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6-Cinnamoyl-4-Arylaminothienopyrimidines As Highly Potent Cytotoxic Agents: Design, Synthesis and Structure-Activity Relationship Studies Publisher Pubmed



Toolabi M1 ; Moghimi S2 ; Bakhshaiesh TO3 ; Salarinejad S1 ; Aghcheli A1 ; Hasanvand Z1 ; Nazeri E3 ; Khalaj A1 ; Esmaeili R3 ; Foroumadi A1, 2
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran

Source: European Journal of Medicinal Chemistry Published:2020


Abstract

In this paper, we described the synthesis and cytotoxic activities of two new series of thieno[2,3-d]pyrimidine and thieno[3,2-d] pyrimidine derivatives. Most of the synthesized compounds had significant antiproliferative activities against PC3, MDA-MB-231, A549, and HeLa cell lines in comparison to the reference drug, erlotinib. Compounds N-(4-((3,5-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)cinnamamide 8e and (E)-N-(4-((3,4-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)-3-(4-methoxyphenyl)acrylamide 8g with IC50 values of 4 nM and 33 nM, respectively, against HeLa cell line were chosen for further studies. The apoptosis induced activity and cell cycle arrest were determined and the results provided evidence that these compounds induced cell death via apoptosis and arrested cell growth in sub-G1 phase. In addition, western blot analysis manifested the promising result of suppressing the EGFR signaling pathway (p-EGFR/p-ERK1/2). The docking studies appreciated the considerable potency of compound 8e based on hydrogen and covalent binding interactions. Eventually, in silico pharmacokinetic prediction indicated the acceptable bioavailability of all final compounds. © 2019 Elsevier Masson SAS
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