Disruption of the Microtubule Network and Inhibition of VEGFR2 Phosphorylation by Cytotoxic N,O-Coordinated Pt(II) and Ru(II) Complexes of Trimethoxy Aniline-Based Schiff Bases

Abstract

Platinum-based complexes are one of the most successful chemotherapeutic agents having a significant ground in cancer chemotherapy despite their side effects. During the past few decades, Ru(II) complexes have been emerging as efficient alternatives owing to their promising activities against platinum-resistant cancer. The pathway of action, lipophilicity, and cytotoxicity of a Pt or Ru complex may be tuned by varying the attached ligands, the coordination mode, and the leaving group. In this work, we report a family of Pt(II) and Ru(II) complexes ( 1−5) of three N,O and N,N donor-based trimethoxyanilines containing Schiff bases with the general formula [Pt II (L)(DMSO)Cl], [Ru II (L)(pcymene)Cl], [Ru II (L)(p-cymene)Cl] + , and [Pt II (L)Cl 2 ]. All of the complexes are characterized by different analytical techniques. 1 H NMR and electrospray ionization mass spectrometry (ESI-MS) data suggest that the N,O-coordinated Pt(II) complexes undergo slower aquation compared to the Ru(II) analogues. The change of the coordination mode to N,N causes the Ru complexes to be more inert to aquation. The N,O-coordinating complexes show superiority over N,Ncoordinating complexes by displaying excellent in vitro antiproliferative activity against different aggressive cancer cells, viz., triplenegative human metastatic breast adenocarcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2.In vitro cytotoxicity studies suggest that Pt(II) complexes are more effective than their corresponding Ru(II) analogues, and the most cytotoxic complex 3 is 10−15 times more toxic than the clinical drugs cisplatin and oxaliplatin against MDA-MB-231 cells. Cellular studies show that all of the N,O-coordinated complexes (1−3) initiate disruption of the microtubule network in MDA-MB-231 cells in a dose-dependent manner within 6 h of incubation and finally lead to the arrest of the cell cycle in the G2/M phase and render apoptotic cell death. The disruption of the microtubule network affects the agility of the cytoskeleton rendering inhibition of tyrosine phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a key step in angiogenesis. Complexes 1 and 2 inhibit VEGFR2 phosphorylation in a dose-dependent fashion. Among the Pt(II) and Ru(II) complexes, the former displays higher cytotoxicity, a stronger effect on the cytoskeleton, better VEGFR2 inhibition, and strong interaction with the model nucleobase 9-ethylguanine (9-EtG).

Trifluoromethyl substitution enhances photoinduced activity against breast cancer cells but reduces ligand exchange in Ru(ii) complex

“…Importantly, this level of activity is $10fold greater than that of oxaliplatin and cisplatin against MDA-MB-231 cells, and more potent than a number of promising new platinum and ruthenium compounds. 70,71 [3,2-a:2 0 ,3 0 -c]phenazine), with EC I 50 ¼ 4.6 AE 0.5 mM, a lead compound reported by us previously that generates 1 O 2 and releases pyridine. 56 As described earlier, when solutions of 1-5 are irradiated in water, the CH 3 CN ligand in each complex is substituted with a solvent H 2 O molecule, resulting in the corresponding Ru(II) mono-aqua complex.…”

Synthesis, Structure and Cytotoxicity of N,N and N,O‐Coordinated RuII Complexes of 3‐Aminobenzoate Schiff Bases against Triple‐negative Breast Cancer

“…The IC 50 values of the N,O coordinated complexes match well with our previously reported N,O coordination bearing ligands in terms of efficacy. [67,75] Thus, esterification and variation of the aldehyde groups, accompanied by change in coordination mode from N,N to N,O, showed wide variation in cytotoxicity profile against MDA-MB-231. In some previous reports, the switch of coordination mode from N,N to N,O resulted in increased efficacy.…”

A Review on the Advancements in the Field of Metal Complexes with Schiff Bases as Antiproliferative Agents

“…Additionally, the cellular target of compound 34 was predicted by molecular docking studies, suggesting that it possesses a high affinity to specifically bind the BIR3 domain of XIAP. Acharya et al (2021) [59] studied Pt-and Ru-based complexes, which are two of the most successful chemotherapeutic agents having a significant role in cancer chemotherapy despite their side effects. Pt(II) and Ru(II) complexes (35)(36)(37)(38) containing Schiff bases displayed an in vitro antiproliferative activity against different aggressive cancer cells, viz., human pancreatic carcinoma (MIAPaCa-2), hepatocellular carcinoma (HepG2), triple-negative human metastatic breast adenocarcinoma (MDA-MB-231), human embryonic kidney (HEK-293), and human foreskin fibroblast (HFF-1) compared to the clinical drug oxaliplatin, used as reference (IC 50 = 5.7, 9.8, 19.2, 2.1 and 7.0 µM, respectively).…”