Discovery and development of unique small molecule chromene based ligands and combretastatin analogs as potential second generation vascular disrupting agents towards cancer chemotherapy.

Includes bibliographical references (p. 299-309).Cancer is a devastating disease, which remains one of the leading causes of death worldwide. In our continuing quest to help find a cure for cancer, we have discovered and developed new small molecule vascular disrupting agents also known as VDAs for the treatment of cancer. Vascular disrupting agents, by definition, cause a rapid collapse in tumor blood flow, and an effective agent will cause a prolonged period of vascular shutdown, culminating in extensive tumor cell necrosis. The possibility of targeting a tumor's vasculature using small molecule VDAs is currently under active investigation and lead compounds, like combretastatin-A4P, combretastatin-A1P, AC7700 and ZD6126 are in clinical trials for the treatment of cancer, here in the US and in the UK. In this study, a small library of thirteen unique chromenes have been synthesized and evaluated for their anti-cancer efficacy against a panel of human cancer cell lines, and against the P388 mouse leukemia cell line. The inhibition of tubulin assembly data has also been obtained for some of the compounds. Two of the chromenes synthesized show remarkable cytotoxicity (GI50 values) against prostate, lung, CNS-Giobl, and breast adenocarcinoma cancer cell lines. Their ED50 values against the P388 cancer cell line are better than one of the lead compounds combretastatin-A1 (CA-1). In addition, one of these compounds has an IC50 value of 2-4 µM which is comparable to that of bench lead compounds. This compound, therefore, has the potential for further development as a clinical candidate for the treatment of cancer. Further, combretastatin-A4 (CA-4) and CA-1 analogs have been synthesized and their biological activity has been evaluated. Collaborative research efforts (as a member of a research team of the Pinney laboratory) for the synthesis of a dihydronaphthalene analog, trouble shooting in a project centered on the synthesis of a precursor of CA-1 which would ultimately be suitable for radiolabeling, and a scaling up project of OXi8007 were also undertaken. OXi8007 is now in advanced preclinical development for the treatment of cancer and ophthalmology studies. A significant attempt has also been undertaken for the total synthesis of ZD6126 phenol whose phosphate prodrug was recently evaluated in clinical trials for the treatment of cancer. ZD6126 is currently prepared by semi-synthesis starting from colchicine.by Phyllis Arthasery.Ph.D