title: Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine.
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 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.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. m.tercel@auckland.ac.nz
authors.forename: M
authors.initials: M
authors.lastname: Tercel
authors.forename: A E
authors.initials: AE
authors.lastname: Lee
authors.forename: A
authors.initials: A
authors.lastname: Hogg
authors.forename: R F
authors.initials: RF
authors.lastname: Anderson
authors.forename: H H
authors.initials: HH
authors.lastname: Lee
authors.forename: B G
authors.initials: BG
authors.lastname: Siim
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D020552:Comet Assay; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D020714:Maximum Tolerated Dose; D051379:Mice; D009368:Neoplasm Transplantation; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D007093:Imidazoles; C438595:N,N-bis(2-chloroethyl)-N-methyl-N-((1-methyl-4-nitro-5-imidazolyl)methyl)ammonium chloride; D009574:Nitro Compounds; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; D000644:Quaternary Ammonium Compounds; D004247:DNA