Bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) as a novel apoptosis-inducing anticancer agent

In a systematic effort to identify a potent anticancer agent, we synthesize d 15 oxovanadium(IV) complexes and examined their cytotoxic activity agains t 14 different human cancer cell lines. The oxovanadium compounds included mono and bis ancillary ligands of 1,10-phenanthroline (phen) [VO(phen), VO( phen)(2), VO(Me-2-phen), VO(Me-2-phen)(2), VO(Cl-phen), VO(Cl-phen)(2), VO( NO2-phen), VO(NO2-phen)(2)], 2,2'-bipyridyl (bipy) [VO(bipy), VO(bipy)(2), VO[Me-2-bipy), VO(Me-2-bipy)(2)], and 2-2'-bipyrimidine(bipym) [VO(bipym) a nd VO(bipym)(2)], linked via nitrogen atoms, and 5'-bromo-2'-hydroxyacetoph enone (acph) [VO(acph)(2)], linked via oxygen donor atom. The mono-chelated [VO(Me-2-phen), compound 3] and bis-chelated-phen[VO(Me-2-phen)(2), compou nd 4] complexes were the most potent oxovanadium compounds and killed targe t cancer cells at low micromolar concentrations. Notably, the dimethyl subs titution of the phenanthroline rings was essential for the anticancer activ ity of both compound 4 [VO(Me-2-phen)(2)] and compound 3 [VO(Me-2-phen)] be cause unsubstituted bis-chelated and mono-chelated phen oxovanadium(IV) com plexes [VO(phen), compound 1, or VO(phen)(2), compound 2] were less active. Addition of a chloro or nitro group to the phen complexes did not signific antly improve the cytotoxic activity of the unsubstituted oxovanadium(IV) c omplexes. Irrespective of the ligands, bis-chelated phenanthroline containi ng compounds showed better activity than the mono-chelated phenanthroline c ontaining complexes. The marked differences in the cytotoxic activity of ox ovanadium(IV) complexes containing different heterocyclic ancillary ligands suggest that the cytotoxic activity of these compounds is determined by th e identity of the five-member bidentate ligands, as well as the nature of t he substitutents on the heterocyclic aromatic rings. Our results presented herein provide experimental evidence that oxovanadium compounds induce apop tosis in human cancer cells, Oxovanadium compounds, especially the lead com pound VO(Me-2-phen)(2), may he useful in the treatment of cancer.