title: Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs.
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 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.
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Minrui
authors.initials: M
authors.lastname: Ou
authors.affiliation: College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Wu
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Lue
authors.initials: L
authors.lastname: Wang
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Zou
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA, 98105, USA.
authors.forename: Yitong J
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: College of Chemistry, Fuzhou University, Fuzhou, 350002, China.|Biopharmaceutical Photocatalysis State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, 350002, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Shao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008546:Melanoma, Experimental; D051379:Mice; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D000970:Antineoplastic Agents; D014315:Triterpenes; D000097245:Ursolic Acid
keywords: anticancer drug; cytotoxicity; synthesis; ursolic acid derivatives