Synthesis and Biological Evaluation of QRSTUVWXYZA′ Domains of Maitotoxin

被引:30
|
作者
Nicolaou, K. C. [1 ]
Heretsch, Philipp [1 ]
Nakamura, Tsuyoshi [2 ]
Rudo, Anna [2 ]
Murata, Michio [3 ]
Konoki, Keiichi [4 ]
机构
[1] Rice Univ, Dept Chem, BioSci Res Collaborat, Houston, TX 77005 USA
[2] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[3] Osaka Univ, Grad Sch Sci, Dept Chem, Toyonaka, Osaka 5600043, Japan
[4] Tohoku Univ, Grad Sch Agr Sci, Aoba Ku, Sendai, Miyagi 9818555, Japan
基金
日本科学技术振兴机构; 美国国家卫生研究院;
关键词
RING-CLOSING METATHESIS; CYCLIC ENOL ETHERS; STEREOSELECTIVE-SYNTHESIS; STEREOCHEMICAL ASSIGNMENT; OLEFIN METATHESIS; CHEMICAL-SYNTHESIS; POLYCYCLIC ETHERS; SUB-UNITS; CONSTRUCTION; SYSTEM;
D O I
10.1021/ja509829e
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The synthesis of QRSTUVWXYZA' domains 7, 8, and 9 of the highly potent marine neurotoxin maitotoxin (1), the largest secondary metabolite isolated to date, is described. The devised synthetic strategy entailed a cascade Takai-Utimoto ester olefination/ring closing metathesis to construct ring Y, a hydroxydithioketal cyclization/methylation sequence to cast ring X, a Horner-Wadsworth-Emmons coupling of WXYZA' ketophosphonate 11 with QRSTU aldehyde 12 to form enone 10, and a reductive hydroxyketone ring closure to forge ring V. 2D NMR spectroscopic analysis and comparison of C-13 chemical shifts with those of the corresponding carbons of maitotoxin revealed close similarities supporting the originally assigned structure of this region of the natural product. Biological evaluations of various synthesized domains of maitotoxin in this and previous studies from these laboratories led to fragment structure activity relationships regarding their ability to inhibit maitotoxin-elicited Ca2+ influx in rat C6 glioma cells.
引用
收藏
页码:16444 / 16451
页数:8
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