Small-molecule inhibitors of tubulin polymerization as vascular disrupting agents and prodrugs targeting tumor-associated hypoxia.
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Shi, Zhe, 1988-
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The tumor microenvironment provides a number of promising targets for selective treatment with anticancer agents. Aberrant tumor-associated neovascularization offers one such targeting opportunity. Compounds referred to as vascular disrupting agents (VDAs) cause morphological changes in endothelial cells lining tumor-associated vasculature leading to selective and irreversible reduction in blood flow thus starving tumors of necessary oxygen and nutrients, ultimately culminating in necrosis. Combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are natural products derived from the South African tree Combretum caffrum that inhibit tubulin polymerization and demonstrate dual mechanism of action functioning both as antiproliferative agents and separately as VDAs. Inspired by the molecular architecture of colchicine and the combretastatin family of natural products, several 2-aryl-3-aryol-indole analogues were designed and synthesized to further enhance structure activity relationship considerations around our previously discovered lead indole-based anticancer agent, OXi8006. These indole analogues were evaluated for their ability to inhibit tubulin assembly and for their cytotoxicity against several human cancer cell lines. An amino analogue showed a comparable inhibition of tubulin assembly (IC50 = 0.83 µM) to the reference compound OXi8006. In addition to the synthesis of new analogues and prodrugs, a mechanistic study related to the formation of a key intermediate (2-arylindole) was also carried out utilizing a 13C-labeled molecule. A wide variety of solid tumor cancers are characterized by profound regions of hypoxia, which provides a unique opportunity for targeted cancer therapy. A promising strategy involves the hypoxia-selective release of potent anticancer agents facilitated through reductase-mediated cleavage of non-toxic bioreductively activatable prodrug conjugates (BAPCs). A series of BAPCs were synthesized that incorporate parent anticancer agents OXi8006 (indole), OXi6196 (dihydronaphthalene), and KGP18 (benzosuberene) that incorporate a variety of nitro-bearing heteroaromatic triggers. The cytotoxicity of these BAPCs was evaluated under both normoxic and hypoxic conditions to determine their hypoxia cytotoxicity ratio (HCR). Several of these BAPCs demonstrated promising HCR values (>7) in the A549 lung cancer cell line. The most promising BAPC (OXi6196-monomethylthiophene trigger) demonstrated anti-vascular activity in a preliminary in vivo study in an orthotopic syngeneic breast tumor mouse model (4T1/BALB/c), as evidenced through bioluminescence imaging (BLI) and histology.