Novel Approaches Towards The Discovery of Tumor-Selective Histone Deacetylase Inhibitors

Abstract

Novel Approaches Towards The Discovery of Tumor-Selective Histone Deacetylase Inhibitors Idris Raji 229 pages Directed by Dr. Adegboyega K. Oyelere Developing safer and/ or more effective chemotherapeutics has been a long-standing challenge in the drug discovery field. To address these shortcomings, the designed-multiple ligand (DML) and targeted approaches were used to design novel series of histone deacetylase inhibitors (HDACi). Under the DML approach, bifunctional compounds capable of binding to both histone deacetylase and cyclooxygenase enzymes were made. A subset of the bifunctional compounds was significantly less toxic towards healthy cells compared to the US Food Drug and Administration (FDA) approved HDACi, vorinostat, despite their impressive anticancer profiles. On the other hand, the targeted approach was conceptualized to address the lack of efficacy in solid tumors seen with clinically approved HDACi. Two different series of compounds are reported herein as potential interventions in lung cancer and melanoma. In one of the series, clarithromycin- known for its preferential accumulation in lung tissues, was incorporated into the structures of HDACi to generate clarithromycin-targeted HDACi. With the eventual goal of achieving compounds that will preferentially localize in lung cancer tissues, the clarithromycin-targeted HDACi showed very good anticancer profiles in in vitro studies. The second series of compounds generated using the targeted approach are aimed as potential intervention in melanoma. In this approach, a template, known as benzamide, with high affinity for melanin, was incorporated into the design of HDACi. The benzamide compounds obtained showed some promise in melanoma cell lines, and warrant further studies to optimize for potency.