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Design and Synthesis of Pyrimido[4,5-B]Indoles and Furo[2,3-D]

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Design and Synthesis of Pyrimido[4,5-B]Indoles and Furo[2,3-D] Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Spring 2015 Design and synthesis of pyrimido[4,5-b]indoles and furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential or as inhibitors of tubulin or thymidylate synthase Ravi Kumar Vyas Devambatla Follow this and additional works at: https://dsc.duq.edu/etd Recommended Citation Devambatla, R. (2015). Design and synthesis of pyrimido[4,5-b]indoles and furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential or as inhibitors of tubulin or thymidylate synthase (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/482 This Immediate Access is brought to you for free and open access by Duquesne Scholarship Collection. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Duquesne Scholarship Collection. For more information, please contact [email protected]. DESIGN AND SYNTHESIS OF PYRIMIDO[4,5-b]INDOLES AND FURO[2,3-d]PYRIMIDINES AS SINGLE AGENTS WITH COMBINATION CHEMOTHERAPY POTENTIAL OR AS INHIBITORS OF TUBULIN OR THYMIDYLATE SYNTHASE A Dissertation Submitted to The Graduate School of Pharmaceutical Sciences Duquesne University In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medicinal Chemistry By Ravi Kumar Vyas Devambatla May 2015 Copyright by Ravi Kumar Vyas Devambatla 2015 Name: Ravi Kumar Vyas Devambatla DESIGN AND SYNTHESIS OF PYRIMIDO[4,5-b]INDOLES AND FURO[2,3-d]PYRIMIDINES AS SINGLE AGENTS WITH COMBINATION Dissertation: CHEMOTHERAPY POTENTIAL OR AS INHIBITORS OF TUBULIN OR THYMIDYLATE SYNTHASE Degree: Doctor of Philosophy Date: March 17, 2015 APPROVED & ACCEPTED Aleem Gangjee, Ph.D. (Committee Chair) Professor of Medicinal Chemistry Graduate School of Pharmaceutical Sciences Duquesne University, Pittsburgh, PA APPROVED Marc W. Harrold, Ph.D. (Committee member) Professor of Medicinal Chemistry Graduate School of Pharmaceutical Sciences Duquesne University, Pittsburgh, PA APPROVED Patrick T. Flaherty, Ph.D. (Committee member) Associate Professor of Medicinal Chemistry Graduate School of Pharmaceutical Sciences Duquesne University, Pittsburgh, PA APPROVED David J. Lapinsky, Ph.D. (Committee member) Associate Professor of Medicinal Chemistry Graduate School of Pharmaceutical Sciences Duquesne University, Pittsburgh, PA APPROVED Lawrence H. Block, Ph.D. (Committee member) Professor of Pharmaceutics, Emeritus Graduate School of Pharmaceutical Sciences Duquesne University, Pittsburgh, PA APPROVED James K. Drennen, Ph.D. Associate Dean, Research and Graduate Programs Graduate School of Pharmaceutical Sciences Duquesne University, Pittsburgh, PA APPROVED J. Douglas Bricker, Ph.D. Dean of Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA iii ABSTRACT DESIGN AND SYNTHESIS OF PYRIMIDO[4,5-b]INDOLES AND FURO[2,3-d]PYRIMIDINES AS SINGLE AGENTS WITH COMBINATION CHEMOTHERAPY POTENTIAL OR AS INHIBITORS OF TUBULIN OR THYMIDYLATE SYNTHASE By Ravi Kumar Vyas Devambatla May 2015 Dissertation supervised by Professor Aleem Gangjee This dissertation describes an introduction, background and research progress in the areas of multitargeted single agents and tubulin inhibitors in cancer chemotherapy and selective Toxoplasma gondii TS inhibitors for the treatment of toxoplasmosis. Tubulin inhibitors are important antitumor agents that disrupt microtubule dynamics. Thymidylate synthase (TS) inhibitors prevent cell division by interfering with de novo thymidylate synthesis. Antiangiogenic agents target tumor angiogenesis crucial for tumor growth and metastasis. Under normal circumstances, angiogenesis is typically limited to tumor cells and is mediated by receptor tyrosine kinases (RTKs). Combination chemotherapies of RTK inhibitors with cytotoxic agents that target either TS or tubulin have shown significant promise and several preclinical and clinical studies with such combinations are in progress. Multitargeted single agents with dual antiangiogenic and iv cytotoxic mechanisms could avoid the major limitations associated with cancer chemotherapy: multidrug resistance and dose limiting toxicities. This dissertation focuses on the design and synthesis of pyrimido[4,5-b]indoles and furo[2,3-d]pyrimidines as potential single agents with dual antiangiogenic and cytotoxic activities. These efforts led to the identification of structural features that are necessary for inhibition of RTKs and/or tubulin polymerization. Novel synthetic strategies were developed for efficient synthesis of 2,4-diamino-5-thioaryl-pyrimido[4,5-b]indoles and 4-anilino-5-methyl-furo[2,3- d]pyrimidines. Taxanes and vinca alkaloids are widely used tubulin inhibitors in cancer