Novel C,N-Cyclometalated Benzimidazole Ruthenium(II) and Iridium(III) Complexes as Antitumor and Antiangiogenic Agents: A Structure–Activity Relationship Study

A series of novel C,N-cyclometalated benzimidazole ruthenium­(II) and iridium­(III) complexes of the types [(η⁶-<i>p</i>-cymene)­RuCl­(κ²-<i>N</i>,<i>C</i>-L)] and [(η⁵-C₅Me₅)­IrCl­(κ²-<i>N</i>,<i>C</i>-L)] (HL = methyl 1-butyl-2-arylbenzimidazole­carboxylate) with varying substituents (H, Me, F, CF₃, MeO, NO₂, and Ph) in the R₄ position of the phenyl ring of 2-phenylbenzimidazole chelating ligand of the ruthenium (<b>3a</b>–<b>g</b>) and iridium complexes (<b>4a</b>–<b>g</b>) have been prepared. The cytotoxic activity of the new ruthenium­(II) and iridium­(III) compounds has been evaluated in a panel of cell lines (A2780, A2780cisR, A427, 5637, LCLC, SISO, and HT29) in order to investigate structure–activity relationships. Phenyl substitution at the R₄ position shows increased potency in both Ru and Ir complexes (<b>3g</b> and <b>4g</b>, respectively) as compared to their parent compounds (<b>3a</b> and <b>4a</b>) in all cell lines. In general, ruthenium complexes are more active than the corresponding iridium complexes. The new ruthenium and iridium compounds increased caspase-3 activity in A2780 cells, as shown for <b>3a</b>,<b>d</b> and <b>4a</b>,<b>d</b>. Compound <b>4g</b> is able to increase the production of ROS in A2780 cells. Furthermore, all the new compounds are able to overcome the cisplatin resistance in A2780cisR cells. In addition, some of the metal complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926 at 0.5 μM, the ruthenium derivatives <b>3g</b> (Ph) and <b>3d</b> (CF₃) being the best performers. QC calculations performed on some ruthenium model complexes showed only moderate or slight electron depletion at the phenyl ring of the C,N-cyclometalated ligand and the chlorine atom on increasing the electron withdrawing effect of the R substituent