Date of Award

12-16-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Dr. Binghe Wang

Second Advisor

Dr. Donald Hamelberg

Third Advisor

Dr. Maged Henary

Abstract

Anthraquinone Project

Previously, we reported a class of MDM2-MDM4 dimerization inhibitors that upregulate p53 and showed potent anticancer activity in animal models. However, water solubility hinders their further development. Herein we synthesized a series of anthraquinone analogs for studying the structure-activity relationship, including BW-AQ-238, a potent anthraquinone analog that enables us to develop a prodrug approach to overcome the solubility problem. The prodrugs of BW-AQ-238 were made by esterification of the hydroxyl group with various natural amino acids. Cytotoxicity in Hela and EU-1 cells, aqueous solubility, and the release kinetics of these prodrugs in buffer and in the presence of hydrolytic enzymes were studied. The results demonstrate that the amino acid prodrug approach significantly improved the water solubility while maintaining the potency of the parent drug.

Photosensitizer Project

An aryl furan methylene rhodanine compound BW-PS-105 was found to have potent photo-induced cytotoxicity in MCF-7 breast cancer cell and HeLa cervical carcinoma cell lines. Structure-activity relationship in the efficiency of singlet oxygen generation and photo-induced cytotoxicity was studied by changing the substitution on the phenyl ring. The results indicate significant potential for developing such aryl furan rhodanines for photodynamic therapy.

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