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Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Fall 1-1-2017 Target Based Design and Synthesis of Fused Pyrimidines in the Potential Treatment of Cancer and Opportunistic Infection Khushbu Shah Follow this and additional works at: https://dsc.duq.edu/etd Part of the Medicinal and Pharmaceutical Chemistry Commons Recommended Citation Shah, K. (2017). Target Based Design and Synthesis of Fused Pyrimidines in the Potential Treatment of Cancer and Opportunistic Infection (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/234 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. For more information, please contact [email protected]. TARGET BASED DESIGN AND SYNTHESIS OF FUSED PYRIMIDINES IN THE POTENTIAL TREATMENT OF CANCER AND OPPORTUNISTIC INFECTION 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 Khushbu Shah December 2017 Copyright by Khushbu Shah 2017 TARGET BASED DESIGN AND SYNTHESIS OF FUSED PYRIMIDINES IN THE POTENTIAL TREATMENT OF CANCER AND OPPORTUNISTIC INFECTION By Khushbu Shah Approved October 25, 2017 ________________________________ ________________________________ Aleem Gangjee, Ph. D. Marc W. Harrold, Ph. D. Professor of Medicinal Chemistry Professor of Medicinal Chemistry Graduate School of Pharmaceutical Sciences Graduate School of Pharmaceutical Sciences (Committee Chair) (Committee Member) ________________________________ _____________________________ Patrick T. Flaherty, Ph. D. Kevin Tidgewell, Ph. D. Associate Professor of Medicinal Chemistry, Assistant Professor of Medicinal Chemistry Graduate School of Pharmaceutical Sciences Graduate School of Pharmaceutical Sciences (Committee Member) (Committee Member) ________________________________ ________________________________ Lauren O'Donnell, Ph. D. J. Douglas Bricker, Ph. D. Associate Professor of Pharmacology Dean, School of Pharmacy and Graduate School of School of Pharmacy and Graduate School of Pharmaceutical Sciences Pharmaceutical Sciences (Committee Member) _______________________________ James K Drennen III, Ph. D. Associate Dean, Research and Graduate Programs, Graduate School of Pharmaceutical Sciences iii ABSTRACT TARGET BASED DESIGN AND SYNTHESIS OF FUSED PYRIMIDINES IN THE POTENTIAL TREATMENT OF CANCER AND OPPORTUNISTIC INFECTION By Khushbu Shah December 2017 Dissertation supervised by Dr. Aleem Gangjee This dissertation describes an introduction, background and research progress in the areas of agents designed as (a) selective Pneumocystis jirovecii dihydrofolate reductase (pjDHFR) inhibitors for pneumocystis pneumonia (PCP) infection; (b) inhibitors of microtubule polymerization and multiple receptor tyrosine kinase (RTK) for potential treatment of cancer; and (c) substrates for tumor-targeted therapy for cancer. PCP is a host species-specific infection. Most of the drugs, synthesized and evaluated so far, have been tested against Pneumocystis carinii dihydrofolate reductase (the causative organism in rats), which would not necessarily be effective against pjDHFR (the causative organism in humans). Trimethoprim-sulfamethoxazole (TMP-SMX) combination, which has been used for PCP for decades, has major limitations due to low inhibitory potency of TMP, side-effects of SMX and emergence of resistant strains iv expressing mutated dihydropteroate synthase enzyme (target of SMX). For patients unresponsive or resistant to this treatment, newer drugs are critically needed. The absence of an X-ray crystal structure of pjDHFR poses a large gap in drug discovery efforts. The status quo, as it pertains to designing selective inhibitors for an enzyme, is to exploit the amino acid differences between the active sites of the desired and undesired target enzyme. Structure based design, using a pjDHFR homology model and through identification of amino acid differences between pjDHFR and hDHFR active sites, has been presented in the text. Novel synthetic strategies were developed for efficient synthesis of 6- and 7- substituted 5-methyl-pyrrolo[2,3-d]pyrimidine-2,4-diamines, N6-substituted pyrido[3,2- d]pyrimidine-2,4,6-triamines, 6-(arylthio)pyrido[3,2-d]pyrimidine-2,4-diamines and 7- (arylthio)pyrido[3,2-d]pyrimidine-2,4-diamines. In cancer chemotherapy, the two major limitations are the dose-limiting toxicities of clinically used agents and development of resistant to the treatment. Combination chemotherapy with antiangiogenic agents and microtubule targeting agents has shown an advantage against both these drawbacks. Single agents with both antiangiogenic activity and cytotoxicity would afford a therapy that circumvents