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.
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Authors | Zhong-Jin Yang, Wei-Zhi Ge, Qiu-Ying Li, Yaxin Lu, Jian-Miao Gong, Bei-Jia Kuang, Xiaonan Xi, Haiting Wu, Quan Zhang, Yue Chen |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 58
Issue 17
Pg. 7007-20
(Sep 10 2015)
ISSN: 1520-4804 [Electronic] United States |
PMID | 26226279
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Sesquiterpenes
- Fluorine
- parthenolide
- costunolide
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Topics |
- Animals
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Drug Screening Assays, Antitumor
- Fluorine
- Half-Life
- Halogenation
- Humans
- Microsomes, Liver
(metabolism)
- Rats
- Sesquiterpenes
(chemical synthesis, chemistry, pharmacology)
- Stereoisomerism
- Structure-Activity Relationship
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