DNA binding, topoisomerase inhibition and cytotoxicity of palladium(II) complexes with 1,10-phenanthroline and thioureas

Abstract

Metallointercalators represent a promising alternative in cancer chemotherapy. We present herein DNA binding, topoisomerase inhibition and cytotoxic studies on a series of complexes of general formulae [Pd (phen)(tu ⁄) 2 ] 2+ incorporating the intercalator 1,10-phenanthroline and thiourea ligands (L = thiourea 1, N-methylthiourea 2, N,N 0-dimethylthiourea 3). DNA-unwinding results showed that the complexes can induce the unwinding of the plasmid DNA. The binding constants (K b) for the interaction of the complexes with SS-DNA were determined by UV spectroscopy. Competitive experiments with ethidium bromide (EB) were investigated by fluorescence spectroscopy and show that all the complexes were able to displace EB from the DNA-EB complex. The results suggest that they may interact with DNA by intercalation. Compounds were tested against human oral carcinoma cell line (KB), human breast cancer cell line (MCF7) and cisplatin-resistant human breast cancer cell line (MCF7-R) and showed good cytotoxic activity towards MCF7-R. Compounds 2 and 3 were also able to cause topo II inhibition.

The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines

“…In this regard, we have previously shown that bipyridyl complexes of Pt(II) with thiourea are able to inhibit TOPO-II activity [9] and, more recently, Barra et al showed that three Pd(phen) complexes, including our [Pd(phen)tu 2 ]Cl 2 and [Pd(phen)(Me-tu) 2 ]Cl 2 , were also active as TOPO-II inhibitors in a dose-dependent manner [14]. We confirmed here that metal phenanthroline complexes were active TOPO-II inhibitors, and showed again that Pd(phen) were the most active TOPO-II inhibitors among the tested metal planar complexes, even at the smallest concentration tested.…”

“…It has been reported that both AT and GC base pairs may stably bind the phenanthroline ligand, but its affinity is larger for the GC base pair [29]. In this regard, some Pd(phen) compounds, including our [Pd(phen)tu 2 ]Cl 2 and [Pd(phen)(Me-tu) 2 ]Cl 2 , have been suggested to form hydrogen bonds with guanosine [14]. Therefore, our complexes bearing the phenanthroline moiety, in particular those with Pd(II), are likely powerful nucleic acid inhibitors.…”

“…In the next step of our effort to rationalize the cytotoxicity results, we tested the ability of these complexes to bind DNA by intercalating between bases [10,11,14,17]. We thus compared the intercalation ability of the eight complexes of the Series A and C by means of an ethidium bromide (EB) fluorometric displacement assay that took advantage of the much higher fluorescence quantum yield of DNA-bound EB relative to free EB [6,18].…”

“…The predicted stacked structure of the complex of phen with AT base pairs is found complementary to the available crystal structure. However, in certain crystal structures, the phen ligand is found partially intercalated within two thymine nucleobases [13].Recently, Barra et al [14] have addressed the structural determinants of the bioactivity of Pd(II) complexes of general formulae [Pd(phen)(tu) 2 ] 2+ , incorporating the intercalator phen and thiourea (tu) with the latter either unsubstituted or N-methylor N,N-dimethyl-substituted. DNA binding experiments suggested that the ancillary thiourea ligands did not affect the intercalating ability, as already observed for Pt-bipy-thiourea complexes [6].…”

Synthesis, characterization and antitumor activity of palladium(II) complexes of imidazolidine-2-thione

“…Motivated by the aforementioned observations, and as a part of our continuing research program in the field of coordination and biological chemistry of metal complexes [12][13][14][15][16][17][18][19], we present herein the synthesis and characterization of the complexes cis-[PdX 2 (imzt)(PPh 3 )] {imzt = imidazolidine-2-thione; PPh 3 = triphenylphosphine; X = Cl (1), Br (2), I (3), SCN (4)}, together with the effect of complexes 1-4 on the viability of U87MG human glioma cells.…”