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Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Fall 12-21-2018 Pyrrolo[2,3-d]pyrimidine Classical Antifolates for Targeted Cancer Chemotherapy- Applications of Bioisosteric and Regioisomeric Substitutions for Improved Tumor-Selectivity and Potency Manasa Punaha Ravindra Follow this and additional works at: https://dsc.duq.edu/etd Part of the Medicinal Chemistry and Pharmaceutics Commons Recommended Citation Punaha Ravindra, M. (2018). Pyrrolo[2,3-d]pyrimidine Classical Antifolates for Targeted Cancer Chemotherapy- Applications of Bioisosteric and Regioisomeric Substitutions for Improved Tumor-Selectivity and Potency (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1747 This One-year Embargo 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. PYRROLO[2,3-d]PYRIMIDINE CLASSICAL ANTIFOLATES FOR TARGETED CANCER CHEMOTHERAPY- APPLICATIONS OF BIOISOSTERIC AND REGIOISOMERIC SUBSTITUTIONS FOR IMPROVED TUMOR-SELECTIVITY AND POTENCY 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 By Manasa Punaha Ravindra December 2018 Copyright by Manasa Punaha Ravindra 2018 PYRROLO[2,3-d]PYRIMIDINE CLASSICAL ANTIFOLATES FOR TARGETED CANCER CHEMOTHERAPY- APPLICATIONS OF BIOISOSTERIC AND REGIOISOMERIC SUBSTITUTIONS FOR IMPROVED TUMOR-SELECTIVITY AND POTENCY By Manasa Punaha Ravindra Approved August 28, 2018 _______________________________ ____________________________ Aleem Gangjee, Ph. D. Marc W. Harrold, Ph. D. Distinguished Professor of Medicinal Professor of Medicinal Chemistry Chemistry Graduate School of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Duquesne University, Duquesne University (Committee member) (Committee Chair) _______________________ _______________________ Patrick T. Flaherty, Ph. D. Kevin Tidgewell, Ph. D. Associate Professor of Medicinal Chemistry Associate Professor of Medicinal Chemistry Graduate School of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Duquesne University, Duquesne University, (Committee member) (Committee member) ____________________ ______________________ Lauren O’Donnell, Ph. D. Carl Anderson Associate Professor, Pharmacology Associate Professor Graduate School of Pharmaceutical Sciences Division Head, Pharmaceutical, (Committee member) Administrative & Social Sciences Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA ________________________________ J. Douglas Bricker, Ph. D. Dean, School of Pharmacy and the Graduate School of Pharmaceutical Sciences Duquesne University, Pittsburgh, PA iii ABSTRACT PYRROLO[2,3-d]PYRIMIDINE CLASSICAL ANTIFOLATES FOR TARGETED CANCER CHEMOTHERAPY- APPLICATIONS OF BIOISOSTERIC AND REGIOISOMERIC SUBSTITUTIONS FOR IMPROVED TUMOR-SELECTIVITY AND POTENCY By Manasa Punaha Ravindra December 2018 Dissertation supervised by Dr. Aleem Gangjee In 2018, it is estimated that 1,735,350 new cases of cancer and 609,640 deaths from the disease will be diagnosed in the United States alone. Conventional chemotherapy is by far the most successful category of clinical oncology, having cured (complete remission (CR), without return) or provided clinical benefit to millions of people. However, since its earliest discovery, the major causes of failure of conventional cancer chemotherapy have been dose-limiting toxicities and development of resistance. There is a desperate ongoing search for new cancer therapies as tumor-targeted agents (without harming normal cells or tissues) with low propensity for the development of resistance. Clinically used antifolates methotrexate (MTX; DHFR inhibitor), pemetrexed (PMX; TS and GARFTase inhibitor), pralatrexate (PTX; DHFR inhibitor), and raltitrexed (RTX; TS inhibitor), have two major disadvantages: (1) dose-limiting toxicities due to iv ubiquitous transport via the reduced folate carrier (RFC) and (2) drug-resistance; mutation and/or overexpression of RFC and target enzymes resulting in inadequate transport, reduced cellular retention, and decreased potency. However, two other folate transporters that are narrowly expressed in healthy tissue while overexpressed in many different types of cancer are the folate receptors (FRs) (epithelial ovarian cancer (EOC), NSCLC, renal, endometrial, colorectal, breast cancers, hematologic malignancies, etc.) and the proton- coupled folate transporter (PCFT) (ovarian and NSCLC). Our aim is to design classical antifolates for selective uptake by FRs and PCFT over RFC and inhibition of multiple folate metabolizing enzymes in their monoglutamate forms. Successful identification of such small molecule single agents will potentially (a) have tumor-targeting action and (b) combat