the treatment of osteoporosis and other bone diseases. The physicochemical properties of the side-chain nitrogen and its position relative to the bisphosphonate P-C-P backbone are associated with the potency of N-BPs in inhibiting human farnesyl pyrophosphate synthase (FPPS), which is believed to be the biochemical target of these drugs. By computer-simulated docking with AutoDock 3 and predictive pKa calculation studies, we designed a small library of compounds to examine the relationship between nitrogen basicity and drug potency in risedronate analogs. A number of analogs, containing either electron-donating or electron-withdrawing substituents on the pyridinyl ring system, were evaluated for antiresorptivepotency in a standard assay.; The docking software was further used to evaluate a series of risedronate analogs in which alkyl substituents of variable length replaced the alpha-OH group attached to the carbon atom of the P-C-P bisphosphonate backbone. Representative examples were synthesized and submitted for evaluation of anti-resorptive activity, as well as for X-ray crystallographic analysis of the FPPS-inhibitor complexes.; Inhibitor-active site docking analysis, synthesis, and X-ray crystallography of the inhibitor-enzyme complex were also applied to the interactions of FPPS with [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid), NE-10501, an analog of risedronate in which the side-chain configuration is rigidified by incorporation of a fused 5-membered ring. A docking analysis predicted preferential binding of the R-enantiomer. To test this prediction, the compound was resynthesized using a significantly improved synthetic method developed in our laboratory. X-ray crystallographic analysis of the inhibitor-enzyme complex confirmed the presence of only the R-enantiomer in the active site. However, the Xray data indicated that the Mg2+ ion content of the active site was lower than in the risedronate complex, suggesting an explanation for the relatively decreased potency of NE-10501 as compared to the clinically employed drug.; Preliminarily to the above investigations, detailed synthetic procedures were worked out for the following benchmark N-BP compounds: [1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid), (hydroxymethylene)bis(phosphonic acid), and [2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid). Several unsuccessful attempts to synthesize the first example of a tetrakisphosphonate alsoare outlined. |
| Keyword | bisphosphonates; osteoporosis; molecular modeling; enzyme inhibition |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1385 |
| Rights | Hogan, James Michael |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Hogan-20080723 |
| Archival file | uscthesesreloadpub_Volume17/etd-Hogan-20080723.pdf |
Description
| Title | Page 1 |
| Full text | DESIGN AND SYNTHESIS OF BISPHOSPHONATE ANALOGS AS INHIBITORS OF FARNESYL PYROPHOSPHATE SYNTHASE by James Michael Hogan A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) August 2008 Copyright 2008 James Michael Hogan |
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