title: The effect of sulfonate leaving groups on the hypoxia-selective toxicity of nitro analogs of the duocarmycins.
abstract: A series of 3-substituted (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate (nitroCBI) prodrugs containing sulfonate leaving groups undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents. They were evaluated (along with chloride leaving group analogs for comparison) for their cytotoxicity against cultures of SKOV3 and HT29 human tumor cell lines under both aerobic and hypoxic conditions. Sulfonates with neutral side chains (e.g., 5,6,7-trimethoxyindole; TMI) show consistently higher hypoxic cytotoxicity ratios (HCRs) (34-246) than the corresponding chloro analogs (2.8-3.1) in SKOV3 cells, but these trends do not hold for compounds with cationic or polar neutral side chains.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Amir
authors.initials: A
authors.lastname: Ashoorzadeh
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Atwell
authors.forename: Frederik B
authors.initials: FB
authors.lastname: Pruijn
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.forename: Moana
authors.initials: M
authors.lastname: Tercel
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Stevenson
mesh_terms: D000476:Alkanesulfonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000476:Alkanesulfonates; D018906:Antineoplastic Agents, Alkylating; D000080890:Duocarmycins; D007211:Indoles; D009574:Nitro Compounds; D011355:Prodrugs; D011760:Pyrrolidinones; D004247:DNA; C058289:duocarmycin A