Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors

Abstract

Novel series of aminopyrimidines bearing a biologically active cyclohexenone 3a–f and oxo-selaneylidene moiety 4, besides selenadiazolopyrimidines (5a–e and 7), were synthesised using 5,6-diaminouracils as starting materials. Compound 3a exhibited strong anti-proliferative activity against three cell lines: HepG-2 (IC₅₀ 14.31 ± 0.83 µM), A-549 (IC₅₀ 30.74 ± 0.76 µM), and MCF-7 (IC₅₀ 27.14 ± 1.91 µM). Also, it was four times more selectively cytotoxic against WI-38 cell lines than doxorubicin. Furthermore, Topoisomerase II (IC₅₀ 4.48 ± 0.65 µM) and HSP90 (IC₅₀ 1.78 ± 0.11 µM) were both strongly inhibited in vitro by 3a. The cell cycle was halted at the G1-S phase, and total apoptotic cells were 65 times more than control Hep-G2 cells. Besides, it increased caspase-3 gene expression, triggering mitochondrial cell death. Molecular docking study indicated that it could bind to Topoisomerase II and HSP90 binding sites in an inhibitory mode. Its geometric properties were investigated using the density functional theory (DFT). Furthermore, compound 3a demonstrated in silico good oral bioavailability.

Graphical Abstract

Keywords:

• Pyrimidines
• Topoisomerase II
• HSP90
• Anti-proliferative
• in silico studies

Acknowledgement

Hanan A. AL-Ghulikah extend her appreciation to Princess Nourah bint Abdulrahman University Researchers Supporting Project number [PNURSP2023R95], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number [PNURSP2023R95], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.