Arene ruthenium dichloro complexes containing isonicotinic ester ligands: Synthesis, molecular structure and cytotoxicity

A series of p-cymene ruthenium dichloro complexes containing isonicotinic ester ligands, [(arene)RuCl2NC5H4-4-COO–C6H4–p-O-(CH2)n-CH3] (n = 1: 1, n = 3: 2, n = 5: 3, n = 7: 4, n = 9: 5, n = 11: 6, n = 13: 7, n = 15: 8), were prepared from p-cymene ruthenium dichloro dimer and the corresponding isonicotinic ester ligand. The single-crystal X-ray analysis of 1 shows the molecule to adopt the usual pseudo-tetrahedral piano-stool geometry, the isonicotinic ester ligand being coordinated through the nitrogen atom. The cytotoxicity of all complexes and of the free ligands was studied towards human ovarian cancer cells; high activities were observed only for n = 9 (presenting a chain with ten carbon atoms), both as far as the free ligands and the complexes are concerned. Based on this result, a new isonicotinic ester ligand with a C10 substituent containing a terminal alcohol function, NC5H4-4-COO–C6H4–p-O–(CH2)10–OH, was synthesized by a four-step method, and arene ruthenium complexes thereof, [(arene)RuCl2NC5H4-4-COO–C6H4–p-O–(CH2)10–OH] (arene = C6H6: 9a, arene = p-MeC6H4Pri: 9b, arene = C6Me6: 9c) were prepared. The complexes 9a and 9b show indeed remarkable anticancer activities, the IC50 values for human ovarian cancer cells being in the submicromolar range. The highest cytotoxicity was observed for complex 9b, with IC50 values of 0.18 μM for A2780 and 3.04 μM for the cisplatin-resistant mutant A2780cisR.