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

Samar El-Kalyoubi; Samiha A El-Sebaey; A M Rashad; Hanan A Al-Ghulikah; Mostafa M Ghorab; Sherin M Elfeky

doi:10.1080/14756366.2023.2198163

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

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2198163. doi: 10.1080/14756366.2023.2198163.

Authors

Samar El-Kalyoubi¹, Samiha A El-Sebaey², A M Rashad^{3

4}, Hanan A Al-Ghulikah⁵, Mostafa M Ghorab⁶, Sherin M Elfeky⁷

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
³ Accelerator and Ion Sources Department, Nuclear Research Center, Atomic Energy Authority, Cairo, Egypt.
⁴ Central Lab for Elemental and Isotopic Analysis, NRC, Atomic Energy Authority, Cairo, Egypt.
⁵ Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
⁶ Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt.
⁷ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

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.

Keywords: Anti-proliferative; HSP90; Pyrimidines; Topoisomerase II; in silico studies.

MeSH terms

A549 Cells
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / pharmacology
Cell Cycle / drug effects
Cell Proliferation / drug effects
Computer Simulation
Gene Expression Regulation / drug effects
HSP90 Heat-Shock Proteins* / antagonists & inhibitors
Hep G2 Cells
Humans
MCF-7 Cells
Pyrimidines* / chemical synthesis
Pyrimidines* / pharmacology
Topoisomerase II Inhibitors* / chemical synthesis
Topoisomerase II Inhibitors* / pharmacology

Substances

Pyrimidines
Topoisomerase II Inhibitors
HSP90 Heat-Shock Proteins
Antineoplastic Agents

Grants and funding

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