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-p-cymene)­RuCl­(κ2-N,C-L)] and [(η5-C5Me5)­IrCl­(κ2-N,C-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 (3a–g) and iridium complexes (4a–g) 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
(3g and 4g, respectively) as compared to
their parent compounds (3a and 4a) 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 3a,d and 4a,d. Compound 4g 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 3g (Ph) and 3d (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.