title: Hypoxia-activated prodrugs: substituent effects on the properties of nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) prodrugs of DNA minor groove alkylating agents.
abstract: Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. m.tercel@auckland.ac.nz
authors.forename: Moana
authors.initials: M
authors.lastname: Tercel
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Atwell
authors.forename: Shangjin
authors.initials: S
authors.lastname: Yang
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Stevenson
authors.forename: K Jane
authors.initials: KJ
authors.lastname: Botting
authors.forename: Maruta
authors.initials: M
authors.lastname: Boyd
authors.forename: Eileen
authors.initials: E
authors.lastname: Smith
authors.forename: Robert F
authors.initials: RF
authors.lastname: Anderson
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.forename: Frederik B
authors.initials: FB
authors.lastname: Pruijn
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism* / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000378:metabolism*; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D014410:Tumor Stem Cell Assay
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007211:Indoles; D011355:Prodrugs; D004247:DNA