Defense Date

7-9-2019

Graduation Date

Summer 8-10-2019

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Aleem Gangjee

Committee Member

Patrick T. Flaherty

Committee Member

Kevin Tidgewell

Committee Member

Marc W. Harrold

Committee Member

Rehana Leak

Keywords

Single-agents, RTKs, One-carbon metabolism inhibitors, Anti-opportunistic agents, Pyrimidine, Pyridine, Fluorine, Methyl, Tumor-targeted

Abstract

This dissertation describes the design, synthesis and biological evaluation of monocyclic, bicyclic and tricyclic pyrimidine-based heterocycles as a) single agents with combination chemotherapy potential having dual antiangiogenic effects and cytotoxic effects or b) one-carbon metabolism inhibitors for targeted tumor therapy; or c) selective Pneumocystis jirovecii (pj) dihydrofolate reductase (pjDHFR) inhibitors for pneumocystis pneumonia (PCP) infection.

The work in this dissertation is centered on identifying structural features that are necessary for inhibition of tubulin polymerization or thymidylate synthase as well as for inhibition of one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), epidermal growth factor receptor (EGFR) and/or platelet-derived growth factor receptor β (PDGFR- β) in single entities. Single agents with both antiangiogenic activities as well as cytotoxicity (via disruption of microtubule dynamics or thymidylate synthase inhibition) would afford agents that circumvent pharmacokinetic problems of multiple agents, avoid drug-drug interactions, could be used at lower doses to alleviate toxicity, be devoid of overlapping toxicities, and delay or prevent tumor cell resistance.

Synthesis of substituted quinazoline and pyrido[3,2-d]pyrimidines is described. It also reviews the synthesis of multi-transporter (PCFT and FR) selective 5-substituted pyrrolo[2,3-d]/[3,2-d]pyrimidines as targeted one-carbon metabolism enzymes (GARFTase/AICARFTase and/or SHMT2) inhibitors circumventing both dose-limiting toxicity and tumor resistance associated with most prescribed antitumor agents like pemetrexed.

PCP is a host species-specific infection. Current therapies such as 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 expressing mutated dihydropteroate synthase enzyme (target of SMX). For patients unresponsive or resistant to this treatment, newer drugs are critically needed. Structure-based design, using a pjDHFR homology model and through the identification of amino acid differences between pjDHFR and hDHFR active sites, has been presented in the text. Synthesis of proposed 2,4-diaminopyrimidine analogs is presented here.

This dissertation exemplifies the use of various structural features such as a pyridyl ring, fluoro, and methyl groups as high impact medicinal chemistry design tools. The pyridyl ring has been used to introduce both conformational flexibility and restriction, whereas the combined stereoelectronic effects of the pyridyl and fluoro groups are also assessed.

Language

English

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