chemotherapy. However, their clinical use is compromised by two major mechanisms of drug resistance: the overexpression of Pgp and III-tubulin. This dissertation describes the design and synthesis of pyrimido[4,5-b]indoles as tubulin inhibitors that circumvent Pgp and III-tubulin mediated resistance. This work identified the structural features crucial for tubulin inhibition for the pyrimido[4,5-b]indole scaffold. Infection by Toxoplasma gondii can lead to toxoplasmosis in immune compromised patients such as organ transplant, cancer and AIDS patients. Current therapy involving combination of sulfadiazine and pyrimethamine is limited by drug resistance and treatment failures. The thymidylate synthase‒dihydrofolate reductase enzyme is important for thymidylate synthesis in T. gondii, and hence can be targeted to treat T. gondii infection. TS is highly conserved across species and selectivity for tgTS over human TS is significantly more challenging. The present work provides an efficient synthesis of 2-diamino-4-oxo-5-thioaryl-pyrimido[4,5-b]indoles as selective tgTS inhibitors. v Dedicated to My Mom and Dad vi ACKNOWLEDGEMENTS I would never have been able to finish my dissertation without the guidance of my committee members, help from colleagues, and support from my parents and wife. I would like to express my deepest gratitude to my advisor, Professor Dr. Aleem Gangjee, for his guidance and support which made the research presented in this dissertation possible. I am indebted to him for his scientific guidance and training and also for providing me with an excellent atmosphere for doing research. I sincerely thank the members of my dissertation committee: Drs. Marc W. Harrold, David J. Lapinsky, Patrick T. Flaherty, Lawrence H. Block and Aleem Gangjee for their valuable insights and guidance. I would like to thank Drs. Bruce Beaver and Fraser Fleming for their valuable courses in Organic Chemistry. I wish to express my sincere appreciation to Ms. Nancy Hosni, Ms. Jackie Farrer, Ms. Mary Caruso, and Ms. Deborah Willson for their unconditional assistance in administrative issues. I would like to thank the Graduate School of Pharmaceutical Sciences for financial support. I am extremely grateful to Drs. Roheeth K Pavana, Ranganadh Velagaleti, Nilesh Zaware and Sudhir Raghavan and Ms. Shruti Choudhary and Mr. Arpit Doshi for their constructive criticism and support which made this dissertation possible. I would like to thank my family including my sister and brother-in-law for believing in me and also for their precious support. Finally, I would like to express my love and gratitude to my wife, Pranaya Devambatla for her constant support and for standing by me during good times and bad. vii TABLE OF CONTENTS Page ABSTRACT ....................................................................................................................... iv DEDICATION ................................................................................................................... vi ACKNOWLEDGEMENTS .............................................................................................. vii LIST OF ABBREVIATIONS ............................................................................................ ix LIST OF TABLES ........................................................................................................... xiii LIST OF FIGURES ...........................................................................................................xv LIST OF SCHEMES...................................................................................................... xviii I. BIOLOGICAL REVIEW .................................................................................................1 II. CHEMICAL REVIEW .................................................................................................37 III. STATEMENT OF THE PROBLEM ...........................................................................61 IV. CHEMICAL DISCUSSION. .......................................................................................84 V. EXPERIMENTAL ......................................................................................................101 VI. SUMMARY ...............................................................................................................148 VII. BIBLIOGRAPHY ....................................................................................................152 VIII. APPENDIX .............................................................................................................183 viii LIST OF ABBREVIATIONS 5 10 5,10-CH2THF N ,N -Methylene tetrahydrofolate 5-FU 5-Fluorouracil 5-F-5'-dCR 5-Fluoro-5'-deoxycytidine 5-F-5'-dUR 5-Fluoro-5'-deoxyuridine 5-F-dUMP
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