David P. Brown

Synthesis and Evaluation of Natural Product Hybrids as New Microtubule-binding Drug Candidates

David P. Brown, St. John’s College of Liberal Arts and Sciences, Department of Chemistry

Abstract
The lack of tumor selectivity of anticancer drugs and the onset of multidrug resistance (mdr) have given momentum to the development of target-specific agents as new classes of cytotoxic compounds with reduced systemic toxicity. Current investigative efforts have been geared towards the development of conjugates of potent antiproliferative agents and polyunsaturated fatty acids (PUFAs) as new microtubule binding drugs (MBDs). PUFAs are ideal as vectors in that they are naturally occurring, are readily incorporated into the lipid bilayer of tumor cells, and have independently exhibited anticancer activity against several cell lines and thus have been evaluated in preclinical and clinical studies. Furthermore, docosahexaenoic acid (DHA), one of the most widely studied PUFA, has been categorized as a nutritional additive by the US Food and Drug Administration (FDA) thus making DHA and its metabolites safe to humans. These PUFA-Drug conjugates by design will target and disrupt one or more of the individual components of the neovascularization process, which may include endothelial cell adhesion, migration, and cell interactions, all of which are involved in tumor neovascularization. The terminal objective of this study is to indentify more target-specific MBDs with greater therapeutic antivascular selectivity relative to their cancer cell cytoxicity.