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

Abstract

Ovarian cancer is the most lethal gynecological malignancy, often because of the frequent insurgence of chemoresistance to the drugs currently used. Thus, new therapeutical agents are needed. We tested the toxicity of 16 new DNA-intercalating agents to cisplatin (cDDP)-sensitive human ovarian carcinoma cell lines and their resistant counterparts. The compounds were the complexes of Pt(II) or Pd(II) with bipyridyl (bipy) and phenanthrolyl (phen) and with four different thiourea ancillary ligands. Within each of the four series of complexes characterized by the same thiourea ligand, the Pd(phen) drugs invariably showed the highest anti-proliferative efficacy. This paralleled both a higher intracellular drug accumulation and a more efficient DNA intercalation than all the other metal-bidentate ligand combinations. The consequent inhibition of topoisomerase II activity led to the greatest inhibition of DNA metabolism, evidenced by the inhibition of the expression of the folate cycle enzymes and a marked perturbation of cell-cycle distribution in both cell lines. These findings indicate that the particular interaction of Pd(II) with phenanthroline confers the best pharmacokinetic and pharmacodynamic properties that make this class of DNA intercalators remarkable inhibitors, even of the resistant cell growth.

DNA Interaction with Coordination Compounds of Cd(II)containing 1,10-Phenanthroline

“…It is known that the phenanthroline ligands can enhance the antiproliferative activity of Pd(II) and Pt(II) complexes. Complexes of Pd(II) with phenanthroline have good pharmacokinetic and pharmacodynamic properties that make this class of compounds remarkable inhibitors, even of resistant cell growth [5]. Simple 1,10-phenanthrolines as excellent N-donor bidentate chelating ligands have been widely used to construct such compounds because of their excellent coordinating ability.…”

The Cytotoxic Effect of Copper (II) Complexes with Halogenated 1,3-Disubstituted Arylthioureas on Cancer and Bacterial Cells

“…Among tested palladium complexes of N, N-disubstituted thioureas, those endowed with furoyl and ethyl groups were the most effective against human breast cancer cells, as compared to the platinum-derived standard drug [ 10 ]. On the other hand, Marverti et al [ 11 ] introduced a series of thiourea-Pd (II) compounds that acted as productive growth inhibitors of cisplatin-sensitive ovarian cancer cell lines and their resistant counterparts. Coordinates altered malignant cell metabolism via inhibition of thymidylate synthase and dihydrofolate reductase expression.…”