A practical synthesis of kifunensine analogues as inhibitors of endoplasmic reticulum α-mannosidase I
A practical synthesis of kifunensine analogues as inhibitors of endoplasmic reticulum α-mannosidase I
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DOI：
10.1021/jo0516382
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发表时间：
2005-11-25
影响因子：
3.6
通讯作者：
Pearson, WH
中科院分区：
文献类型：
--
作者：
Hering, KW;Karaveg, K;Pearson, WH
本文描述了一种有效的I类A -甘露糖苷酶抑制剂kifunenine(1)的实际合成，该合成从廉价且容易获得的起始材料l -抗坏血酸（15）开始。受保护的氨基醇（(2R,3R,4R,5R)-5-氨基-2,3:4,6-二异丙基二氧己醇，11）作为关键中间体，从中制备了几种N-1取代的基夫纳酶类似物（包括n -甲基、n -环己基和n -双（羟甲基）甲基）和2-去草酸基夫纳酶类似物（包括N-H和n -甲基），并筛选了几种抑制人内质网a-甘露糖苷酶I （ER Man 1）和小鼠高尔基a-甘露糖苷酶IA （Golgi Man IA）的活性物质。还制备了几种假双糖基夫纳酶类似物，其中甘露糖残基通过二碳、三碳或四碳连接剂连接到基夫纳酶的N-1和亲和结合基夫纳酶类似物，并对其生物活性进行了评估。虽然合成的N-1基夫纳辛类似物被发现对I类α -甘露糖苷酶的抑制作用不如基夫纳辛本身，但双（羟甲基）甲基基夫纳辛类似物6被证明有选择性地抑制ER Man I而不是高尔基Man IA。
A practical synthesis of the potent class I a-mannosidase inhibitor kifunensine (1) beginning from the inexpensive and readily available starting material L-ascorbic acid (15) is described. The protected amino-alcohol ((2R,3R,4R,5R)-5-amino-2,3:4,6-diisopropylidenedioxyhexanol, 11) served,as a key intermediate from which several N-1 substituted kifunensine analogues (including N-methyl, N-cyclohexyl, and N-bis(hydroxymethyl)methyl) and 2-desoxakifunensine analogues (including N-H and N-methyl) were prepared and screened for inhibition of human endoplasmic reticulum a-mannosidase I (ER Man 1) and mouse Golgi a-mannosidase IA (Golgi Man IA), In addition, several pseudodisaccharide kifunensine analogues in which a mannose residue was tethered to N-1 of kifunensine via a two-, three-, or four-carbon linker and an affinity-bound kifunensine analogue were also prepared and evaluated for biological activity. While the synthesized N-1 kifunesine analogues were found to be less potent inhibitors of Class I alpha-mannosidases than kifuensine itself, the bis(hydroxymethyl)methylkifunensine analogue 6 was shown to selectively inhibit ER Man I over Golgi Man IA.