Defense Date

8-30-2017

Graduation Date

Fall 1-1-2017

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

David J. Lapinsky

Committee Member

Kevin Tidgewell

Committee Member

Rehana Leak

Committee Member

J. Douglas Bricker

Abstract

Dose limiting toxicity and development of multidrug resistance by the tumors are the major limitations of current cancer chemotherapy. Microtubule targeting agents (MTAs) are a structurally diverse set of compounds that disrupt microtubule dynamics and exert their anticancer effect. Among the various classes of such agents, the colchicine site binding agents are particularly important as they circumvent the Pgp and β-III tubulin mediated clinical resistance. These resistance mechanisms, when manifested, are a major reason for the failure of clinically used agents such as taxanes and vinca alkaloids. A series of monocyclic pyrimidine analogs were designed and synthesized as colchicine site binding agents to overcome Pgp and β-III tubulin meditaed drug resistance.
Multitargeted single agents with dual mechanism of actions, containing both cytostatic and cyotoxic components are particularly relevant to cancer chemotherapy as they have the potential to overcome multidrug resistance and dose limiting toxicities. Antiangiogenic agents target tumor angiogenesis, an important phenomenon for tumor growth and metastasis. The angiogenic effect is mediated by receptor tyrosine kinases (RTKs) and therefore, RTK inhibitors are used widely in the treatment of various types of cancers. To overcome the limitations of current cancer chemotherapy namely, dose limiting toxicity and multidrug resistance, quinazolines were designed and synthesized as dual acting MTA and RTK inhibitors.
Toll-like receptors (TLRs) are key mediators in regulating the inflammatory response. Currently, more than 50 clinical trails of TLR agonists in the treatment of cancer are being conducted, either alone or in combination. Multitargeted single agents with dual acting MTA and TLR agonist (2,5-diaminoquinolines) were designed and synthesized as potential anticancer agents. A major part of this project covers the Pd-catalyzed cross coupling reaction optimization on the 2,5-diaminoquinolines including mechanistic details of the coupling reaction.
Opportunistic infection by Pneumocystis jirovecii in immunocompromised patients such as organ transplant, cancer and AIDS patients is associated with high mortality. The current treatment involving the use of a combination of trimethoprim and sulfamethoxazole is limited by drug resistance, treatment failures and adverse side effects. 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. Incorporating the key differences in the active site residues in pjDHFR and hDHFR, thieno[2,3-d]pyrimidines were designed and synthesized as selective pjDHFR inhibitors.
In addition, molecular modeling studies were performed on a series of pyrimido[4,5-b]indoles and cyclopenta[d]pyrimidines to explain their observed in vitro biological activities. Molecular modeling studies were also performed on a series of furo[2,3-d]pyrimidines and pyrrolo[3,2-d]pyrimidines to explain their biological activities on multiple targets (colchicine site of tubulin and multiple RTKs).

Language

English

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