TY - JOUR
T1 - 6-Cinnamoyl-4-arylaminothienopyrimidines as highly potent cytotoxic agents
T2 - Design, synthesis and structure-activity relationship studies
AU - Toolabi, Mahsa
AU - Moghimi, Setareh
AU - Bakhshaiesh, Tayebeh Oghabi
AU - Salarinejad, Somayeh
AU - Aghcheli, Ayoub
AU - Hasanvand, Zaman
AU - Nazeri, Elahe
AU - Khalaj, Ali
AU - Esmaeili, Rezvan
AU - Foroumadi, Alireza
N1 - Funding Information:
This work was supported and funded by Tehran University of Medical Sciences and Health Services Grant no.; 96-04-33-36978 ; and National Institute for Medical Research Development Grant no. 962567 . Appendix A
Publisher Copyright:
© 2019 Elsevier Masson SAS
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - Antiproliferative activity
KW - Cytotoxic
KW - EGFR
KW - Thienopyrimidine
KW - α,β-unsaturated carbonyl
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U2 - 10.1016/j.ejmech.2019.111786
DO - 10.1016/j.ejmech.2019.111786
M3 - Article
C2 - 31671308
AN - SCOPUS:85074152664
SN - 0223-5234
VL - 185
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 111786
ER -