Design and Synthesis of Benzosuberene Analogs as Potential Inhibitors of Tubulin Polymerization




Pettus, Kellen

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The natural products colchicine and combretastatin A-4 (CA4) both function as potent inhibitors of tubulin polymerization and have provided universal inspiration for a wide-range of structurally diverse small-molecule derivatives and analogs. A series of fused aryl-cycloalkyl and aryl-heterocyclic compounds were designed and synthesized by the Pinney Group with the goal of expanding structure-activity relationship considerations associated with the colchicine binding site on the tubulin heterodimer. Benzosuberene-based analogs represent one class of molecules that bear structural similarity to colchicine and CA4. A sub-set of these molecules demonstrated binding to the colchicine site and subsequent inhibition of tubulin polymerization. Exemplary within this class of molecules is a benzosuberene analog referred to as KGP18, which proved to be profoundly cytotoxic (low pM range) against a variety of human cancer cell lines (collaboration with the Trawick Laboratory). KGP18 (akin to CA4) further functioned as a proficient vascular disrupting agent (VDA), imparting selective, and presumably irreversible damage to tumor-associated vasculature in a mouse model of human cancer (collaboration with the Mason Laboratory, UT Southwestern). This current study is focused on the synthesis of a variety of KGP18 analogs designed to further investigate functional group diversity around the benzosuberene molecular core. One example of an on-going synthetic target includes a chalcone-like benzosuberene-based molecule bearing two iodo groups flanking a single methoxy moiety on the pendant aryl ring. These iodine atoms replace methoxy groups (present in KGP18) and their incorporation will allow us to investigate both structural and electronic implications in regard to colchicine site binding.



Small Molecule Inhibitors of Tubulin Polymerization Targeted for the Colchicine Binding Site in Cancer Cells