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

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.

A decade's overview of 2‐aminothiophenes and their fused analogs as promising anticancer agents

“…[55,56] In 2022, a series of thieno [2,3-d]pyrimidine derivatives containing morpholine were developed by Elmenier and her co-authors to evaluate their PI3K inhibition activity. [57] From 22 derivatives, compound 10 with the 3-hydroxyphenyl group had the most significant activity with an average growth inhibition of 41.8% and 47.3%. According to the structure-activity relationship, the morpholine moiety maintained the activity by binding with the Val amino acid in the hinge region as well as the hydroxyl group on position 3 of the phenyl ring as changing its position or the replacing with its bioisostere results in a significant decrease in the activity.…”

Design and Efficient Synthesis of New 4-Amino-Substituted 2-(4-Bromobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines of Anticancer Interest and Their In Silico Study

“…Some of these compounds are summarised in Figure 2. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] Interestingly, it has been noted that 4-amino substituents, whether aryl/aryl alkyl or urea, play a crucial role in binding to cancer proteins. These findings, particularly regarding the 6-membered ring fused theino [2,3-d]pyridines and their medicinal properties, prompted us to develop a more efficient delivery system for new 4-amino substituted 5,6,7,8tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidines.…”

Recent updates on thienopyrimidine derivatives as anticancer agents

“…Recently in 2022, Elmenier et al synthesized and evaluated a series of 2-aryl-4-morpholinothieno[2,3-d]pyrimidine derivatives as PI3K inhibitors against various isomers PI3Kα, β, and γ in addition to their anticancer activity versus NCI 60 cell lines (Fig. 6) [77]. The enzymatic activity of compounds 29 and 30 with a 3-hydroxyphenyl ring was good for PI3Kβ (62% and 72%) and PI3Kγ (70% and 84%), correspondingly.…”