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.