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

• Published in: Journal of medicinal chemistry Vol. 58; no. 18; pp. 7310 - 7327
• Main Authors: Yellol, Jyoti, Pérez, Sergio A, Buceta, Alicia, Yellol, Gorakh, Donaire, Antonio, Szumlas, Piotr, Bednarski, Patrick J, Makhloufi, Gamall, Janiak, Christoph, Espinosa, Arturo, Ruiz, José
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.09.2015; Amer Chemical Soc
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Caspase 3 - metabolism; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Chemistry, Medicinal; Cisplatin - pharmacology; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Crystallography, X-Ray; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Activation; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Humans; Hydrolysis; Hydrophobic and Hydrophilic Interactions; Iridium; Life Sciences & Biomedicine; Mice; Models, Molecular; Molecular Structure; Neovascularization, Physiologic - drug effects; Pharmacology & Pharmacy; Reactive Oxygen Species - metabolism; Ruthenium; Science & Technology; Serum Albumin - metabolism; Structure-Activity Relationship; ANTICANCER ACTIVITY; ORGANOMETALLIC COMPOUNDS; IN-VITRO; BINDING MODES; HYDROGEN-BOND; ZETA VALENCE QUALITY; CRYSTAL-STRUCTURE; BASIS-SETS; LIGAND; METAL-COMPLEXES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01194

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.