Concise syntheses of potent chaperone drug candidates, N-octyl-4-epi-¦Â-valinenamine (NOEV) and its 6-deoxy derivative, from (+)-proto-quercitol

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• 作者：Shinichi Kuno^a ; ^{kuno-s@hokkochem.co.jp} ; Atsushi Takahashi^a ; Seiichiro Ogawa^b
• 关键词：Aminocyclitol ; Carbasugar ; Chemical chaperone ; Glycosidase inhibitor ; Quercitol ; Wittig reaction
• 刊名：Carbohydrate Research
• 出版年：2013
• 出版时间：7 March, 2013
• 年：2013
• 卷：368
• 期：Complete
• 页码：8-15
• 全文大小：355 K

文摘

Described are the efficient syntheses of ¦Â-galactose-type unsaturated carbasugar amine, N-octyl-4-epi-¦Â-valienamine (1a, NOEV) and 6-deoxy NOEV (12), starting from (+)-proto-quercitol (2), which is readily provided by the bioconversion of myo-inositol. NOEV is a potent chemical chaperone drug candidate for G_M1-gangliosidosis. An intermediate alkadiene benzoate was prepared from 2 in five steps, with the key step being a Wittig reaction with an enol ester. The 6-deoxy derivative 12 was conveniently synthesized from the versatile intermediate dibromo compound 6, which was also an intermediate in the synthesis of NOEV. Enzyme inhibition assays demonstrated that 12 possessed stronger inhibitory activity than the parent 1a, suggesting that the C-6 position of the 4-epi-¦Â-valienamine-type inhibitor could have hydrophobic interactions at the ¦Â-galactosidase active site residues.