Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs. (14th July 2015)

• Record Type: Journal Article
• Authors: Yang, Xiang; Li, Yuanfang; Jiang, Wei; Ou, Minrui; Chen, Yali; Xu, Yu; Wu, Qiong; Zheng, Qing; Wu, Fuqiang; Wang, Lue; Zou, Wentao; Zhang, Yitong J.; Shao, Jingwei
• Is Part Of: Chemical biology & drug design. Volume 86:Number 6(2015:Dec.)
• Page Start: 1397
• Page End: 1404
• Publication Date: 2015-07-14
• Subjects: anticancer drug -- cytotoxicity -- synthesis -- ursolic acid derivatives; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12608
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : Ursolic acid (UA ) is a natural product which has been shown to possess a wide range of pharmacological activities, in particular those with anticancer activity. In this study, 13 novel ursolic acid derivatives were designed and synthesized in an attempt to further improve compound potency. The structures of the newly synthesized compounds were confirmed using mass spectrometry, infrared spectroscopy, and 1 H NMR. The ability of theUA derivatives to inhibit cell growth was assayed against both various tumor cell lines and a non‐pathogenic cell line, HELF. Analysis of theoretical toxicity risks for all derivatives was performed using OSIRIS and indicated that the majority of compounds would present moderate to low risks. Pharmacological results indicated that the majority of the derivatives were more potent growth inhibitors thanUA . In particular, 5b demonstrated IC50 values ranging from 4.09 ± 0.27 to 7.78 ± 0.43 μ m against 12 different tumor cell lines. Flow cytometry analysis indicated that5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed thatUA could bind to cyclins D1 (Cyc D1) and cyclin‐dependent kinases (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of5b could bind with glucokinase (GK), glucose transporter 1 (GLUT1), and ATPase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that5b was capable of inducing apoptosis and decreasing cell viability in a dose‐dependent manner. Abstract : A series ofUA piperazine derivatives were designed and synthesized to improve the anticancer activity and to explore the structure‐activity relationships. The effects of the most potent compound5b on cell proliferation, apoptosis induction and cell cycle were evaluated. Furthermore, we also analyzed the protein‐ligand interaction with5b by using molecular modelling studies.