Cytotoxic Ruthenium(II) Complexes of Pyrazolylbenzimidazole Ligands That Inhibit VEGFR2 Phosphorylation

Abstract

Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [Ru II (p-cym)(L)-X] + [where the ligand L is 2-(1H-pyrazol-1-yl)-1H-benzo [d]imidazole (L1) substituted at the 4 position of the pyrazole ring by Cl (L2), Br (L3), or I (L4) and X = Cl − and I − ] were synthesized and characterized using various analytical techniques. Complexes 1 and 3 were also characterized by single-crystal X-ray crystallography, and they crystallized as a monoclinic crystal system in space groups P2 1 /n and P2 1 /c, respectively. The complexes display good solution stability at physiological pH 7.4. The iodido-coordinated pyrazolylbenzimidazole ruthenium(II) p-cymene complexes (2, 4, 6, and 8) are more resistant toward hydrolysis and have less tendency to form monoaquated complexes in comparison to their chlorido analogues (1, 3, 5, and 7). The halido-substituted 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole ligands, designed as organic-directing molecules, inhibit vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. In addition, the ruthenium(II) complexes display a potential to bind to DNA bases. The cytotoxicity profile of the complexes (IC 50 ca. 9−12 μM for 4−8) against the triple-negative breast cancer cells (MDA-MB-231) show that most of the complexes are efficient. The lipophilicity and cellular accumulation data of the complexes show a good correlation with the cytotoxicity profile of 1−8. The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis. The inhibition of VEGFR2 phosphorylation with the representative ligands L2 and L4 and the corresponding metal complexes 3 and 7 in vitro shows that the organic-directing ligands and their complexes inhibit VEGFR2 phosphorylation. Besides, L2, L4, 3, and 7 inhibit the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and proto-oncogene tyrosine-protein kinase (Src), capable of acting downstream of VEGFR2 as well as independently. Compounds L2, L4, 3, and 7 have a lesser effect on ERK1/2 and more prominently affect Src phosphorylation. We extended the study for L2 and 3 in the Tg(fli1:gfp) zebrafish model and found that L2 is more effective in vivo compared to 3 in inhibiting angiogenesis.

Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes Chelating Hybrid sp2-N/sp3-N Donor Ligands to Achieve Improved Anticancer Selectivity

“…310 and 370 nm were observed, respectively. These absorption bands below 300 nm can be attributed to spin-allowed ligand-centered π–π* transitions and the absorption bands between 300 and 450 nm were considered to be associated with charge transfer or d–d transitions, which is similar to some reported half-sandwich Ir­(III), Rh­(III), and Ru­(II) complexes. − …”

Inhibition of NF-κB-Mediated Proinflammatory Transcription by Ru(II) Complexes of Anti-Angiogenic Ligands in Triple-Negative Breast Cancer

“…The complexes exhibits Ru–C bond distances spanning from 2.16 to 2.23 Å. Additionally, the distance of ca. 1.68 Å between the Ru­(II) and the centroid of the p -cymene ring in 4 and 5 matches well with existing literature . The Ru–N1 (pyrazole ring nitrogen) bond length (2.108–2.112 Å) was longer than the Ru–N2 (benzimidazole ring nitrogen) bond length (2.071–2.079 Å) and the N1–Ru–N2 subtends an angle of 75.92(18) and 75.40(7)° in 4 and 5 , respectively.…”

“…HMEC-1 is an immortalized dermal endothelial cell line that can be employed as a substitute for primary human endothelial cells for such studies. VEGFR2 serves as the principal mediator of VEGF-induced intracellular signaling, which has high significance in wound healing and tumor growth , by VEGF165a in the HMEC-1 cell line and treated with 10 μM of L3 , L5 , 6 , 12 and compared to our previously reported L3 p , 3 p . The ligands are more efficient and effectively suppress the phosphorylation of Y 1175 .…”

Synthesis of a half-sandwich complex of ruthenium(ii) with a nonsymmetric bis-nitrogen donor ligand: biological investigations

“…Furthermore, structures and bond lengths of Ru-arene complexes containing N,N-donor ligands that behave as bidentate have been reported to be comparable to those of 1. 41,42 In addition, the crystal packing view for 1 is presented in Fig. S8 (ESI †), and it shows that there are multiple short contacts both inside and between the molecules.…”