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

Abstract

A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(η(6)-p-cymene)RuCl(κ(2)-N,C-L)] and [(η(5)-C5Me5)IrCl(κ(2)-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.

Antiangiogenic platinum through glycan targeting

“…The extent to which our observations may explain anti-angiogenic and vascular disturbing properties of recently reported platinum–metal complexes should be explored. 48,49 Indeed our findings may be relevant to the biological function at the molecular level of the Ru-based NAMI-A, the prototypical anti-metastatic coordination compound, which has undergone clinical trials based on its anti-metastatic properties. 50 …”

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

“…There was no distinct variation in the cytotoxicities for these complexes due to the substitutions, but the CF 3 substitution was found to increase the efficacy of 8e in almost all of the cell lines. 164 Most of these compounds were more efficacious than cisplatin in A427 and HT29 cell and were able to kill A2780cisR cells with IC 50 values of 0.96–3.26 μM.…”

“…determined the effects of varying substituents (H, Me, F, CF 3 , MeO, NO 2 , and Ph) in the R4 position of the phenyl ring of 2-phenylbenzimidazole chelating ligand on the anticancer efficacy of the complexes. 164 The hydrolysis of the ruthenium−chlorido bond was relatively rapid for 8c , 8d , and 8h . The relative hydrophobicities, according to RP-UPLC-QTOF-MS studies, were: 8d < 8c < 8h .…”

Investigation of binding properties of dicationic styrylimidazo[1,2‐a]pyridinium dyes to human serum albumin by spectroscopic techniques

“…These molecules exhibit anti-viral, anti-inflammatory, anti-tumor, analgesic, anti-pyretic, anti-ulcer and anti-bacterial properties, and drugs containing imidazo[1,2-a]pyridine ring such as zolpidem (hypnotic) are currently available on the market (22)(23)(24). The association of the compounds 2a and 2b with HSA exhibited similar effects and moderate binding constants by fluorimetric titration compared with the interactions studies in which the metal used complexes of benzimidazole derivatives with HSA (27,28). We prepared two dicationic styrylimidazo[1,2-a]pyridinium dyes, called 2a and 2b for this purpose (Scheme 1) (25,26).…”