Development of Bimetallic Titanocene-Ruthenium-Arene Complexes As Anticancer Agents: Relationships between Structural and Biological Properties

A series of bimetallic titanium-ruthenium complexes of general formula (η5-C5H5)(μ-η5:κ1-C5H4(CR12)nPR2R3)TiCl2RuCl2 (n = 0, 1, 2 or 4; R1 = H or Me; R2 = H, Ph, or Cy; R3 = Ph or Cy) have been synthesized, including two novel compds. as well as two cationic derivs. of formula [(η5-C5H5)(μ-η5:κ1-C5H4(CH2)nPPh2)TiCl2] (η6-p-cymene)RuCl (n = 0 or 2). The solid state structure of two of these compds. was also established by x-ray crystallog. The complexes showed a cytotoxic effect on human ovarian cancer cells and were markedly more active than their Ti or Ru monometallic analogs titanocene dichloride and RAPTA-C, resp. Studies of cathepsin B inhibition, an enzyme involved in cancer progression, showed that enzyme inhibition by the bimetallic complexes is influenced by the length of the alkyl chain in between the metal centers. Complementary ESI-MS studies provided evidence for binding of a Ru(II) fragment to proteins.