Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs
| Autor: | Yitong J. Zhang, Minrui Ou, Qiong Wu, Xiang Yang, Xu Yu, Wentao Zou, Yali Chen, Fuqiang Wu, Lue Wang, Yuanfang Li, Jingwei Shao, Jiang Wei, Qing Zheng |
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| Rok vydání: | 2015 |
| Předmět: |
Cell Survival
Melanoma Experimental Antineoplastic Agents Apoptosis Biology Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship Ursolic acid Cell Line Tumor Drug Discovery Animals Humans Viability assay Cytotoxicity Cell Proliferation Pharmacology Cell growth Organic Chemistry Acridine orange Cell Cycle Checkpoints Hep G2 Cells Triterpenes chemistry Cell culture Docking (molecular) Drug Design Cancer cell MCF-7 Cells Molecular Medicine Drug Screening Assays Antitumor HT29 Cells HeLa Cells |
| Zdroj: | Chemical biologydrug design. 86(6) |
| ISSN: | 1747-0285 |
| Popis: | 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 IC50 values ranging from 4.09 ± 0.27 to 7.78 ± 0.43 μm 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 (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b 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 that 5b was capable of inducing apoptosis and decreasing cell viability in a dose-dependent manner. |
| Databáze: | OpenAIRE |
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