Selective hypoxia-cytotoxins based on vanadyl complexes with 3-aminoquinoxaline-2-carbonitrile-N1,N4-dioxide derivatives

J Inorg Biochem. 2006 Aug;100(8):1358-67. doi: 10.1016/j.jinorgbio.2006.03.012. Epub 2006 Apr 25.

Abstract

A new vanadyl complex with the formula VO(L1)2, where L1=3-amino-6(7)-chloroquinoxaline-2-carbonitrile N(1), N(4)-dioxide, has been synthesized and characterized by elemental analyses, conductometry, fast atom bombardment mass spectroscopy (FAB-MS) and electronic, Fourier transform infrared (FTIR), Raman, nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopies. Results were compared with those previously reported for analogous vanadium complexes with other 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives as ligands. As an effort to develop novel metal-based selective hypoxia-cytotoxins and to improve bioavailability and pharmacological and toxicological properties of aminoquinoxaline carbonitrile N-dioxides bioreductive prodrugs, the new complex and VO(L)2 complexes, with L=3-amino-6(7)-bromoquinoxaline-2-carbonitrile N1,N4-dioxide (L2) and 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide (L3), were subjected to cytotoxic evaluation in V79 cells in hypoxic and aerobic conditions. The complexes resulted in vitro more potent cytotoxins than the free ligands (i.e. potencies P(VO(L1)2)=3.0, P(L1)=9.0 microM) and Tirapazamine (P=30.0 microM) and showed excellent selective cytotoxicity in hypoxia, being no cytotoxic in oxia. In addition, the solubility in hydrophilic solvents resulted significantly higher for the vanadyl complexes than for the free ligands. These results could be indicative that complexation of the quinoxaline-2-carbonitrile N1,N4-dioxide derivatives with vanadium could improve their bioavailability. In addition, a new aspect of the series has been investigated. A detailed comparison of the electrochemical behavior of the free ligands and the complexes has been performed searching for a correlation between reduction potentials of the complexes and their activities and hypoxia selectivities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Hypoxia
  • Cells, Cultured
  • Cytotoxins / chemical synthesis
  • Cytotoxins / chemistry*
  • Cytotoxins / pharmacology*
  • Electrochemistry
  • Fibroblasts / drug effects
  • Ligands
  • Molecular Structure
  • Nitriles / chemical synthesis
  • Nitriles / chemistry*
  • Nitriles / pharmacology
  • Quinoxalines / chemical synthesis
  • Quinoxalines / chemistry*
  • Quinoxalines / pharmacology
  • Vanadates / chemical synthesis
  • Vanadates / chemistry*
  • Vanadates / pharmacology*

Substances

  • 3-aminoquinoxaline-2-carbonitrile-N1,N4-dioxide
  • Antineoplastic Agents
  • Cytotoxins
  • Ligands
  • Nitriles
  • Quinoxalines
  • Vanadates