pharmacokinetic problems of multiple agents, avoids drug-drug interactions, lowers the drug dose, decrease overlapping toxicities, and delays or prevents tumor cell resistance. The work in this dissertation discusses the development of fused pyrimidines, aimed to inhibit tubulin polymerization as well as act as antiangiogenic agents which inhibit one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), platelet derived growth factor receptor-β (PDGFRβ) and epidermal growth factor receptor (EGFR), using molecular modeling studies. This work also reviews the synthesis pyrrolo[3,2- v d]pyrimidines and thieno[3,2-d]pyrimidines and discusses novel synthetic strategies for substituted pyrrolo[3,2-d]pyrimidines and thieno[3,2-d]pyrimidines. Cancer cells transport folates through reduced folate carrier (RFC), Proton-Coupled Folate Transporter (PCFT) and/or Folate receptors (FR). Among several targeting strategies for cancer cells, selectively targeting through PCFT and FRs, over RFC have been successfully investigated. The next valid step in the field is to carry out a structure based design of agents to gain selectivity for PCFT and/or FRs transport over RFC and thus avoid dose-limiting toxicities. Absence of X-ray crystal structures for PCFT and RFC make this step impossible. The work in this dissertation discusses our efforts to fulfil this gap in the literature by developing a 3D QSAR pharmacophore for PCFT and RFC. PMX, the most widely used antifolate has three disadvantages: (i) transport by RFC; (ii) dependence on its polyglutamylation for potency; and (iii) development of resistance due to mutagenesis in the target enzyme (thymidylate synthase). This dissertation focuses on development of substituted-pyrrolo[3,2-d]pyrimidines to combat the above-mentioned drawbacks of PMX, using the X-ray crystal structures of intracellular targets and transporters and using the basic principles of scaffold hopping and bioisosteric replacements. The work described herein discusses our efforts to obtain agents with inhibition of two or more intracellular targets to inhibit de novo purine biosynthesis. Synthetic efforts for the development of pyrrolo[3,2-d]pyrimidines with different linkers and aryl substitutions have been discussed. vi Dedicated to my parents vii ACKNOWLEDGEMENT I sincerely thank Dr. Aleem Gangjee for giving me the opportunity to pursue research in his laboratory, for his constant support and guidance over the last five years. His advice and patience, throughout my term here, have been critical. He has been more than supportive in my quest to pursue new research strategies and extracurricular assignments. I will forever be indebted to him for all the scientific and life lessons that I have learnt from him. I would like to thank my committee members: Dr. Marc Harrold, Dr. Patrick Flaherty, Dr. Kevin Tidgewell and Dr. Lauren O’Donnell for their guidance and support. I would especially like to thank Dr. David Lapinsky, Dr. Kevin Tidgewell and Dr. Lauren O’Donnell for continuously encouraging me during stressful times. I would also like to express my gratitude to Dr. Jelena Janjic and Dr. Khalid Kamal who served as a major source of inspiration to me. I would like to thank Dr. James Drennen and the Graduate School of Pharmaceutical Sciences for the constant support which has aided me in accomplishing my research, travelling to conferences and developing my overall persona as an independent researcher. I would like to thank Arpit, Priya, Manasa, Mohit, Rishabh, Shruti, Sudhir and Suravi for joining me in creating beautiful ever-lasting memories in Pittsburgh. None of the research work at Graduate School of Pharmaceutical Sciences is possible without Jackie Farrer, Mary Caruso and Deborah Wilson. I would especially thank Nancy Hosni for playing multiple roles- an administrative assistant, a friend, a colleague and source of constant encouragement. viii Center of Teaching Excellence (CTE) and Ms. Diane Rhodes have been instrumental in helping me develop as a teaching assistant and I would like to thank them for enabling me to fulfil my goals. I would also like to express gratitude to entire committee of the Women in Science at Duquesne University for inviting me to contribute to their mission. My parents have been amazing role models, who have encouraged me to be independent and confident. Along with them, I would like to thank my brother, Chaitanya for being my pillar of strength. Finally, I would express gratitude to my husband, Saurabh for his unconditional love, unwavering support and his innumerable sacrifices.

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