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 synthesized 15 oxovanadium(IV) complexes and examined their cytotoxic activity against 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(Me2-phen), VO (Me2-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(Me2-bipy), VO(Me2-bipy)2], and 2-2'-bipyrimidine(bipym) [VO(bipym) and VO-(bipym)2], linked via nitrogen atoms, and 5'-bromo-2'-hydroxyacetophenone (acph) [VO(acph)2], linked via oxygen donor atom. The mono-chelated [VO(Me2-phen), compound 3] and bis-chelated-phen[VO(Me2-phen)2, compound 4] complexes were the most potent oxovanadium compounds and killed target cancer cells at low micromolar concentrations. Notably, the dimethyl substitution of the phenanthroline rings was essential for the anticancer activity of both compound 4 [VO(Me2-phen)2] and compound 3 [VO(Me2-phen)] because unsubstituted bis-chelated and mono-chelated phen oxovanadium(IV) complexes [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 significantly improve the cytotoxic activity of the unsubstituted oxovanadium(IV) complexes. Irrespective of the ligands, bis-chelated phenanthroline containing compounds showed better activity than the mono-chelated phenanthroline containing complexes. The marked differences in the cytotoxic activity of oxovanadium(IV) complexes containing different heterocyclic ancillary ligands suggest that the cytotoxic activity of these compounds is determined by the identity of the five-member bidentate ligands, as well as the nature of the substitutents on the heterocyclic aromatic rings. Our results presented herein provide experimental evidence that oxovanadium compounds induce apoptosis in human cancer cells. Oxovanadium compounds, especially the lead compound VO(Me2-phen)2, may be useful in the treatment of cancer.
Narla
R K
RK
Department of Experimental Oncology, Parker Hughes Institute, St. Paul, Minnesota 55113, USA.
Dong
Y
Y
D'Cruz
O J
OJ
Navara
C
C
Uckun
F M
FM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C411475:bis(4,7-dimethyl-1,10-phenanthroline)sulfatooxovanadium(IV); C075743:oxovanadium IV; D014638:Vanadates; D004247:DNA