A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights.

Autor: Al-Sanea MM; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf Province, Saudi Arabia., Obaidullah AJ; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia., Shaker ME; Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt., Chilingaryan G; Institute of Biomedicine and Pharmacy, Russian-Armenian University, Yerevan 0051, Armenia., Alanazi MM; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia., Alsaif NA; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia., Alkahtani HM; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia., Alsubaie SA; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia., Abdelgawad MA; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf Province, Saudi Arabia.; Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2021 Jan 14; Vol. 26 (2). Date of Electronic Publication: 2021 Jan 14.
DOI: 10.3390/molecules26020412
Abstrakt: Background: Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold ( HI 5 ) was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound.
Methods: The potential anti-cancerous effect of HI 5 was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies.
Results: The results revealed that HI 5 exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of HI 5 was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, HI 5 blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers ( syn and anti ) is responsible for binding affinity and intrinsic activity of HI 5 . However, the molecular dynamic studies have confirmed that the syn -isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity.
Discussion: These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer.
Databáze: MEDLINE
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