Wennekes Tom, van den Berg Richard J B H N, Donker Wilma, van der Marel Gijsbert A, Strijland Anneke, Aerts Johannes M F G, Overkleeft Herman S
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
J Org Chem. 2007 Feb 16;72(4):1088-97. doi: 10.1021/jo061280p. Epub 2007 Jan 23.
In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reported here are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involved in the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decade due to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that an increasing number of pathological processes are being linked to excessive glycosphingolipid levels, glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presented here demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the 1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramide synthase. The beta-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramide synthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketed as treatment for Gaucher disease under the commercial name Zavesca.
在本文中，我们展示了金刚烷-1-基-甲氧基官能化的1-脱氧野尻霉素衍生物的一种直接合成方法。所采用的合成路线具有灵活性，可用于制备多种亲脂性单官能化和双官能化的1-脱氧野尻霉素衍生物。本文报道的化合物是基于先导化合物4的亲脂性亚氨基糖，先导化合物4是参与糖鞘脂葡萄糖神经酰胺代谢的三种酶的有效抑制剂。在过去十年中，这三种酶之一的葡萄糖神经酰胺合酶的亚氨基糖基抑制剂因其在糖鞘脂生物合成中的关键作用而受到越来越多的关注。再加上越来越多的病理过程与过量的糖鞘脂水平相关，葡萄糖神经酰胺合酶成为一个非常有吸引力的治疗和研究靶点。我们在此展示的结果表明，将亲脂性部分从氮原子重新定位到1-脱氧野尻霉素环系统上的其他位置并不会产生更有效的或更具选择性的葡萄糖神经酰胺合酶抑制剂。β-氮杂-C-糖苷类似物（17）对葡萄糖神经酰胺合酶保留了最佳抑制效力，并且比作为治疗戈谢病的药物N-丁基-1-脱氧野尻霉素（3，商品名为Zavesca）更具活性。
