Ruthenium(ii) p-cymene complexes of a benzimidazole-based ligand capable of VEGFR2 inhibition: hydrolysis, reactivity and cytotoxicity studies

Abstract

The design of Ru or other metal-based anticancer agents may achieve better and faster optimization if the ligands used are also designed to have standalone functions. In this scenario, even after dissociation from the metal complex under adverse conditions, the ligand would have anti-cancer properties. In our work, we have generated a bispyrazole-containing benzimidazole ligand with potency against vascular endothelial growth factor receptor 2 (VEGFR2), which is known to have roles in vasculogenesis/angiogenesis. This ligand was used to obtain ternary Ru(ii) p-cymene complexes with the formulations [(η-p-cymene)Ru(HL)(Cl)](Cl) (1), [(η-p-cymene)Ru(HL)(Br)](Br) (2) and [(η-p-cymene)Ru(HL)(I)](I) (3). H NMR data supports that hydrolysis of the complex is governed by halide substitution, and the extent of hydrolysis followed the trend 3> 1 > 2. All the complexes have low affinity towards DNA bases (average K ∼ 10 M for CT DNA); however, all the complexes are cytotoxic in nature, with IC values less than 15 μM. The presence of excess glutathione (GSH) liberates HL from the complexes in solution. The ability of the Ru complex to impair mitochondrial function and reduce the cellular GSH pool is thought to be the reason that it retains activity in the presence of GSH despite the ability of GSH to degrade the complexes. The chloride analogue 1 shows the best in vitro cytotoxicity against a prostate cancer cell line (LNCaP), with an IC of 6.4 μM. The complexes show anti-proliferative activity by the mitochondria-mediated intrinsic apoptotic pathway. Docking studies showed that HL has high affinity towards vascular endothelial growth factor receptor 2 (VEGFR2). The complexes show anti-metastatic activity (in vitro) at almost non-toxic dosages, and the effect is sustained even 48 h after removal of the complexes from the culture media.

Design, Synthesis, Characterization and Biological Evaluation of Ruthenium Complexes of Flavonethiosemicarbazones as Antiproliferative and Mycobacterial Activities

“…The presence of 2,2′‐bipyridyl in the complexes MB1 to MB3 have been confirmed due to the appearance of signals at δ 7.50, 7.70, 8.15, 8.85 ppm. While the appearance of resonances at 7.90 (d), 8.35 (d), and 8.90 ppm are indicative of the presence of 1,10 phenanthroline co‐ligand in the complexes MP1 to MP3 . Therefore, the integrated FTIR and 1 H NMR spectral studies suggest that the flavonethiosemicarbazone ligand coordinates to Ru(II) center through their C=S and imine group to produce five membered chelate ring (Scheme ).…”

Antibacterial and Cytotoxic Activity of Ruthenium‐p‐cymene Complexes with 2‐Methylquinolin‐8‐ol Derivatives

“…To illustrate this effect, the chemical shift range for carbon atoms C‐2, C‐8 and C‐10 for ligands ( 2–11 ) and complexes ( 12–22 ) are presented in Table 1. These are the most affected carbon atoms and the increase in the chemical shift values suggest a decrease in electron density of quinoline moiety exerted by ruthenium coordination [4] . A full list of 13 C NMR data can be found in the Supplementary material (Table S1).…”

“…These are the most affected carbon atoms and the increase in the chemical shift values suggest a decrease in electron density of quinoline moiety exerted by ruthenium coordination. [4] A full list of 13 C NMR data can be found in the Supplementary material (Table S1).…”

“…The p-cymene group is the "stool top" with three coordination sites occupied by an N,O-chelate and a chlorido as a monodentate ligand around the ruthenium center. [2] A large number of these type of complexes exert anticancer activity against colon, [2b] breast, [3] ovary, [3] prostate, [4] and pancreas cell lines; [5] additionally, antibacterial activity has also been reported for them. [6] Although not all bioactive ligandruthenium complexes results as potent, [7] several organic compounds bearing N,O-moieties with reported biological activities have been used to build ruthenium(II) complexes, such are the pyrazolone [8] and quinoline derivatives ( Figure 1).…”

Synthesis, Characterization and Cytotoxicity Evaluation on Monocytic Cell Line THP1 of Ru(II) Complexes with 1, 2-Disubstituted Benzimidazoles

“…The gas phase geometry optimizations for all the complexes were performed by using DFT with the B3LYP exchange correlation functions and using Gaussion-09. 30 The full geometry optimisation were performed by using the LANL2DZ basis set for metal ion and 6-31G(d) basis set for C, H, and N atoms. The geometry optimised structures of the complexes show the similarity with the reported crystal structure of the similar type of the moiety.…”