title: Hypoxic selectivity and solubility--investigating the properties of A-ring substituted nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-ones (nitroCBIs) as hypoxia-activated prodrugs for antitumor therapy.
abstract: Nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-ones (nitroCBIs) are a new class of prodrugs for antitumor therapy that undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents. Although hindered by poor aqueous solubility, several examples have shown activity against hypoxic tumor cells in vivo. Here we investigate structural properties that influence hypoxic selectivity in vitro, and show that for high hypoxic selectivity nitroCBIs should combine an electron-withdrawing group of H-bond donor capacity on the A-ring, with a basic substituent on the minor groove-binding side chain. Substitution on the A-ring is compatible with the introduction of functionality that can improve water solubility.
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: Shangjin
authors.initials: S
authors.lastname: Yang
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Atwell
authors.forename: Eileen
authors.initials: E
authors.lastname: Smith
authors.forename: Yongchuan
authors.initials: Y
authors.lastname: Gu
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 / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility
chemical_list: C445728:1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; D018906:Antineoplastic Agents, Alkylating; D003521:Cyclopropanes; D007211:Indoles; D011355:Prodrugs; D004247:DNA