Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors

Abstract

The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC₅₀ values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC₅₀ 10-28 nM) bearing hydrophobic groups (Me, F, CF₃ and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 μM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.

Antiangiogenic 1‐Aryl‐3‐[3‐(thieno[3,2‐b]pyridin‐7‐ylthio)phenyl]ureas Inhibit MCF‐7 and MDA‐MB‐231 Human Breast Cancer Cell Lines Through PI3K/Akt and MAPK/Erk Pathways

“…Altogether, our findings indicate that since these compounds also inhibit some angiogenic steps in endothelial cells [Machado et al, 2015] and in the present study consistently showed anticancer effects at very low concentrations in breast cancer cell lines, particularly in MDA-MB-231 cells, these molecules may have wide therapeutic and/or adjuvant application in the treatment of the most aggressive TNBC. Compounds 1c (R 2 ¼ Me) and 1e (R 1 ¼ Cl, R 2 ¼ CF 3 ) were the most promising compounds, being thus considered for further studies.…”

“…Our previous studies were focused on the inhibitory effects of new 1-aryl-3- [3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas on several steps of angiogenesis, targeting VEGFR-2 tyrosine kinase activity [Machado et al, 2015]. The fact that cancer cells generally overexpress receptors with tyrosine kinase activity (similar to VEGFR-2), led us to investigate whether these compounds also affected breast cancer cells.…”

“…1,1a-e) VEGFR-2 tyrosine kinase inhibitors. These compounds have shown to affect various steps of angiogenesis in human umbilical vein endothelial cells including endothelial cell proliferation, apoptosis, migration, and capillary structure formation in a dose dependent manner, by targeting VEGFR-2 tyrosine kinase signaling pathway [Machado et al, 2015]. The purpose of the present study was to investigate the anticancer potential of the same compounds using two different human breast cancer cell lines, MCF-7-Estrogen receptor (ER) positive and MDA-MB-231-ER, Progesterone receptor (PR) and Human epidermal growth factor receptor 2 (HER2) triple negative (TNBC), highlighting the effects on proliferation, migration and on PI3K/Akt and MAPK/Erk signaling pathways.…”

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…Type II inhibitors induce the inactive DFG‐out conformation of the activation loop, enabling them to occupy the hinge region and an adjacent allosteric site. Hydrogen bond interactions between inhibitors and RTKs afford a common binding conformation for design of inhibitors …”

“…Hydrogen bond interactions between inhibitors and RTKs afford a common binding conformation for design of inhibitors. 194 The three types of RTKIs share a basic architecture for construction, which can be defined by four key interactions:…”