Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine

Nitrobenzyl quaternary salts of nitrogen mustards have been previously repo rted as hypoxia-selective cytotoxins. In this paper we describe the synthes is and evaluation of a series of heterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosen to cover a range of on e-electron reduction potentials (from -277 to -511 mV) and substitution pat terns. All quaternary salt compounds were less toxic in vitro than mechlore thamine, and all were more toxic under hypoxic than aerobic conditions, alt hough the differentials were highly variable within the series. The most pr omising analogue, imidazole 2, demonstrated DNA crosslinking selectively in hypoxic RIF-1 cells, and was active in vivo in combination with radiation or cisplatin. However, 2 also produced unpredictable toxicity in vivo, sugg estive of nonspecific nitrogen mustard release, and this has restricted fur ther development of these compounds as hypoxia-selective cytotoxins.