Synthesis, X-ray structure, and anti-leukemic activity of oxovanadium(IV) complexes

In a systematic effort to identify and develop effective anticancer agents, four oxovanadium(IV) complexes with 1,10-phenanthroline (Phen) or 4,7-dimethyl-1,10-phenanthroline (Me₂-Phen) as ligand(s) were synthesized and characterized. Among the four oxovanadium(IV) complexes synthesized, the crystal structure of the bis(phenanthroline)oxovanadium(IV) complex bis(1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO₄)(Phen)₂], compound 1) has been determined. Compound 1 crystallized in the space group P2₁/n with unit cell parameters a=14.2125 (17) A, b=10.8628 (13) A, c=20.143 (2) A, α=90°, β=102.569 (2)°, γ=90°, V=3035.3 (6) A³, and Z=4. The refinement of compound 1 by full-matrix least-squares techniques gave an R factor of 0.0785 for 4356 independent reflections. The structure contains two enantiomorphous molecules, Λ and Δ, which are related by an inversion center. Compound 1 exhibited 3.5-fold more potent cytotoxic activity against NALM-6 human leukemia cells than the mono(phenanthroline)oxovanadium(IV) complex (diaqua)(1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO₄)(Phen)(H₂O)₂], compound 2) (IC₅₀ values: 0.97±0.10 μM versus 3.40±0.20 μM; P=0.0004). Methyl substitution in the phenanthroline ligand enhanced the anti-leukemic activity of the mono(phenanthroline)oxovanadium(IV) complex 4.4-fold (IC₅₀ values: 0.78±0.10 μM, compound 4, versus 3.40±0.20 μM, compound 2; P=0.0003) and the anti-leukemic activity of the bis(phenanthroline)oxovanadium(IV) complex 5.7-fold (IC₅₀ values: 0.17±0.02 μM, compound 3, versus 0.97±0.10 μM, compound 1; P=0.001). The leading oxovanadium compound bis(4,7-dimethyl-1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO₄)(Me₂-Phen)₂], compound 3) triggered the production of reactive oxygen species (ROS) in human leukemia cells, caused G₁-arrest and inhibited clonogenic growth at nanomolar concentrations.