title: N-alkylated cyclen cobalt(III) complexes of 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol DNA alkylating agent as hypoxia-activated prodrugs.
abstract: A series of cobalt complexes of the potent DNA minor groove alkylator 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol (seco-6-azaCBI-TMI) were prepared from a series of N-substituted cyclen ligands. The final N-substituted complexes carried formal overall charges ranging from +2 to -2 and showed limited improvements in solubility. They showed similar stabilities to that of the complex with the unsubstituted cyclen ligand, and large but variable attenuation of the cytotoxicity of the free alkylator (2-30-fold), compared to 150-fold for the unsubstituted ligand. However, they had oxic/hypoxic ratios (2-22-fold) comparable to that of the unsubstituted cyclen complex (5).
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Lu
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Stevenson
authors.forename: John Yu-Chih
authors.initials: JY
authors.lastname: Chang
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Brothers
authors.forename: David C
authors.initials: DC
authors.lastname: Ware
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Moana
authors.initials: M
authors.lastname: Tercel
mesh_terms: D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001391:Azo Compounds / Q000737:chemistry; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003035:Cobalt / Q000737:chemistry; D000080027:Cyclams; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007211:Indoles / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D014131:Trace Elements / Q000737:chemistry
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001391:Azo Compounds; D000080027:Cyclams; D006571:Heterocyclic Compounds; D007211:Indoles; D011355:Prodrugs; D014131:Trace Elements; C511528:azachloromethylbenzindoline; D003035:Cobalt; D004247:DNA; C038072:cyclen