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New diphenyl-1H-pyrazoles were synthesized and screened for CDK2 inhibition where 8d, 9b, 9c, and 9e exhibited promising activity (IC 50 = 51.21, 41.36, 29.31, and 40.54 nM respectively) compared to R-Roscovitine (IC 50 = 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 (GI 50 ranges; 0.181-5.19, 1.07-4.12 and 1.07-4.82 µM, respectively) and (Full panel GI 50 (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.

Titel:	Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs).
Autor/in / Beteiligte Person:	Mohammed, EZ ; Mahmoud, WR ; George, RF ; Hassan, GS ; Omar, FA ; Georgey, HH
Zeitschrift:	Bioorganic chemistry, Jg. 116 (2021-11-01), S. 105347
Veröffentlichung:	Amsterdam : Elsevier ; <i>Original Publication</i>: New York, London, Academic Press., 2021
Medientyp:	academicJournal
ISSN:	1090-2120 (electronic)
DOI:	10.1016/j.bioorg.2021.105347
Schlagwort:	Antineoplastic Agents chemical synthesis Antineoplastic Agents chemistry Apoptosis drug effects Cell Cycle drug effects Cell Line, Tumor Cell Proliferation drug effects Cyclin-Dependent Kinases metabolism Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Humans Models, Molecular Molecular Structure Protein Kinase Inhibitors chemical synthesis Protein Kinase Inhibitors chemistry Pyrazoles chemical synthesis Pyrazoles chemistry Structure-Activity Relationship Antineoplastic Agents pharmacology Cyclin-Dependent Kinases antagonists & inhibitors Protein Kinase Inhibitors pharmacology Pyrazoles pharmacology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Bioorg Chem] 2021 Nov; Vol. 116, pp. 105347. <i>Date of Electronic Publication: </i>2021 Sep 11. MeSH Terms: Antineoplastic Agents / pharmacology ; Cyclin-Dependent Kinases / antagonists & inhibitors ; Protein Kinase Inhibitors / pharmacology ; Pyrazoles / pharmacology ; Antineoplastic Agents / chemical synthesis ; Antineoplastic Agents / chemistry ; Apoptosis / drug effects ; Cell Cycle / drug effects ; Cell Line, Tumor ; Cell Proliferation / drug effects ; Cyclin-Dependent Kinases / metabolism ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Models, Molecular ; Molecular Structure ; Protein Kinase Inhibitors / chemical synthesis ; Protein Kinase Inhibitors / chemistry ; Pyrazoles / chemical synthesis ; Pyrazoles / chemistry ; Structure-Activity Relationship Contributed Indexing: Keywords: Anti-proliferative; CDK inhibitors; Molecular docking; Pyrazole based derivatives Substance Nomenclature: 0 (Antineoplastic Agents) ; 0 (Protein Kinase Inhibitors) ; 0 (Pyrazoles) ; EC 2.7.11.22 (Cyclin-Dependent Kinases) Entry Date(s): Date Created: 20210923 Date Completed: 20220104 Latest Revision: 20220104 Update Code: 20231215

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Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs).