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Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs
Author(s) -
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
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12608
Subject(s) - chemistry , ursolic acid , cell cycle , biochemistry , cell cycle checkpoint , cell culture , viability assay , cell growth , hela , cyclin dependent kinase , acridine orange , stereochemistry , cell , apoptosis , biology , genetics , chromatography
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 the UA 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 than UA . In particular, 5b demonstrated IC 50 values ranging from 4.09 ± 0.27 to 7.78 ± 0.43 μ m against 12 different tumor cell lines. Flow cytometry analysis indicated that 5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed that UA could bind to cyclins D1 (Cyc D1) and cyclin‐dependent kinases ( CDK 6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b could bind with glucokinase ( GK ), glucose transporter 1 ( GLUT 1), and ATP ase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that 5b was capable of inducing apoptosis and decreasing cell viability in a dose‐dependent manner.