Molecular overlay-guided design of new CDK2 inhibitor thiazepinopurines: Synthesis, anticancer, and mechanistic investigations

Ebtehal M Husseiny; Hamada S Abulkhair; Asmaa Saleh; Najla Altwaijry; Riham A Zidan; Fatma G Abdulrahman

doi:10.1016/j.bioorg.2023.106789

Molecular overlay-guided design of new CDK2 inhibitor thiazepinopurines: Synthesis, anticancer, and mechanistic investigations

Bioorg Chem. 2023 Nov:140:106789. doi: 10.1016/j.bioorg.2023.106789. Epub 2023 Aug 17.

Authors

Ebtehal M Husseiny¹, Hamada S Abulkhair², Asmaa Saleh³, Najla Altwaijry⁴, Riham A Zidan⁵, Fatma G Abdulrahman¹

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City 11754, Cairo, Egypt.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University-Egypt, International Coastal Road, New Damietta 34518, Egypt.
³ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia. Electronic address: asali@pnu.edu.sa.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
⁵ Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.

PMID: 37611530
DOI: 10.1016/j.bioorg.2023.106789

Abstract

Adopting the molecular overlay approach, three novel sets of thiazepinopurines with expected cytotoxicity and CDK2 inhibition potential were designed and synthesized. This was accomplished through the heteroannelation of purines, for the first time, with thiazepine. The obtained thiazepinopurines derivatives were assessed for their cytotoxicity toward tumor cells of three different types, HepG2, MCF-7, and PC-3 as well as one normal cell (WI38). Among the studied compounds, 3b and 3c exhibited significant antiproliferative activity against tumor cells presenting IC₅₀ range of 5.52-17.09 µM in comparison with Roscovitine (9.32-13.82 µM). Additionally, both compounds displayed superior selectivity indices (SI = 3.00-7.15) toward tested cancer cells. The 4-chlorophenyl analog 3b has shown the best selectivity index, and hence it has been subjected to additional investigations to determine its proper mechanistic effect. Accordingly, the CDK2 inhibition potential, apoptosis induction, and cell cycle analysis of MCF-7 were evaluated. Results revealed that this analog displayed a potent CDK2 inhibition potential with an IC₅₀ value of 0.219 µM. Findings also showed that 3b was thought to arrest MCF-7 cell cycle at S phase together with apoptosis induction by the increased expression of Bax, Caspase-8, and -9 markers with a concomitant decrease in Bcl-2 expression. Besides, the probable interaction of 3b with CDK2 binding pocket was investigated by molecular docking.

Keywords: CDK2; Design; Docking; Overlay; Purine; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Death
Cyclin-Dependent Kinase 2
Humans
MCF-7 Cells
Molecular Docking Simulation
Thiazepines* / pharmacology

Substances

Thiazepines
CDK2 protein, human
Cyclin-Dependent Kinase 2