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An Effort to Address Antibiotic Resistance

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An Effort to Address Antibiotic Resistance Desmethyl Analogs of Telithromycin: An Effort to Address Antibiotic Resistance A Dissertation Submitted to the Temple University Graduate Board in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy By Venkata Velvadapu August, 2011 Examining Committee Members: Dr. Rodrigo B. Andrade, Research Advisor, Chemistry Dr. Franklin A. Davis, Committee Chair, Chemistry Dr. William M. Wuest, Committee Member, Chemistry Dr. Kevin C. Cannon, External Committee Member, Chemistry i © by Venkata Velvadapu 2011 All Rights Reserved ii ABSTRACT The development of antibiotic resistance has been an inevitable problem leading to an increased demand for novel antibacterial drugs. To address this need, we initiated a structure-based drug design program wherein desmethyl analogues (i.e., CH 3H) of the 3rd -generation macrolide antibiotic telithromycin were prepared via chemical synthesis. Our approach will determine the biological functions of the methyl groups present at the C-4, C-8 and C-10 position of the ketolide. These structural modifications were proposed based on the structural data interpreted by Steitz and co-workers after obtaining crystal structures of macrolides erythromycin and telithromycin bound to the 50S ribosomal subunits of H.marismortui. Steitz argued that in bacteria, A2058G mutations confer resistance due to a steric clash of the amino group of guanine 2058 with the C-4 methyl group. In turn, we hypothesize that our desmethyl analogs are predicted to address antibiotic resistance arising from this mutation by relieving the steric clash. To readily access the analogs, we proposed to synthesize, 4,8,10-tridesmethyl telithromycin, 4,10-didesmethyl telithromycin, 4,8-didesmethyl telithromycin and 4- desmethyl telithromycin as four targeted desmethyl analogs of telithromycin. This thesis includes the total synthesis and biological evaluation of 4,8,10-tridesmethyl telithromycin and 4,10-didesmethyl telithromycin analogs and the progress towards the total synthesis of 4-desmethyl telithromycin analog. We employed Nozaki-Hiyama-Kishi (NHK) and ring closing metathesis (RCM) reactions as the two macrocyclization methods towards the total synthesis of these analogs. The RCM was superior compared to the NHK macrocyclization where in grams of these macrocycles were accessible. An optimized method for installing the desosamine iii sugar onto the C-5 alcohol using the Woodward’s thiopyrimidine donor was developed. Baker’s one-pot carbamoylation/intramolecular aza-Michael method was utilized to install the oxazolidinone side chain of telithromycin. The total synthesis of 4,8,10-tridesmethyl telithromycin required 42 steps overall (31 steps in the longest linear sequence). The analog 4,10-didesmethyl telithromycin was synthesized in 44 steps overall (32 steps in the longest linear sequence). These analogs were able to inhibit bacterial growth, presumably by targeting the bacterial ribosome. In addition, 4,8,10-tridesmethyl telithromycin analog was more potent than telithromycin against an A2058T mutant and 4,10-didesmethyl telithromycin analog was more potent than 4,8,10-tridesmethyl telithromycin against an A2058G mutant. Also, a concise synthesis of D-desosamine was accomplished in five steps and in 15% overall yield from commercial methyl α-D-glucopyranoside. Other efforts involved the contribution of key intermediates towards the total synthesis of 4,8-didesmethyl telithromycin are described. iv Dedication This dissertation is dedicated to my wonderful wife Soujanya whose constant support and encouragement made my tough journey possible. v ACKNOWLEDGMENTS First and foremost I give my utmost thanks to my thesis advisor, Dr. Rodrigo B. Andrade, for his support and guidance throughout the duration of my PhD career at Temple University. His understanding, perception and hands-on expertise served as an example for my graduate career. I will always remember him for what he has done for me. His enthusiasm, scientific curiosity and innovative ideas are something I will strive for in my career. Most of all his fascination towards chemistry, Indian food and his clichés are something I will always cherish. I wish him the best and hope to see him continue being a great mentor. I would like to give special thanks to Dr. Franklin A. Davis, as my defense committee chair and my mentor for my first years at Temple. I would like to thank Dr. William M. Wuest and Dr. Kevin C. Cannon for their valuable suggestions, guidance, and willingness to serve on my doctoral dissertation committee. I am grateful to Osmania University, MNR PG College faculty Dr. Srinivas Reddy, Dr. Saritha Rajender and Dr. Sarbani Pal for providing constant encouragement, support, and