Potent and selective anticancer activity of half-sandwich ruthenium and osmium complexes with modified curcuminoid ligands

We have recently reported a series of half-sandwich ruthenium(ii) complexes with curcuminoid ligands showing excellent cytotoxic activities (particularly ionic derivatives containing PTA (PTA = 1,3,5-triaza-7-phosphaadamantane). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of a long hydrophobic chain obtained by replacing the OH-groups, present in curcumin and bisdemethoxycurcumin, with the palmitic acid ester. We report the synthesis of ruthenium(ii) and osmium(ii) p-cymene derivatives containing palmitic acid curcumin ester ligands ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene)dipalmitate (p-curcH) and ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(4,1-phenylene)dipalmitate (p-bdcurcH). Complexes [M(ii)(cym)(p-curc)/(p-bdcurc)(Cl)] 1-4 (M = Ru or Os) are neutral, whereas [M(ii)(cym)(p-curc)/(p-bdcurc)(PTA)][SO3CF3] 5-8 are salts obtained when the chloride ligand is replaced by the PTA ligand. Stability studies performed on 1-8 in DMSO-PBS under physiological conditions (pH = 7.4) indicate that the complexes remain intact. The complexes exhibit potent and selective cytotoxic activity against an ovarian carcinoma cell line and its cisplatin-resistant form (A2780 and A2780cis), and non-cancerous human embryonic kidney (HEK293T) cells. To define the structure-activity relationships (SAR), the compounds have been compared with other Ru(ii) and Os(ii) complexes with curcuminoid ligands previously reported. SAR data reveal that the bisdemethoxycurcumin complexes are generally more active and selective than analogous curcumin-containing complexes.

Automated summary

In this study, a series of half-sandwich ruthenium(ii) complexes with curcuminoid ligands were prepared and investigated for their cytotoxic activities. The introduction of a long hydrophobic chain by replacing the OH-groups in curcumin and bisdemethoxycurcumin with palmitic acid ester was found to enhance the cytotoxicity. The complexes showed potent and selective cytotoxic activity against ovarian carcinoma cells and their cisplatin-resistant form.