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.

Graphical Abstract

Keywords:

• Thieno[2,3-d] pyrimidine
• PI3K and its isoforms
• lipid kinase
• cancer
• molecular docking

Acknowledgements

The authors express their thanks to the Center of Excellence for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, for performing the NMR spectroscopy of the compounds. The authors are very grateful to the National Cancer Institute “NCI,” Maryland, USA for the in vitro anticancer screening of all the synthesized compounds and would like to thank Thermo Fischer Scientific and Nawah Scientific Inc for performing the PI3K inhibitory assay and IC₅₀ for the synthesized compounds, respectively.

Author contributions

K.A.M. Abouzid designed the whole study. K.A.M. Abouzid and D.S. Lasheen supervised the chemistry work. F.M. Elmenier synthesised the compounds, performed the molecular modelling study, discussed results and prepared this manuscript. All the authors reviewed and approved the manuscript.

Disclosure statement

The authors have declared no conflict of interests.

Data availability statement

All data generated or analysed during this study are included in this published article in the main manuscript.