Pyrazole ring-containing isolongifolanone derivatives as potential CDK2 inhibitors: Evaluation of anticancer activity and investigation of action mechanism

• Published in: Biomedicine & pharmacotherapy Vol. 139; p. 111663
• Main Authors: Wang, Yunyun, Shi, Wei, Wu, Chenliang, Wan, Lin, Zhao, Yuxun, Zhang, Chenglong, Gu, Wen, Wang, Shifa
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.07.2021; Elsevier
• Subjects: 3D culture models; Anti-cancer activity; Apoptosis; Isolongifolanone; P53 signaling pathway; Pyrazole derivatives; Pyrazole derivatives; P53 signaling pathway; Isolongifolanone; 3D culture models; Anti-cancer activity; Apoptosis
• DOI: 10.1016/j.biopha.2021.111663
• ISSN: 0753-3322

Isolongifolanone is a high value-added sustainable natural product. Recent studies have demonstrated that isolongifolanone possesses anticancer activities. In this study, a series of novel pyrazole ring-containing isolongifolanone derivatives was designed, synthesized, and their anti-proliferative activities in three cancer cell lines were evaluated. Among them, compound 3b exhibited strongest antiproliferative ability on MCF-7 cancer cells and induced the generation of intracellular ROS and mitochondrial depolarization. More importantly, compound 3b still maintained antitumor activity in MCF-7 3D culture systems. The study on molecular mechanism suggested that compound 3b induced apoptosis via activation of caspase-3 and PARP, also via decreasing of Bcl-2 and increasing of Bax and p53. Moreover, compound 3b down-regulated the level of CDK2, a crucial cyclin-dependent kinase which is necessary for the progression of the cells out of the G1 phase of the cell cycle. Docking results showed that compound 3b could bind well with CDK2 by forming hydrogen bonds with amino acid residues (LYS89 and HIS84). These results suggested that compound 3b could be taken as a lead compound for anticancer agents. [Display omitted] •A novel series of pyrazole ring-containing isolongifolanone derivatives were designed and synthesized.•Compound 3b exhibited good antitumor activity against MCF-7 cancer cell line.•Compound 3b down-regulated the level of CDK2 and processed CDK2 inhibitory activity.•Compound 3b promoted the expression of p53 protein, leading to the increased anticancer activity.•Compound 3b exhibited good anticancer activity in MCf-7 spheroidal models.