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J Med Chem. 2001 Oct 11;44(21):3511-22.

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

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Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.


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 of heterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosen to cover a range of one-electron reduction potentials (from -277 to -511 mV) and substitution patterns. All quaternary salt compounds were less toxic in vitro than mechlorethamine, and all were more toxic under hypoxic than aerobic conditions, although the differentials were highly variable 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 radiation or cisplatin. However, 2 also produced unpredictable toxicity in vivo, suggestive of nonspecific nitrogen mustard release, and this has restricted further development of these compounds as hypoxia-selective cytotoxins.

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