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Design, synthesis, and biological evaluation of new thieno[2,3-d] pyrimidine derivatives as targeted therapy for PI3K with molecular modelling study

Authors :
Fatma M. Elmenier
Deena S. Lasheen
Khaled A. M. Abouzid
Source :
Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 37, Iss 1, Pp 315-332 (2022), Journal of Enzyme Inhibition and Medicinal Chemistry, article-version (VoR) Version of Record
Publication Year :
2022
Publisher :
Taylor & Francis Group, 2022.

Abstract

Cancer is one of the most aggressive diseases characterised by abnormal growth and uncontrolled cell division. PI3K is a lipid kinase involved in cancer progression which makes it fruitful target for cancer control. 28 new morpholine based thieno[2,3-d] pyrimidine derivatives were designed and synthesised as anti-PI3K agents maintaining the common pharmacophoric features of several potent PI3K inhibitors. Their antiproliferative activity on NCI 60 cell lines as well as their enzymatic activity against PI3K isoforms were evaluated. Three compounds revealed good cytotoxic activities against breast cancer cell lines, especially T-47D. Compound VIb exhibited the best enzymatic inhibitory activity (72% & 84% on PI3Kβ & PI3Kγ), respectively and good activity on most NCI cell lines especially those with over expressed PI3K. Docking was carried out into PI3K active site which showed comparable binding mode to that of the PI-103 inhibitor. Compound VIb could be optimised to serve as a new chemical entity for discovering new anticancer agents.<br />Graphical Abstract

Details

Language :
English
ISSN :
14756374 and 14756366
Volume :
37
Issue :
1
Database :
OpenAIRE
Journal :
Journal of Enzyme Inhibition and Medicinal Chemistry
Accession number :
edsair.doi.dedup.....741a7e8bceb72b020a043bb27b576c6d