Synthesis of 2,4,6-Substituted Pyrrolo[2,3-D]Pyrimidines As Potential Anticancer Agents Si Yang

Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Fall 12-1-2017 Synthesis of 2,4,6-Substituted Pyrrolo[2,3-d]pyrimidines as Potential Anticancer Agents Si Yang Follow this and additional works at: https://dsc.duq.edu/etd Part of the Medicinal and Pharmaceutical Chemistry Commons, Natural Products Chemistry and Pharmacognosy Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, and the Pharmaceutics and Drug Design Commons Recommended Citation Yang, S. (2017). Synthesis of 2,4,6-Substituted Pyrrolo[2,3-d]pyrimidines as Potential Anticancer Agents (Master's thesis, Duquesne University). Retrieved from https://dsc.duq.edu/etd/225 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]. SYNTHESIS OF 2,4,6-SUBSTITUTED PYRROLO[2,3-d] PYRIMIDINES AS POTENTIAL ANTICANCER AGENTS A Thesis Submitted to the Graduate School of Pharmaceutical Sciences Duquesne University In partial fulfillment of the requirements for the degree of Master of Science By Si Yang December 2017 Copyright by Si Yang 2017 SYNTHESIS OF 2,4,6-SUBSTITUTED PYRROLO[2,3-d] PYRIMIDINES AS POTENTIAL ANTICANCER AGENTS By Si Yang Approved November 16th, 2017 ________________________________ ________________________________ Aleem Gangjee Marc W. Harrold Professor of Medicinal Chemistry Professor of Medicinal Chemistry (Committee Chair) (Committee Member) ________________________________ Patrick Flaherty Assistant Professor of Medicinal Chemistry (Committee Member) iii ABSTRACT SYNTHESIS OF 2,4,6-SUBSTITUTED PYRROLO[2,3-d] PYRIMIDINES AS POTENTIAL ANTICANCER AGENTS By Si Yang December 2017 Thesis supervised by Professor Aleem Gangjee More and more people are suffering from cancers. Scientists have been putting so much effort to wish find a solution which can defeat tumor cells. As analogs of folic acid which is essential for human being life, antifolates are currently clinically used for cancer chemotherapy. Under the guidance of Professor Aleem Gangjee, I had been focusing on synthesizing a series of pyrrolo[2,3-d]pyrimidines to investigate its inhibitory potency against tumor cells over normal tissues during my Master degree in Duquesne University. This thesis will focus on the introduction of the background and work have been done in the areas of antifolates development, such as folate function, its three uptake mechanisms inside human cells, antifolates’ role in chemotherapy, et. al. In addition, the Structure-Activity-Relationship design rationale for the series of antifolates will also be iv discussed. Nevertheless, the details of synthesizing these pyrrolo[2,3-d]pyrimidines as potential antifolates have been described, including chemistry reviews on the pyrrolo[2,3- d]pyrimidine scaffold, and the challenges encountered and the solutions how to solve or improve in order to achieve better yield. In this study, sixty new compounds have been synthesized and ten antifolates have been sent for biological evaluation. v DEDICATION Dedicated To My Family For Their Love And Support vi ACKNOWLEDGEMENT I would like to thank all the people who have helped me to make this work done. Especially, I’ll give my most appreciation to Dr. Aleem Gangjee, my supervisor. Without his help, support and guidance, I could not have made this thesis possible. Not only his enthusiastic passion on scientific research that set a good example for me, but also his support both financially and in spirit. I would like to thank all my thesis committee members: Drs. Marc W. Harrold, Patrick Flaherty, and Aleem Gangjee for their academic and knowledge support. Also, I want to acknowledge Dr Larry H. Matherly at the Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine for his cooperation on research. I would like to express my sincere appreciation to Dr. James Drennen for his thoughtfulness and kindness during my master degree at Duquesne University. As a Dean, he tried his best to help me. I wish to thank Nancy Hosni and Jackie Farrer for their help at all time. In the end, I want to give my great appreciation to my family for their love and support. vii TABLE OF CONTENTS Page Abstract .............................................................................................................................. iv Dedication .......................................................................................................................... vi Acknowledgement ............................................................................................................ vii List of Tables ..................................................................................................................... ix List of Figures ......................................................................................................................x List of Schemes ................................................................................................................. xii List of Abbreviations .........................................................................................................xv I. Biochemical Review .........................................................................................................1 II. Chemical Review ..........................................................................................................45 III. Statement of The Problem ...........................................................................................67 IV. Chemical Discussion ...................................................................................................79 V. Summary .......................................................................................................................95 VI. Experimental ................................................................................................................96 Bibliography ....................................................................................................................127 Appendix 1 .......................................................................................................................159 Appendix 2 .......................................................................................................................168 Appendix 3 .......................................................................................................................174 viii LIST OF TABLES Page Table 1 Pyrimidines as GARFTase Inhibito ..................................................................42 Table 2 IC50’s (in nM) for 6-substituted pyrrrolo[2,3-d]pyrimidine thienoyl antifolates 3-4, and analogs with fused aromatic side chain 135-138 and Classical Antifolates in hRFC, hPCFT, and FR-Expressing Cell Lines ..........................165 Table 2 IC50’s (in nM) for 6-substituted pyrrrolo[2,3-d]pyrimidine phenyl antifolates 2 and analogs with naphthoic ring as side chain 139, 140 and Classical Antifolates in hRFC, hPCFT, and FR-Expressing Cell Lines ..........................166 Table 4 IC50’s (in nM) for 6-substituted pyrrrolo[2,3-d]pyrimidine thienoyl antifolates 3-4, and analogs with amino acid modification 141-144 and Classical Antifolates in hRFC, hPCFT, and FR-Expressing Cell Lines ..........................167 ix LIST OF FIGURES Page Figure 1 Structure of folic acid .........................................................................................1 Figure 2 Structure of classical folates ...............................................................................2 Figure 3 Cellular folate metabolism in the cytosol and mitochondria ..............................4 Figure 4 Representative examples of classical antifolates (and their principal target(s)) .............................................................................................................6 Figure 5 Representative examples of nonclassical antifolates (and their principal target(s)) .............................................................................................................7 Figure 6 Homeostasis of folates and cellular accumulation of antifolates .......................9 Figure 7 Human RFC topology model............................................................................10 Figure 8 Three-dimensional (3D) homology models of human RFC .............................12 Figure 9 Model for trafficking of human folate receptors ..............................................18 Figure 10 Structures of folate receptors depicting states of biological trafficking ...........19 Figure 11 Conformational changes in the hFR ligand binding pocket during states of biological trafficking ........................................................................................20 Figure 12 Crystal structure of FR bound to folic acid ....................................................21 Figure 13 Structural and biochemical analysis of FRa–folic acid interactions ................23 Figure 14 Interaction map of folic acid with ligand-binding-pocket residues ..................25 Figure 15 Schematic structure of human PCFT membrane topology...............................30 Figure 16 De novo Purine Biosynthesis ............................................................................33 Figure 17 Proposed mechanism for GARFTase ...............................................................37

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