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

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• 作者：Jyoti Yellol ; Sergio A. P茅rez ; Alicia Buceta ; Gorakh Yellol ; Antonio Donaire ; Piotr Szumlas ; Patrick J. Bednarski ; Gamall Makhloufi ; Christoph Janiak ; Arturo Espinosa ; Jos茅 Ruiz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7310-7327
• 全文大小：880K
• ISSN：1520-4804

文摘

A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(畏⁶-p-cymene)RuCl(魏²-N,C-L)] and [(畏⁵-C₅Me₅)IrCl(魏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鈥?b>g) and iridium complexes (4a鈥?b>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鈥揳ctivity 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 渭M, 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.