title: Cross-bridged cyclen or cyclam Co(III) complexes containing cytotoxic ligands as hypoxia-activated prodrugs.
abstract: A series of cobalt(III) complexes of the potent DNA minor groove alkylator (1-(chloromethyl)-5-hydroxy-1H-pyrrolo[3,2-f]quinolin-3(2H)-yl)(5,6,7-trimethoxy-1H-indol-2-yl)methanone (3; seco-CPyI-TMI), with cyclam or cyclen auxiliary ligands (L3 and L5) containing a cross-bridging ethylene (CH2CH2) group or the N,N'-dimethyl derivatives of these (L4 and L6), was prepared. Two 8-quinolinato (2) model complexes of these, [Co(L3)(2)](ClO4)2 and [Co(L6)(2)](ClO4)2, and the aquated derivative [Co(L6)(H2O)2](OTf)3 were characterized by X-ray crystallography. Electrochemistry of the 8-quinolinato model complexes showed that the Co(III)/(II) reduction potential was lowered relative to the unsubstituted cyclen ligand. Evaluation of the cytotoxicity of the racemic seco-CPyI cobalt complexes in vitro showed considerable attenuation of their cytotoxicity relative to the free alkylator and marked hypoxic selectivity, especially [Co(L3)(3)](2+) (9), which was 81-212-fold more potent under hypoxia than 20% oxygen in a panel of 10 human tumor cell lines. However, 9 did not elicit significant killing of hypoxic cells in HT29 tumor xenografts, suggesting possible pharmacological limitations in vivo.
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: John Yu-Chih
authors.initials: JY
authors.lastname: Chang
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Lu
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Stevenson
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Brothers
authors.forename: George R
authors.initials: GR
authors.lastname: Clark
authors.forename: K Jane
authors.initials: KJ
authors.lastname: Botting
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Ferry
authors.forename: Moana
authors.initials: M
authors.lastname: Tercel
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: David C
authors.initials: DC
authors.lastname: Ware
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003035:Cobalt / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008024:Ligands; D011355:Prodrugs; C024560:cyclam; D003035:Cobalt; C038072:cyclen