title: Design and synthesis of natural product derivatives with selective and improved cytotoxicity based on a sesquiterpene scaffold.
abstract: Brasilamide E (1) is a bisabolane sesquiterpenoid isolated from the solid-substrate fermentation cultures of a plant endophytic fungus Paraconiothyrium brasiliense. The compound specifically inhibited proliferation of the MCF-7 cells, but did not show cytotoxicity towards the negative controls HaCaT and NIH3T3 cells (IC50>50 μM). To improve its potency while maintain selectivity, a total of 27 derivatives of 1 were designed, synthesized, and evaluated for in vitro cytotoxicity against six tumor cell lines and the negative control NIH3T3 cells. Among these compounds, compound 12b showed significantly improved potency against the MCF-7, HeLa, and HO8910 cells with IC50 values of 0.13-0.25 μM compared to 1 (IC50 8.47-18.00 μM), and remained nontoxic to the NIH3T3 cells.
authors.affiliation: State Key Laboratory of Toxicology & Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Toxicology & Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, PR China.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Toxicology & Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Toxicology & Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, PR China. Electronic address: cheys@im.ac.cn.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Che
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001203:Ascomycota / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D012717:Sesquiterpenes
keywords: Brasilamide E; Cytotoxicity; Derivatives; Selectivity; Synthesis