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.

Smart design and efficient synthesis of benzimidazole Ru, Ir and Rh cyclometalated complexes are reported with promising cytotoxic activity against HT29, T47D, A2780 and A2780cisR cancer cell lines. Their apoptosis, accumulation, cell cycle arrest, protein binding and DNA binding effects are also discussed.

The design of small molecules that can target the aggregation of Aβ as potential therapeutic agents for Alzheimer's disease is an area of study that has attracted a lot of attention recently. The novel ligand methyl 1-butyl-2-pyridyl-benzimidazole carboxylate was prepared for the synthesis of a series of new iridium(III), ruthenium(II), and platinum(II) 2-pyridyl-benzimidazole complexes. The crystal structure of the half-sandwich iridium(III) complex was established by X-ray diffraction. An arrangement of two cationic complexes in the unit cell is observed, and it seems to be organized by weak π···π interactions that are taking place between two symmetry-related benzimidazole ring systems. All new compounds inhibited aggregation of Aβ1-42 in vitro as shown by both thioflavin T fluorescence assay and transmission electron microscopy. Among them the Ir compound rescued the toxicity of Aβ1-42 in primary cortical neurons effectively.

A series of 6 substitutionally inert and luminescent iridium(iii) antitumor agents of the type [Ir(CN)(NN)][PF] containing a benzimidazole NN ligand with an ester group as a handle for further functionalization has been prepared. They exhibit IC values in the high nanomolar range in some ovarian and breast cancer cell lines (approximately 100× more cytotoxic than cisplatin (CDDP) in MDA-MB-231) and are located in the actin cortex predominantly as shown by confocal luminescence microscopy. This discovery could open the door to a new large family of drug bioconjugates with diverse and simultaneous functions.

Our study demonstrates that four novel kinetically inert C,N-cyclometalated Ru complexes of the type [Ru(C^N)(N^N) ][PF ] containing a handle for functionalization on the C^N ligand are very potent cytotoxic agents against several different human cancer cell lines and are up to 400-fold more potent than clinically used cisplatin. In addition, the investigated ruthenium complexes are less cytotoxic in noncancerous cells, and exhibit higher selectivity for cancer cells than conventional platinum anticancer drugs. The high potency of the investigated ruthenium compounds can be attributed to several factors, including enhanced internalization and their capability to change mitochondrial transmembrane potential in cells. The new ruthenium complexes also interfere with protein synthesis with a markedly higher potency than conventional inhibitors of DNA translation. Notably, the latter mechanism has not been hitherto described for other cytotoxic Ru compounds and cisplatin.

A series of six osmium(ii) complexes of the type [(η6-p-cymene)Os(C^N)X] (X = chlorido or acetato) containing benzimidazole C^N ligands with an ester group as a handle for further functionalization have been synthesized. They exhibit IC50 values in the low micromolar range in a panel of cisplatin (CDDP)-resistant cancer cells (approximately 10× more cytotoxic than CDDP in MCF-7), decrease the levels of intracellular ROS and reduce the NAD+ coenzyme, and inhibit tubulin polymerization. This discovery could open the door to a new large family of osmium(ii)-based bioconjugates with diverse modes of action.