Dual Targeting of VEGFR2 and C-Met Kinases via the Design and Synthesis of Substituted 3-(Triazolo-thiadiazin-3-yl)indolin-2-one Derivatives as Angiogenesis Inhibitors

Abstract

The vascular endothelial growth factor receptor 2 (VEGFR2) and c-mesenchymal epithelial transition factor (c-Met) are members of receptor tyrosine kinases which have a crucial role in the process of angiogenesis. Isatin moiety is a versatile group that is shared in many compounds targeting both c-Met and VEGFR2 kinases. In this study, we designed and synthesized different derivatives of substituted 3-(triazolo-thiadiazin-3-yl)indolin-2-one derivatives (<b>6a-y</b>) as dual inhibitors for c-Met and VEGFR2 enzymes. Eight compounds <b>6a</b>, <b>6b</b>, <b>6e</b>, <b>6l</b>, <b>6n</b>, <b>6r</b>, <b>6v</b>, and <b>6y</b> were assessed for their anticancer activities against a panel of 58 cancer cell lines according to the US-NCI protocol. Compound <b>6b</b> revealed the most effective antiproliferative potency (GI %), with broad-spectrum activity against different subpanels of the most NCI 58 tumor cell lines. An in vivo hen's egg-chorioallantoic membrane (HET-CAM) angiogenic study was carried out for 21 compounds <b>6a</b>, <b>b</b>, <b>d</b>, <b>f</b>, <b>h</b>, <b>i</b>, <b>k-o</b>, <b>t</b>, and <b>6x</b> to check their mortality and toxicity. At 100 μM concentration, all compounds produced 100% mortality of the chick embryos. At 40 μM concentration, 13 compounds did not exhibit any detectable mortality (nontoxic) and revealed a potent antiangiogenic effect. Seven compounds <b>6b</b>, <b>6d</b>, <b>6f</b>, <b>6n</b>, <b>6o</b>, <b>6t</b>, and <b>6x</b> significantly decreased the number of blood vessels, and compound <b>6b</b> was the most effective antiangiogenic agent comparable to dexamethasone. Molecular docking studies were conducted for compound <b>6b</b> to investigate its mode of interaction within the binding site of both c-Met and VEGFR2 kinases.