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

Esraa Z Mohammed; Walaa R Mahmoud; Riham F George; Ghaneya S Hassan; Farghaly A Omar; Hanan H Georgey

doi:10.1016/j.bioorg.2021.105347

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

Bioorg Chem. 2021 Nov:116:105347. doi: 10.1016/j.bioorg.2021.105347. Epub 2021 Sep 11.

Authors

Esraa Z Mohammed¹, Walaa R Mahmoud², Riham F George³, Ghaneya S Hassan⁴, Farghaly A Omar⁵, Hanan H Georgey⁶

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt. Electronic address: esraazakaria@o6u.edu.eg.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. Electronic address: riham.eskandar@pharma.cu.edu.eg.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Pharmaceutical Chemistry Department, School of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
⁵ Medicinal Chemistry Department, Faculty of Pharmacy, Assuit University, 71526 Assuit, Egypt.
⁶ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, 11786 Cairo, Egypt.

PMID: 34555628
DOI: 10.1016/j.bioorg.2021.105347

Abstract

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.

Keywords: Anti-proliferative; CDK inhibitors; Molecular docking; Pyrazole based derivatives.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinases / antagonists & inhibitors*
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
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Cyclin-Dependent Kinases