Disruption of the Microtubule Network and Inhibition of VEGFR2 Phosphorylation by Cytotoxic <i>N</i>,<i>O</i>-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 (<b>1</b>-<b>5</b>) of three <i>N</i>,<i>O</i> and <i>N</i>,<i>N</i> donor-based trimethoxyanilines containing Schiff bases with the general formula [Pt^II(L)(DMSO)Cl], [Ru^II(L)(<i>p</i>-cymene)Cl], [Ru^II(L)(<i>p</i>-cymene)Cl]⁺, and [Pt^II(L)Cl₂]. All of the complexes are characterized by different analytical techniques. ¹H NMR and electrospray ionization mass spectrometry (ESI-MS) data suggest that the <i>N</i>,<i>O</i>-coordinated Pt(II) complexes undergo slower aquation compared to the Ru(II) analogues. The change of the coordination mode to <i>N</i>,<i>N</i> causes the Ru complexes to be more inert to aquation. The <i>N</i>,<i>O</i>-coordinating complexes show superiority over <i>N</i>,<i>N</i>-coordinating complexes by displaying excellent <i>in vitro</i> antiproliferative activity against different aggressive cancer cells, <i>viz</i>., triple-negative human metastatic breast adenocarcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. <i>In vitro</i> cytotoxicity studies suggest that Pt(II) complexes are more effective than their corresponding Ru(II) analogues, and the most cytotoxic complex <b>3</b> 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 <i>N</i>,<i>O</i>-coordinated complexes (<b>1</b>-<b>3</b>) 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 <b>1</b> and <b>2</b> 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).