motivation to pursue my research career. I would like to thank Dr. Tapas Paul whose research expertise and practices in the lab supported me throughout my PhD. I would like to thank my fellow graduate students Mr. Bharat Wagh, Mr. Gopal Sirasani, Mr. Justin Kaplan, Mr. Ian Glassford, Mr. Chary Munagla, Mr. Praveen Kokkonda, Mr. Vijay Chatare and Ms. Miseon Lee for their co- operation and support. Bharat, Ian and Justin deserve special mention, as they inspire me vi through sharing scientific discussions as well as discussions about life. I would like to thank Ian and Justin for helping me in editing my thesis. I feel fortunate to have interacted with other students like Dr. Goutham Kodali, Dr. Sunil Kulkarni, Dr. Madhavan, Dr. Rajeshraman Madathingal and Dr. Ramakrishna Edupuganti who have an interesting perspective towards science and life. I would like to thank Dr. Jaykumar Gilbert, Dr. Vassil Boiadjiev and Dr. Shiva Vaddypally for sharing their valuable insight. I would like to thank Dr. Alfred Findeisen for his constant support as a teaching lab coordinator during my teaching assignments. I would also like to thank Dr. Charles DeBrosse for his support and guidance in the NMR facilities. I would like to express my thanks to all the chemistry department staff present and past. I wish to express my deep gratitude to lost friends the late. Mr. Warren Muir, and Mr. George McCurdy. I would like to thank Mr. Dave Plasket for helping to make the glassware. Not to mention, I really appreciate his sense of humor. All this work would not have been possible without the financial support from Temple University and NIH grant number (AI080968). In that regard, I would like to thank the Department of Chemistry at Temple University for their financial support through teaching and research assistantships and providing an opportunity to pursue my graduate studies. Finally, I wish to express my deepest love and gratitude to my parents, Velvadapu Vishnuvardhan Rao, Vijaya Lakshmi, Kumar, Sumona, Srikrishna Sai, Rammurthy, vii Priya, Soujanya, Chakri and Chennakeshava Rao garu for their constant support, guidance, patience and understanding. I would like to thank my friends Mohit, Sandeep, Swapna, Sharavan, Shiva, Ravichandra, Deepan, Shashi, Sid, Srikanth, Satish, and Sushma for sharing memorable moments. Overall I feel nothing is possible without the blessing of “ Shiridi Saibaba ” to whom I owe everything. viii TABLE OF CONTENTS ABSTRACT ……………………………………………………………………………..iii ACKNOWLEDGEMENTS …………………………………………………………….vi LIST OF TABLES ……………………………………………………………………..xiii LIST OF FIGURES ……………………………………………………………………xiv LIST OF SCHEMES………………………………………………………………….xvii CHAPTER 1. Concise Syntheses of D-Desosamine, 2-Thiopyrimidinyl Desosamine Donors and Methyl Desosaminide Analogues from D-Glucose ………………………..1 1.1 Introduction........................................................................................................1 1.2 Background........................................................................................................2 1.3 Korte’s Synthesis of Desosamine (1962)……………………………………...4 1.4 Richardson’s Synthesis of Desosamine (1964)..................................................5 1.5 Newman’s Degradation and Synthesis of Desosamine (1974)………………..6 1.6 Tietze’s Synthesis of Desosamine (1974)…………………….……………….8 1.7 Bauer’s Asymmetric Synthesis of Desosamine (1997)……………………….8 1.8 McDonald’s Asymmetric Formal Synthesis of Desosamine (2004)………….9 1.9 Crotti’s Ring Opening of 2,3-Anhydrosugars (2002)………………………..10 1.10 Present Study……………………………………………………………….11 ix 2. Desmethyl Analogs of Telithromycin to Address Antibiotic Resistance: Synthesis and Biological Evaluation of (-)-4,8,10-Tridesmethyl Telithromycin 2.1 Background…………………………………………………………………..17 2.2 Macrolide Antibiotics………………………………………………………..20 2.3 Erythromycin…………………………………………………………….......21 2.4 Spectrum of Activity…………………………………………………………22 2.5 Drawbacks……………………………………………………………………23 2.6 Second Generation Macrolide Antibiotics…………………………………...24 2.7 Mechanism of Action………………………………………………………...28 2.8 Mechanism of Antibiotic Resistance………………………………………...32 2.8.1 Ribosome Mutation and Modification……………………………………..33 2.8.2 Ribosome Methylation……………………………………………………..33 2.8.3 Efflux of Macrolides……………………………………………………….34 2.8.4 Inactivating Enzymes………………………………………………………34 2.9 Ketolides and Discovery of Telithromycin…………………………………..35 2.10 Third Generation Ketolide Antibiotics……………………………………..41 2.11 Present Study: Desmethylation as a Strategy for Overcoming Antibiotic Resistance………………………………………………………………………..42 2.12 Steitz’s Explanation of Antibiotic Resistance from Structural Data……….44 2.13 Desmethylation Strategy and Proposed Desmethyl Analogs of Telithromycin…………………………………………………………………….46 2.14 Molecular Modeling of Macrolide Conformations…………………………50
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