Defense Date

3-16-2022

Graduation Date

Spring 5-21-2022

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Aleem Gangjee, Ph. D.

Committee Member

Marc W. Harrold, Ph. D.

Committee Member

Patrick T. Flaherty, Ph. D.

Committee Member

Kevin Tidgewell, Ph. D.

Committee Member

Wilson Meng, Ph. D.

Committee Member

Carl A. Anderson, Ph. D.

Committee Member

James K. Drennen III, Ph.D.

Abstract

Dissertation supervised by Dr. Aleem Gangjee

Targeted cancer chemotherapy represents agents that inhibit cancer cell growth by interfering with specific processes that are required for tumor growth. The crucial aim of the treatment administered to cancer patients should be to improve the quality of life and inhibit the progression of the disease. The current failure of conventional cancer chemotherapy is attributed to both toxicities and the development of resistance. There is an unmet need for new cancer therapies of tumor-targeted agents (that work without harming normal cells or tissues) with a low propensity to develop resistance. Multi-targeted single agents with multiple mechanism of actions are particularly relevant to cancer chemotherapy in that they have the potential to overcome dose limiting toxicities and drug resistance.

This dissertation describes an introduction, background, design, synthesis , and biological evaluation in the areas of agents designed as a) selective one-carbon metabolism inhibitors for multi-targeted tumor therapy with 6-substituted thieno[2,3-d]pyrimidine analogs as glycinamide ribonucleotide (GAR) formyltransferase (GARFTase) and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFTase) inhibitors b) single agents with combination chemotherapy potential, with dual antiangiogenic and anti-tubulin effects.

One-carbon metabolism inhibitors have been used for cancer therapy for decades. The clinical efficacy of these currently used agents is limited by a lack of tumor selectivity and the development of drug resistance. Folate is the natural form of water-soluble vitamin B9, and its reduced form (tetrahydrofolate) serves as a 1-carbon (1C) donor which are essential for the synthesis of purine nucleotides and thymidylate. Folates and classical antifolates are ionic compounds which cannot diffuse into cells and must be actively transported. To overcome this limitation, three key transporters of folates and related compounds have evolved in mammalian cells. The ubiquitously expressed reduced folate carrier (RFC) is present in normal and cancer cells and is responsible for the majority transport of cellular folate and antifolate uptake, causes dose-limiting toxicities. Transport of targeted agents via tumor-specific folate receptors (FRα and β) and proton coupled folate transporter (PCFT) over RFC would provide tumor-selectivity and circumvent the dose-limiting toxicities associated with standard antifolate chemotherapy. This report presents the synthesis and structure-activity studies for 6-substituted thieno[2,3-d]pyrimidines to explore the potential of these compounds as multi-targeted tumor selective agents. The biological impact of these novel analogs, including their mechanisms of cellular uptake have been documented, and their intracellular enzyme targets and metabolic effects have been comprehensively established.

Microtubule targeting agents (MTAs) are highly effective agents widely used to treat solid tumors and hematological malignancies; and have become one of the most significant drug classes for cancer chemotherapy. Among MTAs, the colchicine site binding agents are particularly important among the various classes of MTAs, as they circumvent the P-glycoprotein (Pgp) and β-III tubulin isotype mediated clinical resistance. However, no colchicine site binding agents are FDA approved. Angiogenesis is a hallmark of various diseases, especially cancer, as tumors depend on constant nutrients and oxygen to grow. The angiogenic effect is mediated by receptor tyrosine kinases (RTKs) and therefore, RTK inhibitors are widely used in the treatment of various types of cancers. To overcome the limitations of current cancer chemotherapy, namely, dose limiting toxicity and multidrug resistance, novel series of compounds with a purine scaffold were designed, synthesized and evaluated as potential antitumor agents with dual potent microtubule targeting and RTK inhibitory activities.

Molecular modeling studies were performed for the proposed thieno[2,3-d]pyrimidine antifolate analogs, binding modes were generated using X-ray crystal structures of human FRα, FRβ, GARFTase and AICARFTase using an induced-fit docking protocol (Schrödinger LLC) to explore binding interactions and to validate drug targets. To better understand the binding modes of the novel designed purine compounds as dual anti-tubulin and RTK inhibitors, molecular modeling studies were performed in the X-ray crystal structure of tubulin at the colchicine site, and in the crystal structure of VEGFR-2, EGFR and the homology model of PDGFR-β, respectively.

Language

English

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