Synthesis and evaluation of nitroheterocyclic phosphoramidates as hypoxia-selective alkylating agents

A series of novel nitroheterocyclic phosphoramidates has been prepared, and the cytotoxicity of these compounds has been evaluated in clonogenic assay s against B16, wild-type and cyclophosphamide-resistant MCF-7, and HT-29 ce lls under aerobic conditions and HT-29 cells under hypoxic conditions. All compounds were comparable in toxicity to wild-type and resistant MCF-7 cell s and were also selectively toxic to HT-29 cells under hypoxic conditions ( selectivity ratios 1.7 to >20). Analogues lacking the nitro group were not cytotoxic. Electron-withdrawing substituents increased cytotoxicity under a erobic conditions and thereby decreased hypoxic selectivity. In contrast, a n electron-donating substituent markedly decreased both aerobic and hypoxic cytotoxicity but enhanced hypoxic selectivity. Chemical reduction of the n itro group resulted in rapid expulsion of the cytotoxic phosphoramide musta rd. The most potent of these compounds show significant cytotoxicity under both aerobic and hypoxic conditions.