Synthesis, characterization, and biological evaluation of bioreductively activatable prodrug conjugates (BAPCs) of phenstatin, KGP18, OXi6196, combretastatin A-1, and combretastatin A-4.
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Winn, Blake A., 1986-
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Selective targeting of tumors with anticancer agents represents a universally important strategy to improve efficacy and reduce patient side effects. Targeting tumor-associated hypoxia (low oxygen tension) represents one type of promising therapeutic regimen. Bioreductively activatable prodrug conjugates (BAPCs) are designed to be biologically inert under normoxia, however in hypoxic environments they will selectively release their parent anticancer agent. Inhibitors of tubulin polymerization (assembly) are promising anticancer agents for functionalization as their corresponding BAPCs. Upon hypoxia-selective release, these compounds function biologically as antimitotic agents with a subset demonstrating dual mechanistic capability as potent vascular disrupting agents (VDAs), which selectively damage tumor-associated vasculature leading to enhanced tumor necrosis. Phenstatin, OXi6196, combretastatin A-1(CA1), combretastatin A-4 (CA4), and KGP18 are promising anticancer agents for development as BAPCs. These compounds are effective inhibitors of tubulin assembly and demonstrate potent activity in vitro against human cancer cell lines. Synthetic pathways have been identified for the preparation of nitrothienyl prodrugs of CA1 and CA4 using the nor-methyl, mono-methyl, and gem-dimethyl nitrothiophene-based triggers. A regioselective protecting group strategy was utilized in order to synthesize the nitrothiophene triggers regioselectively to the C-2 and C-3 positions of CA1. Tosyl, isopropyl, and tert-butyldimethylsilyl protecting groups were important in establishing this CA1 regioselectivity. Several series of BAPCs were also developed based on phenstatin, KGP18, and Oxi6196 using nor-methyl, mono-methyl, and gem-dimethyl variants of the nitrothiophene, nitrobenzyl, nitroimidazole, and nitrofuran triggers. A selection of the CA1, CA4, and phenstatin BAPCs were evaluated biologically for their ability to inhibit tubulin assembly as well as their stability in aqueous conditions and their ability to undergo enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase.