Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity
Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivativ...
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Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2086866 |
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| author | Asmaa A. Mandour Ibrahim F. Nassar Mohammed T. Abdel Aal Mahmoud A. E. Shahin Wael A. El-Sayed Maghawry Hegazy Amr Mohamed Yehia Ahmed Ismail Mohamed Hagras Eslam B. Elkaeed Hanan M. Refaat Nasser S. M. Ismail |
| author_facet | Asmaa A. Mandour Ibrahim F. Nassar Mohammed T. Abdel Aal Mahmoud A. E. Shahin Wael A. El-Sayed Maghawry Hegazy Amr Mohamed Yehia Ahmed Ismail Mohamed Hagras Eslam B. Elkaeed Hanan M. Refaat Nasser S. M. Ismail |
| author_sort | Asmaa A. Mandour |
| collection | DOAJ |
| description | Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4–15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity. |
| format | Article |
| id | doaj-art-1e6ab14dd8874e4886ee7d210668ea2f |
| institution | DOAJ |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-1e6ab14dd8874e4886ee7d210668ea2f2025-08-20T03:22:12ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013711957197310.1080/14756366.2022.2086866Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activityAsmaa A. Mandour0Ibrahim F. Nassar1Mohammed T. Abdel Aal2Mahmoud A. E. Shahin3Wael A. El-Sayed4Maghawry Hegazy5Amr Mohamed Yehia6Ahmed Ismail7Mohamed Hagras8Eslam B. Elkaeed9Hanan M. Refaat10Nasser S. M. Ismail11Pharmaceutical Chemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo, EgyptFaculty of Specific Education, Ain Shams University (ASU), Cairo, EgyptChemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom, EgyptChemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom, EgyptChemistry Department, College of Science, Qassim University, Qassim, Saudi ArabiaBiochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptBiochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptBiochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptDepartment of Pharmaceutical Organic Chemistry, College of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptDepartment of Pharmaceutical Science, College of Pharmacy, Al Maarefa University, Riyadh, Saudi ArabiaPharmaceutical Chemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo, EgyptPharmaceutical Chemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo, EgyptCyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4–15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.https://www.tandfonline.com/doi/10.1080/14756366.2022.2086866PyrazolopyrimidineCDK2apoptosiscytotoxicityADMET |
| spellingShingle | Asmaa A. Mandour Ibrahim F. Nassar Mohammed T. Abdel Aal Mahmoud A. E. Shahin Wael A. El-Sayed Maghawry Hegazy Amr Mohamed Yehia Ahmed Ismail Mohamed Hagras Eslam B. Elkaeed Hanan M. Refaat Nasser S. M. Ismail Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity Journal of Enzyme Inhibition and Medicinal Chemistry Pyrazolopyrimidine CDK2 apoptosis cytotoxicity ADMET |
| title | Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity |
| title_full | Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity |
| title_fullStr | Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity |
| title_full_unstemmed | Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity |
| title_short | Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity |
| title_sort | synthesis biological evaluation and in silico studies of new cdk2 inhibitors based on pyrazolo 3 4 d pyrimidine and pyrazolo 4 3 e 1 2 4 triazolo 1 5 c pyrimidine scaffold with apoptotic activity |
| topic | Pyrazolopyrimidine CDK2 apoptosis cytotoxicity ADMET |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2086866 |
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