Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs)
| Autor: | Walaa R. Mahmoud, Esraa Z. Mohammed, Hanan H. Georgey, Farghaly A. Omar, Riham F. George, Ghaneya S. Hassan |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Cell Antineoplastic Agents Apoptosis Biochemistry Structure-Activity Relationship Cyclin-dependent kinase Cell Line Tumor Drug Discovery medicine Humans Molecular Biology Protein Kinase Inhibitors Cell Proliferation Cyclin-dependent kinase 1 biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Cyclin-dependent kinase 2 Cell Cycle Cell cycle Ligand (biochemistry) Molecular biology Cyclin-Dependent Kinases medicine.anatomical_structure Cell culture Docking (molecular) biology.protein Pyrazoles Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic chemistry. 116 |
| ISSN: | 1090-2120 |
| Popis: | New diphenyl-1H-pyrazoles were synthesized and screened for CDK2 inhibition where 8d, 9b, 9c, and 9e exhibited promising activity (IC50 = 51.21, 41.36, 29.31, and 40.54 nM respectively) compared to R-Roscovitine (IC50 = 43.25 nM). Furthermore, preliminary anti-proliferative activity screening of some selected compounds on 60 cancer cell lines was performed at the (NCI/USA). Compounds 8a-c displayed promising growth inhibitory activity (mean %GI; 73.74, 94.32 and 74.19, respectively). Additionally, they were further selected by the NCI for five-dose assay, exhibiting pronounced activity against almost the full panel (GI50 ranges; 0.181–5.19, 1.07–4.12 and 1.07–4.82 µM, respectively) and (Full panel GI50 (MG-MID); 2.838, 2.306 and 2.770 µM, respectively). Screening the synthesized compounds 8a-c for inhibition of CDK isoforms revealed that compound 8a exhibited nearly equal inhibition to all the tested CDK isoforms, while compound 8b inhibits CDK4/D1 preferentially than the other isoforms and compound 8c inhibits CDK1, CDK2 and CDK4 more than CDK7. Flow cytometry cell cycle assay of 8a-c on Non-small cell lung carcinoma (NSCL HOP-92) cell line revealed S phase arrest by 8a and G1/S phase arrest by 8b and 8c. Apoptotic induction in HOP-92 cell line was also observed upon treatment with compounds 8a-c. Docking to CDK2 ATP binding site revealed similar interactions as the co-crystallized ligand R-Roscovitine (PDB code; 3ddq). These findings present compounds 8a-c as promising anti-proliferative agents. |
| Databáze: | OpenAIRE |
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