Design, synthesis, biochemical and biological evaluation of benzocyclic and enediyne analogs of combretastatins as potential tubulin binding ligands in the treatment of cancer.

Abstract

One out of four deaths per day in the United States will be caused by cancer in the year 2007. Cancer still remains the second major cause of mortality both in developed as well as developing countries. Small molecule vascular disrupting agents (VDAs) selectively damage the rapidly proliferating tumor vasculature resulting in hypoxia and eventual necrosis. Examples of VDAs currently in clinical development include CA4P, Oxi4503, and AVE8062. Certain VDAs such as CA4P bind to tubulin (following the conversion of CA4P to CA4) at the colchicine binding site, and cause cytoskeletal disruption of the endothelial cells lining the vasculature in the tumor microenvironment. Based on SAR studies, we have designed a series of novel molecules that bear structural resemblance to certain of the combretastatins, displaying the 1, 2-diarylethene and biaryl scaffold respectively. The synthetic ligands designed also include structural features bearing benzocyclic moieties such as indanes, dihydronapthalenes, benzosuberenes and benzocyclo-octanes. The benzocyclic analogs were synthesized and analyzed for their ability to inhibit microtubule polymerization as well as inhibition of growth in selected human cancer cell lines in vitro. Anti-tumor antibiotics such as calicheamycins, comprise enediyne as one of the pharrmacophores which undergoes Bergman cyclization to generate bi-radicals that damage DNA and cause apoptosis. A series of enediyne and ketodiyne analogs bearing combretastatin structural scaffolds were also designed. The enediyne and ketodiyne analogs were designed from the speculation of their dual activity in both DNA intercalation and vascular disruption. Only one such analog was synthesized and analyzed for it ability to inhibit tubulin polymerization. Protocol for the synthesis of radiolabelled prodrug of CA1 (OX16C) was also carried out successfully as a team effort. The trans-analog of OX16C was also synthesized for the purpose of comparative biological studies between the cis- and trans-isomers of CA1 prodrug. The synthesis of both cis- and trans-OX16C were performed following previously established procedures.