Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors
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 cel...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2198163 |
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| author | Samar El-Kalyoubi Samiha A. El-Sebaey A. M. Rashad Hanan A. AL-Ghulikah Mostafa M. Ghorab Sherin M. Elfeky |
| author_facet | Samar El-Kalyoubi Samiha A. El-Sebaey A. M. Rashad Hanan A. AL-Ghulikah Mostafa M. Ghorab Sherin M. Elfeky |
| author_sort | Samar El-Kalyoubi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T02:02:29Z |
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| id | doaj.art-1df0066a07f24a0586d556a33458cb72 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2025-03-20T14:23:02Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-1df0066a07f24a0586d556a33458cb722024-09-09T17:23:19ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138110.1080/14756366.2023.2198163Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitorsSamar El-Kalyoubi0Samiha A. El-Sebaey1A. M. Rashad2Hanan A. AL-Ghulikah3Mostafa M. Ghorab4Sherin M. Elfeky5Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, Port Said, EgyptDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, EgyptAccelerator and Ion Sources Department, Nuclear Research Center, Atomic Energy Authority, Cairo, EgyptDepartment of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi ArabiaDepartment of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, EgyptDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, EgyptNovel 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.https://www.tandfonline.com/doi/10.1080/14756366.2023.2198163PyrimidinesTopoisomerase IIHSP90Anti-proliferativein silico studies |
| spellingShingle | Samar El-Kalyoubi Samiha A. El-Sebaey A. M. Rashad Hanan A. AL-Ghulikah Mostafa M. Ghorab Sherin M. Elfeky Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry Pyrimidines Topoisomerase II HSP90 Anti-proliferative in silico studies |
| title | Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors |
| title_full | Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors |
| title_fullStr | Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors |
| title_full_unstemmed | Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors |
| title_short | Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors |
| title_sort | synthesis dft calculations and anti proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual topoisomerase ii and hsp90 inhibitors |
| topic | Pyrimidines Topoisomerase II HSP90 Anti-proliferative in silico studies |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2198163 |
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