Cross-bridged cyclen or cyclam Co(III) complexes containing cytotoxic ligands as hypoxia-activated prodrugs

Inorg Chem. 2013 Jul 1;52(13):7688-98. doi: 10.1021/ic4006967. Epub 2013 Jun 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cobalt / chemistry*
  • Cobalt / pharmacology
  • Cobalt / therapeutic use
  • Coordination Complexes / chemistry*
  • Coordination Complexes / pharmacology
  • Coordination Complexes / therapeutic use
  • Crystallography, X-Ray
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology
  • Heterocyclic Compounds / therapeutic use
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Neoplasms / drug therapy
  • Prodrugs / chemistry*
  • Prodrugs / pharmacology
  • Prodrugs / therapeutic use

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Heterocyclic Compounds
  • Ligands
  • Prodrugs
  • cyclam
  • Cobalt
  • cyclen