title: Syntheses and Biological Evaluation of Costunolide, Parthenolide, and Their Fluorinated Analogues.
abstract: Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of the germacrane ring (24). The synthetic strategy features a selective aldol reaction between β,γ-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular α-alkylation of sulfone 21 to construct a 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogues, such as trifluoromethylated analogues 32 and 45. Analogues 32 and 45 maintained high activities against a series of cancer cell lines compared to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media compared with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes.
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.
authors.forename: Zhong-Jin
authors.initials: ZJ
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.
authors.forename: Wei-Zhi
authors.initials: WZ
authors.lastname: Ge
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.
authors.forename: Qiu-Ying
authors.initials: QY
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Accendatech Company, Ltd. , Tianjin 300384, People's Republic of China.
authors.forename: Jian-Miao
authors.initials: JM
authors.lastname: Gong
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.
authors.forename: Bei-Jia
authors.initials: BJ
authors.lastname: Kuang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.|Tianjin International Joint Academy of Biomedicine , Tianjin 300457, People's Republic of China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Xi
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.|Tianjin International Joint Academy of Biomedicine , Tianjin 300457, People's Republic of China.
authors.forename: Haiting
authors.initials: H
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005461:Fluorine; D006207:Half-Life; D054879:Halogenation; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D007783:Lactones
chemical_list: D000970:Antineoplastic Agents; D005461:Fluorine; D012717:Sesquiterpenes; C002669:parthenolide; C002602:costunolide; D007783:Lactones