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

Bioorg Med Chem. 2011 Aug 15;19(16):4861-7. doi: 10.1016/j.bmc.2011.06.076. Epub 2011 Jul 1.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Antineoplastic Agents, Alkylating / chemical synthesis*
  • Antineoplastic Agents, Alkylating / chemistry
  • Antineoplastic Agents, Alkylating / pharmacology
  • Azo Compounds / chemistry
  • Cell Hypoxia / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cobalt / chemistry
  • DNA / chemistry
  • DNA / metabolism
  • Drug Screening Assays, Antitumor
  • Drug Stability
  • Female
  • Heterocyclic Compounds / chemistry
  • Humans
  • Hypoxia / metabolism
  • Indoles / chemistry
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Solubility
  • Trace Elements / chemistry

Substances

  • Antineoplastic Agents, Alkylating
  • Azo Compounds
  • Heterocyclic Compounds
  • Indoles
  • Prodrugs
  • Trace Elements
  • azachloromethylbenzindoline
  • Cobalt
  • DNA
  • cyclen