Graduation Date

Spring 5-8-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Paul C. Trippier

Abstract

Several appealing strategies emerged for selective anticancer therapy. Mitochondrial respiratory complex II (CII) is a potential target for many human diseases, including cancer. We have designed, synthesized, and characterized a library of potent CII inhibitors atpenin A5 and diazoxide analogs with enhanced ‘drug-likeness’ and evaluated their antineoplastic activity. Several of these derivatives showed greater activity and selectivity to inhibit the CII. Design aspects of lead derivatives (16c) include optimum ligand lipophilicity efficiency of >5, and half-life of >3 hours. This derivative displayed potent and selective inhibition of cell proliferation in both multiple human prostate cancer cell lines and reactive stromal cells in a dose-dependent manner which maybe a novel therapeutic strategy which can confer significant benefit to patients. Also, several diazoxide derivatives displayed potent and selective inhibition of cell proliferation in triple-negative breast cancer MDA-MB-468 cells.

Antiangiogenesis drugs play a beneficial role in cancer treatment. Inhibition of vascular endothelial growth factor (VEGF) is one of the significant targets in tumor angiogenesis. Suppressing vascular permeability in tumor cells leads to inhibition of tumor growth by locking the survival factor that delivers the oxygen and nutrients to the tumors. We have designed and synthesized a library of potent VEGF inhibitors that had potency to inhibit the HUVEC-VEGF treated cells.

Inhibition of specific carbonic anhydrases (CA) enzymes emerged as a new strategy for anticancer therapy. The CA isoforms IX and XII were known to be overexpressed in various human solid tumors and play a critical role in regulating tumor acidification, proliferation, and progression. Series of novel sulfonamides containing coumarin moieties were synthesized as potent CA inhibitors. These compounds would be able to selectively target the tumor-associated CA IX and CA XII with high inhibition activity. Several of these compounds have anticancer activity against the MDA-MB-468 cells.

The current dissertation emphasizes on the synthesis and evaluation of novel compounds that inhibit CII, VEGF, and CA as anticancer agents. I envision that further studies will lead to the optimization of the structure-activity relationship of these new derivatives and recognize molecular and signaling pathways that could further result in the outcome of anticancer therapy.

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