Synthesis and Biological Evaluation of QRSTUVWXYZA鈥?Domains of Maitotoxin

详细信息    查看全文

• 作者：K. C. Nicolaou ; Philipp Heretsch ; Tsuyoshi Nakamura ; Anna Rudo ; Michio Murata ; Keiichi Konoki
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：November 19, 2014
• 年：2014
• 卷：136
• 期：46
• 页码：16444-16451
• 全文大小：740K
• ISSN：1520-5126

文摘

The synthesis of QRSTUVWXYZA鈥?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鈥揢timoto ester olefination/ring closing metathesis to construct ring Y, a hydroxydithioketal cyclization/methylation sequence to cast ring X, a Horner鈥揥adsworth鈥揈mmons coupling of WXYZA鈥?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 ¹³C 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鈥揳ctivity relationships regarding their ability to inhibit maitotoxin-elicited Ca²⁺ influx in rat C6 glioma cells.