1. Cross-Bridged Cyclen or Cyclam Co(III) Complexes Containing Cytotoxic Ligands as Hypoxia-Activated Prodrugs
- Author
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John Yu-Chih Chang, Guo-Liang Lu, Ralph J. Stevenson, Penelope J. Brothers, George R. Clark, K. Jane Botting, Dianne M. Ferry, Moana Tercel, William R. Wilson, William A. Denny, and David C. Ware
- Subjects
Models, Molecular ,Ethylene ,Stereochemistry ,chemistry.chemical_element ,Antineoplastic Agents ,Crystallography, X-Ray ,Cyclams ,Ligands ,Electrochemistry ,Inorganic Chemistry ,Mice ,chemistry.chemical_compound ,Cyclen ,Coordination Complexes ,Heterocyclic Compounds ,Cell Line, Tumor ,Neoplasms ,Cyclam ,Animals ,Humans ,Prodrugs ,Physical and Theoretical Chemistry ,Cytotoxicity ,Ligand ,Cobalt ,Cell Hypoxia ,chemistry ,Selectivity - 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.
- Published
- 2013