| Abstract
| - Nitrobenzyl quaternary salts of nitrogen mustards have been previously reported as hypoxia-selective cytotoxins. In this paper we describe the synthesis and evaluation of a series ofheterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosento cover a range of one-electron reduction potentials (from −277 to −511 mV) and substitutionpatterns. All quaternary salt compounds were less toxic in vitro than mechlorethamine, andall were more toxic under hypoxic than aerobic conditions, although the differentials were highlyvariable within the series. The most promising analogue, imidazole 2, demonstrated DNA cross-linking selectively in hypoxic RIF-1 cells, and was active in vivo in combination with radiationor cisplatin. However, 2 also produced unpredictable toxicity in vivo, suggestive of nonspecificnitrogen mustard release, and this has restricted further development of these compounds ashypoxia-selective cytotoxins.
|
