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Cross-Bridged Cyclen or Cyclam Co(III) Complexes Containing Cytotoxic Ligands as Hypoxia-Activated Prodrugs

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journal contribution
posted on 01.07.2013, 00:00 by 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, David C. Ware
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.