Design, synthesis and biological evaluation of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1,3-diphenyl-1H-pyrazole-4-carboxamides as CDK1/Cdc2 inhibitors

• Published in: European journal of medicinal chemistry Vol. 122; pp. 164 - 177
• Main Authors: Ganga Reddy, V., Srinivasa Reddy, T., Lakshma Nayak, V., Prasad, Budaganaboyina, Reddy, Adiyala Praveen, Ravikumar, A., Taj, Shaik, Kamal, Ahmed
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 21-10-2016
• Subjects: Anti-cancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; CDC2 Protein Kinase - antagonists & inhibitors; CDC2 Protein Kinase - chemistry; CDC2 Protein Kinase - metabolism; CDK1 inhibition; Cell cycle; Cell Line, Tumor; Chemistry Techniques, Synthetic; Drug Design; Drug Screening Assays, Antitumor; G2 Phase - drug effects; Humans; Molecular Docking Simulation; Protein Conformation; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Pyrazole; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - metabolism; Pyrazoles - pharmacology; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; CDK1 inhibition; Pyrazole; Anti-cancer activity; Cell cycle; Apoptosis
• DOI: 10.1016/j.ejmech.2016.06.011
• EISSN: 1768-3254
• ISSN: 0223-5234

A series of new (N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives (8–35) were designed, synthesized and evaluated as CDK1/Cdc2 inhibitors. Biological evaluation assays indicated that compounds 16 and 27 showed the most potent growth inhibitory activity against human cancer cell lines (MIAPaCa-2, MCF-7 and HeLa) with GI50 values ranging from 0.13 to 0.7 μM, compared with the positive control nocodazole (0.81–0.95 μM). Flow cytometric analysis revealed that these compounds induce cell cycle arrest in the G2/M phase and Western blot analysis suggested that compound treatment resulted in reduction of CDK1 expression levels in MCF-7 cell line. Moreover, the apoptosis inducing effect of the compounds was studied using Hoechst staining, Rhodamine 123 staining (MMP), carboxy-DCFDA staining (ROS), Annexin V-FITC assay. Based on these studies, two compounds 16 and 27 have been identified as promising new molecules that have the potential to be developed as leads.
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•28 derivatives (8–35) were synthesized and tested for their antiproliferative activity.•Compounds 16 and 27 showed significant cytotoxicity with GI50 0.13–0.7 μM.•Compounds (16 and 27) induces cell cycle arrest in the G2/M phase.•Western blot analysis showed reduction of CDK1 expression levels in MCF-7 cell line.•These can be considered as interesting lead molecules against breast cancer.