resistance development. This dissertation discusses the bioisosteric and regioisomeric optimization of 5- and/or 6-substituted pyrrolo[2,3-d]pyrimidine antifolates for improved tumor-targeted activity. Molecular modeling with the help of known X-ray crystal structures of the transporters and the intracellular enzymes was used to rationalize the design of the analogs. NMR studies that were performed to provide structural evidence for the presence of a conformationally restricting intramolecular fluorine hydrogen bond have been described. v The dissertation also discusses the synthetic efforts for obtaining the pyrrolo[2,3- d]pyrimidine analogs with regioisomeric substitutions, modified linkers and bioisoteric replacements (general structure I) for selective uptake, and inhibition of one or more enzymes in the de novo purine and/or pyrimidine biosynthetic pathway. The present work identified that, depending on the regioisomeric position, fluorine substitution on the side- chain (het)aryl ring improves both potency as well as selectivity, most significantly towards PCFT-expressing cell lines. NMR-based structural evidence led to one of our hypotheses that entropic benefit due to conformational restriction caused by an intramolecular fluorine hydrogen bond may partly be responsible for improved biological activity. The current work led to the identification of a fluorinated pyrrolo[2,3-d]pyrimidine analog 184, the most potent inhibitor of PCFT-expressing Chinese hamster ovarian (CHO) cells (PCFT4 IC50 = 1.5 (0.4) nM). Another important contribution of the current work is the discovery of multi-enzyme inhibitor 201, a C6-methylated version of the clinically used anticancer agent PMX, which showed selectivity over RFC (PMX PC43-10 IC50 = 26.2 nM; 201 PC43-10 IC50 > 1000 nM). Such selectivity can potentially help overcome the dose-limiting toxicities of PMX. The fluorinated and methylated analogs described herein are testimonials for the profound effects that minor structural changes can have on polypharmacology. vi Dedicated to my family vii ACKNOWLEDGEMENT I would like to acknowledge and convey my gratitude to the individuals who were instrumental for the initiation, persistence and completion of my Ph.D. research. First and foremost, I am most grateful to my mother, P. R. Swarnalatha for her unconditional love and support. I would not have made this far if not for her sacrifices and protection. I owe my nature as well as nurture to my late grandfather V. R. Ramachary, grandmother V. R. Laxmi, my maternal uncle V. R. Srinivas, my aunt M. Sangeetha Raman and my late uncle M. S. Raman and I am eternally grateful to them for shaping my future. My deepest appreciation belongs to my beloved father P. K. Ravindra, for making me his number one priority, and making sure that my focus was always on my education while he took care of my day-to-day responsibilities. I will be forever indebted to my advisor, Professor Dr. Aleem Gangjee, for accepting me into his group, and for his guidance and support which made the research presented in this dissertation possible. I am indebted to him for his scientific guidance, training, and for the financial support by providing graduate assistantship. I would also like to acknowledge the valuable lessons taught and suggestions provided from the Duquesne University faculty members: Dr. Michael Cascio, Dr. Lauren O’Donnell, Dr. Patrick T. Flaherty, Dr. Fraser Fleming, Dr. David J. Lapinsky, Dr. Marc W. Harrold, and Dr. Aleem Gangjee. I would like to express my gratitude to Dr. Kevin Tidgewell for agreeing to be a part of my committee during the tail end of my Ph.D. I cannot forget to express my gratitude towards the University of Pittsburgh chemistry faculty, Dr. Scott Nelson and Dr. Peter Wipf from whom I have learnt some of the most viii interesting, relevant and invaluable lessons. I wish to express my sincere appreciation to Mary Caruso, Jackie Farrer, Nancy Hosni, Amelia Stroyne and Deborah Willson for their kind heart, help and assistance. The acknowledgements would not be complete without mentioning my friends, Suravi Chakrabarty, Dr. Shruti Choudhary, Arpit Doshi, Dr. Rishabh Mohan and Dr. Khushbu Shah who became my family and made my stay in Pittsburgh colorful. I am thankful to my friend, philosopher and guide Dr. Poovaiah Palangappa for coming into my life and sticking with me. I cannot forget to thank my friend and one man solution to every problem, Mohit Gupta. I would like to thank all of my graduate school friends, Dr. Shaili Aggarwal, Tanvir Ahmed, Ankur Dashputre, Dr. Taylor
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