Hypoxia-selective nitrobenzyloxycarbonyl derivatives of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines

Some 4- and 2-(nitrobenzyloxycarbonyl)-1,2-bis(methylsulfonyl)-1-(2-chloroe thyl)hydrazines (4, 6, and 7) were synthesized and evaluated for their abil ity to exert preferential toxicity to hypoxic EMT6 mammary carcinoma cells using a colony-forming assay. Of these, the 4,5-dimethoxy-2-nitro analogue 6 (50 mu M, 1-h exposure) caused greater than 3 logs of kill of hypoxic cel ls, with relatively minor toxicity to corresponding aerobic cells. The abil ity of 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues to reach and kil l hypoxic cells of solid tumors was also demonstrated using intradermally i mplanted EMT6 solid tumors in mice. In addition, a possible source of toxic ity to normal tissue, i.e., the activation of the 4-nitrobenzyl derivative 4 by glutathione S-transferase-catalyzed thiolysis, was essentially elimina ted by replacing one of the benzylic methylene protons by a methyl group. T he 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues also appear to be re duced more easily under acidic conditions (pH 6.0) than under neutral condi tions, as measured by differential pulse polarography. Since the pH in hypo xic regions is often lower than that in adjacent aerobic regions, this prop erty should aid in the cytotoxic action of these agents against hypoxic cel ls of solid tumors.