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Synthesis of new arylazopyrazoles as apoptosis inducers: Candidates to inhibit proliferation of MCF‐7 cells
Author(s) -
Ismail Magda M. F.,
Soliman Dalia H.,
Sabour Rehab,
Farrag Amel M.
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000214
Subject(s) - chemistry , pharmacophore , cytotoxicity , stereochemistry , apoptosis , cell culture , cell cycle , cell growth , cyclin dependent kinase 2 , docking (animal) , mcf 7 , imatinib , cell cycle checkpoint , pharmacology , biochemistry , in vitro , biology , cancer research , cancer cell , medicine , cancer , genetics , myeloid leukemia , nursing , human breast
New 4‐arylazo‐3,5‐diamino‐1 H ‐pyrazole derivatives substituted in the 4‐aryl ring with the acetyl moiety were designed and synthesized. The antiproliferative activity of the novel arylazopyrazoles was examined against the MCF‐7 cell line. Among all target compounds, 8b (IC 50 3.0 µM) and 8f (IC 50 4.0 µM) displayed higher cytotoxicity as compared with the reference standard imatinib (IC 50 7.0 µM). Further studies to explore the mechanism of action were performed on the most active hit of our library, 8b , via anti‐CDK2 kinase activity. It demonstrated good inhibitory effects for CDK2 (IC 50 0.24 µM) with 62.5% inhibition, compared with imatinib. The cell cycle analysis in the MCF‐7 cell line revealed apoptosis induction by 8b and cell cycle arrest at the S phase. Docking in the CDK2 active site and pharmacophore modeling confirmed the affinity of 8b to the CDK2 active site. Absorption, distribution, metabolism, and excretion studies revealed that our target compounds are orally bioavailable, with no permeation through the blood–brain barrier.