C-Branched Iminosugars: 伪-Glucosidase Inhibition by Enantiomers of isoDMDP, isoDGDP, and isoDAB鈥?span class="smallcaps">l-isoDMDP Compared to Miglitol and Miglustat

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• 作者：Sarah F. Jenkinson ; Daniel Best ; A. Waldo Saville ; James Mui ; R. Fernando Mart铆nez ; Shinpei Nakagawa ; Takahito Kunimatsu ; Dominic S. Alonzi ; Terry D. Butters ; Caroline Norez ; Frederic Becq ; Yves Bl茅riot ; Francis X. Wilson ; Alexander C. Weymouth-Wilson ; Atsushi Kato ; George W. J. Fleet
• 刊名：The Journal of Organic Chemistry
• 出版年：2013
• 出版时间：August 2, 2013
• 年：2013
• 卷：78
• 期：15
• 页码：7380-7397
• 全文大小：801K
• 年卷期：v.78,no.15(August 2, 2013)
• ISSN：1520-6904

文摘

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. l-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K_i 0.081 渭M for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by l-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.