REMARKABLE STEREOSELECTIVITY IN THE INHIBITION OF ALPHA-GALACTOSIDASE FROM COFFEE BEAN BY A NEW POLYHYDROXYPYRROLIDINE INHIBITOR
REMARKABLE STEREOSELECTIVITY IN THE INHIBITION OF ALPHA-GALACTOSIDASE FROM COFFEE BEAN BY A NEW POLYHYDROXYPYRROLIDINE INHIBITOR
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DOI：
10.1002/anie.199412421
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发表时间：
1994-06-06
期刊：
影响因子：
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通讯作者：
WONG, CH
中科院分区：
文献类型：
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作者：
WANG, YF;TAKAOKA, Y;WONG, CH
方案 2 说明了 1 的更短合成。使用岩藻糖-L-磷酸醛缩酶 [*] 催化磷酸二羟基丙酮 (DHAP)[91 和醛 12 的羟醛反应。去磷酸化后，羟醛产物通过还原胺化转化为 1。对 pH 5.5 下咖啡豆中的 α-半乳糖苷酶进行的抑制分析 [41 of 1] 表明 K,= 5 x M 具有竞争性抑制作用。据我们所知，这是迄今为止已知的最好的 α-半乳糖苷酶吡咯烷抑制剂。看来 2 位和 4 位的立构中心非常关键。当这两个中心之一倒置时，观察到抑制活性显着降低。由于吡咯烷以包膜构象存在，如 2（α-葡萄糖苷酶抑制剂，Ki= 2.8 pM，图 2）的 X 射线结构所示，化合物 1 可能模拟糖苷键断裂时过渡态结构的构象和电荷分布（图 3）。然而，值得注意的是，1 与酶的结合较少
A much shorter synthesis of 1 is illustrated in Scheme 2. Fuculose-l-phosphate aldolase [*] was used to catalyze the aldol reaction of dihydroxyacetone phosphate (DHAP)[91 and aldehyde 12. After dephosphorylation the aldol product was converted into 1 by reductive amination. Inhibition analysis [41 of 1 against a-galactosidase from coffee bean at pH 5.5 indicated a competitive type of inhibition with K,= 5 x M. To our knowledge, this is the best pyrrolidine inhibitor of a-galactosidase known to date. It appears that the stereocenters at the 2-and 4-positions are very critical. A marked decrease of inhibition activity was observed when either one of these two centers was inverted. Since pyrrolidines exist in an envelope conformation, as shown by the X-ray structure of 2 (an inhibitor of a-glucosidase, Ki= 2.8 pM Fig. 2), compound 1 may mimic the Conformation and charge distribution of the transition state structure fur the cleavage of the glycosidic bond (Fig. 3). It is noted, however, that 1 binds the enzyme less