Defense Date

8-31-2020

Graduation Date

Fall 12-18-2020

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Aleem Gangjee

Committee Member

Marc W. Harrold

Committee Member

Patrick T. Flaherty

Committee Member

Kevin J. Tidgewell

Committee Member

David Johnson

Keywords

DHFR Folate Transport Microtubule Targeting Agents Pneumocystis Pneumonia Pyrazolo[4, 3-d]pyrimidines Thieno[2, 3-d]pyrimidines

Abstract

Dose-limiting toxicities of clinically used agents and development of resistance are two significant limitations in cancer chemotherapy. Microtubule targeting agents (MTAs) are a structurally diverse set of compounds that disrupt microtubule dynamics and exert their anticancer effect. Combination chemotherapy with antiangiogenic agents and microtubule targeting agents has shown an advantage against both these drawbacks. Single agents with dual antiangiogenic activity and cytotoxicity would afford a therapy that circumvents pharmacokinetic problems of multiple agents, avoid drug-drug interactions, lower the drug dose, decrease overlapping toxicities, and delay or prevent tumor cell resistance. The work in this dissertation reflects the progress 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 of bicyclic and tricyclic thieno[2,3-d]pyrimidines and pyrazolo[4,3-d]pyrimidines and discusses novel synthetic strategies for substituted thieno[2,3-d]pyrimidines and pyrazolo[4,3-d]pyrimidines.

Pneumocystis pneumonia (PCP) is a form of pneumonia that is caused by the yeast-like fungus Pneumocystis jirovecii. The current treatment involving the use of a combination of trimethoprim and sulfamethoxazole is limited by drug resistance, treatment failures and adverse side effects. Newer drugs are critically needed for patients, unresponsive or resistant to this treatment. Dihydrofolate reductase (DHFR) is an essential enzyme that provides folate cofactor for DNA, RNA, and methionine biosynthesis. Hence, selectively inhibiting pjDHFR is an important strategy for effective treatment of infection by the pathogen. Structure-based design, using pjDHFR homology model and through the 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-(arylthio)pyrido[2,3-d]pyrimidine-2,4-diamines.

Three specialized folate transport systems exist in mammalian cells that include the reduced folate carrier (RFC), folate receptors (FRs) α and β, and the proton-coupled folate transporter (PCFT). Among several targeting strategies for cancer cells, selectively targeting through PCFT and FRs, over RFC have been successfully investigated. To avoid dose-limiting toxicities, the next valid step in the field is to carry out a structure-based drug design to gain selectivity for PCFT and/or FRs transport over RFC. Drug discoveries in these areas become challenging in the absence of X-ray crystal structures 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 the development of substituted-pyrazolo[4,3-d]pyrimidines and pyrrolo[2,3-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 pyrazolo[4,3-d]pyrimidines with different linkers have been discussed.

Language

English

Additional Citations

Golani, L. K.; Islam, F.; O' Connor, C.; Dekhne, A. S.; Hou, Z.; Matherly, L. H.; Gangjee, A. Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier. Bioorg. Med. Chem., 2020, 28, 115544.

Available for download on Saturday, December 18, 2021

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