Targeting G-quadruplex structures with Zn(II) terpyridine derivatives: a SAR study.

Based on the ability of terpyridines to react with G-quadruplex DNA (G4) structures along with the interest aroused by Zn as an essential metal centre in many biological processes, we have synthesized and characterized six Zn chloride or nitrate complexes containing terpyridine ligands with different 4'-substituents. In addition, we have studied their interaction with G4 and their cytotoxicity. Our experimental results revealed that the leaving group exerts a strong influence on the cytotoxicity, since the complexes bearing chloride were more cytotoxic than their nitrate analogues and an effect of the terpyridine ligand was also observed. The thermal stabilization profiles showed that the greatest stabilization of hybrid G4, Tel22, was observed for the Zn complexes bearing the terpyridine ligand that contained one or two methylated 4-(imidazol-1-yl)phenyl substituents, 3Cl and 3(L)2, respectively, probably due to their extra positive charge. Stability and aquation studies for these complexes were carried out and no ligand release was detected. Complexes 3Cl and 3(L)2 were successfully internalized by SW480 cells and they seemed to be localized mainly in the nucleolus. The highest cytotoxicity, G4 selectivity and G4 affinity determined by fluorescence and ITC experiments, and subcellular localization quantified by ICP-MS measurements, rendered 3Cl a very interesting complex from a biological standpoint.

Studies on DNA interaction of organotin(IV) complexes of meso-tetra(4-sulfonatophenyl)porphine that show cellular activity.

The interaction of the diorgano- and triorganotin(IV) derivatives of meso-tetra-(4-sulfonatophenyl)porphine (Me2Sn)2TPPS, (Bu2Sn)2TPPS, (Me3Sn)4TPPS and (Bu3Sn)4TPPS to natural DNA was analysed (together with free meso-tetra-(4-sulfonatophenyl)porphine (TPPS4-) for comparison purposes). Particular attention was paid to (Bu3Sn)4TPPS, a species that shows significant cellular action. Preliminary tests were done on the solution properties of the organotin(IV) compounds (pKA and possible self-aggregation). Spectrophotometric and spectrofluorometric experiments showed that all the investigated organotin(IV) derivatives strongly interact with DNA, the binding energy depending on the dye steric hindrance. In all cases experimental data concur in indicating that external binding mode prevails. Interestingly, fluorescence quenching and viscosity experiments show that the Bu-containing species, and in particular (Bu3Sn)4TPPS, are able to noticeably alter the DNA conformation.