Design, Synthesis, and Biological Evaluation of Novel Benzosuberene Analogues as Potential Cancer Therapeutic Agents




Goddard, Tyler

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Microtubules play an important structural role in the endothelial cells lining tumor vasculature. This vasculature is distinct from that of healthy cells and characterized as immature and chaotic, making it an attractive target for anti-cancer therapy. Small molecule anti-cancer agents known as vascular disrupting agents (VDAs) have the ability to starve tumors of the oxygen and nutrients necessary for their survival and proliferation. Benzosuberene analogues, structurally based in part on the natural products combretastatin A-4 (CA4) and colchicine, bind to the colchicine site on beta tubulin, inhibit the formation of microtubules, and thus function as cytotoxic, antiproliferative agents. Four new analogues of KGP18, the lead benzosuberene based anti-cancer agent, were designed and prepared by chemical synthesis to extend the structure-activity relationship of the benzosuberene class of compounds. Structural modifications incorporated into these analogues include functional group diversity at the 1-position and 2-position on the 6:7 fused ring system, as well as functional group translocations on the pendant aryl ring. All four new benzosuberene analogues were evaluated for their ability to inhibit tubulin assembly and for their cytotoxicity against three different human cancer cell lines. Encouragingly, one of the new analogues strongly inhibited the polymerization of tubulin (IC50 of 1.2 μM), consistent with the activity of the natural product CA4. Although none of the new analogues demonstrated cytotoxicity as pronounced as that of KGP18, their synthesis and biological evaluation will facilitate the design of more potent benzosuberene based compounds in the future.