title: Nitroimidazole-based "extruded mustards' designed as reductively activated hypoxia-selective cytotoxins.
abstract: A new class of nitroimidazole alkanoic acid amides, designed to extrude para-aminophenyl mustard (3a) by intramolecular cyclization following reduction of the nitro group, have been prepared and evaluated for their ability to function as bioreductively activated prodrugs. The mechanism of activation following (bio) reduction was studied using the model compounds (8a-e, 18 and 23a,b) and the related mustard analogues (11a-c and 26a,b). However, the reduced forms of these compounds were found to be relatively stable and not susceptible to intramolecular cyclization. This is in contrast to the corresponding 2-nitrophenylalkyl amides, where the hydroxylamino or amino reduction products (e.g. 27) undergo intramolecular cyclization via a tetrahedral intermediate, resulting in cleavage of the amide and release of an activated aromatic mustard. One of the 2-nitroimidazole mustards (11b) had 20-fold greater toxicity towards aerobic AA8 cells than RB 6145 (4), and a 51-fold greater toxicity towards UV4 cells (which are defective in DNA cross-link repair and thus hypersensitive to cross-linking agents). The cytotoxicity of 11b against AA8 cells was enhanced 3.3-fold under hypoxic conditions, but the compound was inactive against the hypoxic subfraction of cells in KHT tumours in vivo.
authors.affiliation: Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
authors.forename: M P
authors.initials: MP
authors.lastname: Hay
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008466:Mechlorethamine; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D009593:Nitroimidazoles; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007202:Indicators and Reagents; D009588:Nitrogen Mustard Compounds; D009593:Nitroimidazoles; D011355:Prodrugs; D008466:Mechlorethamine