Efficient synthetic methodology for the construction of dihydronaphthalene and benzosuberene molecular scaffolds and structure guided design, synthesis and biological evaluation of novel benzosuberene analogues as inhibitors of tubulin polymerization.
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Niu, Haichan, 1989-
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One promising approach towards cancer treatment involves the use of small-molecule therapeutic agents that selectively disrupt tumor-associated vasculature. These molecules are referred to as vascular disrupting agents (VDAs), and are mechanistically distinct from the well-studied angiogenesis inhibiting agents (AIAs). An established sub-set of VDAs function as inhibitors of tubulin polymerization, which bind to the colchicine binding site on the beta-subunit of heterodimeric tubulin, and interfere with the dynamics inherent to the tubulin-microtubule protein system. This protein system is a key component of the cytoskeleton associated with eukaryotic cells, and provides structural integrity to the endothelial cells that line vasculature. Tumor-associated vasculature is primitive and chaotic due to rapid growth and lack of remodeling and thus is unique in comparison to vasculature associated with healthy tissue. Tumors larger than 3 mm3 require their own vasculature for the supply of oxygen and nutrients, and endothelial cell morphology changes and internal structural collapse caused by microtubule depolymerization can shut down blood flow to tumors, eventually leading to necrosis. The inherent structure differences between tumor-associated vasculature and vasculature associated with healthy tissue makes it a viable approach for selective targeting. Several natural products which are potent inhibitors of tubulin polymerization include combretastatin A-1 (CA1), combretastatin A-4 (CA4), and colchicine. CA1, CA4 and their corresponding water-soluble phosphate prodrug salts, CA1P and CA4P, respectively, have shown positive results in clinical trials, although colchicine was withdrawn years ago as an anti-cancer agent due to its high toxicity to humans. A variety of structural attributes associated with these natural products inspired the Pinney Research Group at Baylor University to develop a variety of compounds as inhibitors of tubulin polymerization. One of the lead compounds is a benzosuberene-based analogue (referred to as KGP18) that is a strong inhibitor of tubulin polymerization, demonstrates profound cytotoxicity against human cancer cell lines, and is highly effective as a VDA (based on preliminary in vivo assessment in mouse models). Twenty-two newly designed and synthesized benzosuberene analogues have been biologically evaluated for their ability to inhibit tubulin assembly, as well as for their cytotoxicity against human cancer cell lines (SK-OV-3, NCI-H460, and DU-145). This was accomplished through collaborative studies to expand known structure activity relationship (SAR) considerations for the benzosuberene and dihydronaphthalene classes of compounds and to investigate efficacy associated with structural and functional group modifications.