Fluorescent Diorganotin(IV) Complexes as Anticancer Agents: Study of Cytotoxicity, Cellular Localization, and Mechanism of Cell Death

Three luminescent mixed ligand diorganotin(IV) complexes[Sn2Ph4(L)(1-3)(DPA)(MeOH)Cl](whereL(1) = (Z)-N-((E)-3-ethoxy-2-hydroxybenzylidene)isonicotinohydrazonic acid,L-2 = (Z)-N-((E)-5-bromo-2-hydroxybenzylidene)isonicotinohydrazonic acid,L-3 = (Z)-N-((E)-2-hydroxy-3-methoxybenzylidene)isonicotinohydrazonicacid, and DPA = dipicolinic acid) (1-3) were synthesizedand characterized physiochemically along with the single-crystal X-raydiffraction analysis of 1 and 3. Aqueousphase stabilities of the complexes were performed with UV-visand H-1 nuclear magnetic resonance, suggesting that theyare stable in aqueous/biological media. The interaction of 1-3 with DNA was evaluated through analytical methods, which supportedthe intercalation mode of binding. Also, the interaction of complexeswith bovine serum albumin was evaluated with fluorescence quenchingexperiments showing static quenching. In addition, the results ofpartition coefficients and cellular uptake suggest that the complexesare hydrophobic and can easily enter the cells. Cytotoxic potentialof 1-3 was evaluated against HeLa, HT-29 (cancerous),and NIH-3T3 (normal) cell lines. Complex 2 is the mostcytotoxic of the series having IC50 4.2 & PLUSMN; 0.7 & mu;Magainst HeLa cells. Furthermore, all the complexes showed an apoptoticcell death confirmed by acridine orange/ethidium bromide, cell cycleanalysis, and Annexin V-FITC/PI double staining assays. Finally, byusing live cell confocal microscopy, it was found that the compoundstarget the mitochondria of cancer cells and raise the reactive oxygenspecies level.