A significant number of solid tumor cancers are characterized by pronounced regions of hypoxia, which provide an opportunity for targeted therapies. One such therapeutic strategy utilizes highly cytotoxic small-molecule anticancer agents or vascular disrupting agents (VDAs), which are synthesized as their corresponding bioreductively activatable prodrug conjugates (BAPCs). Ideally, the BAPC remains structurally intact and non-cytotoxic until it reaches areas of tumor hypoxia in which reductase enzymes such as NADPH cytochrome P450 oxidoreductase cleave the prodrug portion of the conjugate thus releasing the cytotoxic anticancer agent or VDA site-specific to the tumor or tumor microenvironment. The natural products combretastatin A-4 (CA4) and combretastatin A-1 (CA1), originally discovered by Professor George R. Pettit (Arizona State University), have shown significant promise in the clinical trials as VDAs. A gem-dimethylnitrothienyl BAPC of CA4 (previously prepared by Peter Davis and co-workers) demonstrated the ability to release CA4 from A549 cells under hypoxic conditions. Inspired by this work, a series of nitrothiophene-based BAPCs of CA1 were designed for chemical synthesis. The efficacy of these BAPCs will initially be evaluated by determining their differential cytotoxicity under normoxia versus hypoxia in selected human cancer cell lines. The most active BAPCs are candidates for future in vivo evaluation in mice bearing tumors with profound regions of hypoxia.

Bioreductively activatable prodrug conjugates (BAPCs) of combretastatin A-1 (CA1) as anticancer agents targeted towards tumor hypoxia

247th National Meeting (2014)

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