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

V Ganga Reddy; T Srinivasa Reddy; V Lakshma Nayak; Budaganaboyina Prasad; Adiyala Praveen Reddy; A Ravikumar; Shaik Taj; Ahmed Kamal

doi:10.1016/j.ejmech.2016.06.011

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

Eur J Med Chem. 2016 Oct 21:122:164-177. doi: 10.1016/j.ejmech.2016.06.011. Epub 2016 Jun 11.

Authors

V Ganga Reddy¹, T Srinivasa Reddy², V Lakshma Nayak¹, Budaganaboyina Prasad¹, Adiyala Praveen Reddy¹, A Ravikumar³, Shaik Taj¹, Ahmed Kamal⁴

Affiliations

¹ Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
² Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
³ Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India.
⁴ Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India; Catalytic Chemistry Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia. Electronic address: ahmedkamal@iict.res.in.

PMID: 27344493
DOI: 10.1016/j.ejmech.2016.06.011

Abstract

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.

Keywords: Anti-cancer activity; Apoptosis; CDK1 inhibition; Cell cycle; Pyrazole.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
CDC2 Protein Kinase / antagonists & inhibitors*
CDC2 Protein Kinase / chemistry
CDC2 Protein Kinase / metabolism
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
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / metabolism
Pyrazoles / pharmacology*
Reactive Oxygen Species / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Reactive Oxygen Species
CDC2 Protein Kinase