title: Synthesis and biological evaluation of lovastatin-derived aliphatic hydroxamates that induce reactive oxygen species.
abstract: Some hydroxamate compounds induce cancer cell death by intracellular reactive oxygen species (ROS). This study introduced the hydroxamate core into lovastatin, a fungus metabolite clinically used for the treatment of hypercholesterolemia. The resulting compounds were evaluated for the activity for inducing ROS production. Most compounds exhibited higher activity than original lovastatin. Of these compounds, compound 3c had the most potent activity. Test of cytotoxicity in a panel of human cancer cell lines indicated compound 3c had activities superior to cisplatin in prostate cancer PC-3 cells and breast cancer T47D cells. In contrast, it in amounts up to 40μM had a much lower cytotoxic effect on normal human IMR-90 cells. Further profiling of cell cycle progression, cell apoptosis, and DNA damage activated checkpoint signaling pathway revealed the important role of compound 3c-mediated cytotoxicity in ROS generation.
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan; Professional Master Program in Pharmaceutics and Biotechnology, 250 Wu-Xing Street, Taipei Medical University, Taipei 110, Taiwan; Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan.
authors.forename: Ruo-Kai
authors.initials: RK
authors.lastname: Lin
authors.affiliation: Division of Nephrology, Shuang Ho Hospital, 291 Zong-Zheng Road, New Taipei City 235, Taiwan.
authors.forename: Yuh-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
authors.affiliation: Professional Master Program in Pharmaceutics and Biotechnology, 250 Wu-Xing Street, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chang-Lin
authors.initials: CL
authors.lastname: Hsieh
authors.affiliation: TaiMed Biologics Inc., 607 Rui-Guang Road, Taipei 114, Taiwan.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan.
authors.forename: Chih-Chiang
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan; Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan; School of Pharmacy, National Defense Medical Center, 161 Section 6 Min-Quan East Road, Taipei 114, Taiwan. Electronic address: wjhuang@tmu.edu.tw.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; D008148:Lovastatin
keywords: Aliphatic hydroxamate; Fungus metabolite; Lovastatin; Reactive oxygen species