Winchester B G, Cenci di Bello I, Richardson A C, Nash R J, Fellows L E, Ramsden N G, Fleet G
Department of Clinical Biochemistry, Institute of Child Health, University of London, U.K.
Biochem J. 1990 Jul 1;269(1):227-31. doi: 10.1042/bj2690227.
A series of epimers and deoxy derivatives of castanospermine has been synthesized to investigate the contribution of the different chiral centres to the specificity and potency of inhibition of human liver glycosidases. Castanospermine inhibits all forms of alpha- and beta-D-glucosidases, but alteration to any of the five chiral centres in castanospermine markedly decreases the inhibition. 6-Epicastanospermine, which is related to D-pyranomannose in the same way as castanospermine is to D-pyranoglucose, does not inhibit lysosomal (acidic) alpha-mannosidase, but is a good inhibitor of the cytosolic or neutral alpha-mannosidase. Conversely, 1-deoxy-6-epicastanospermine inhibits acidic alpha-mannosidase strongly, but not the neutral alpha-mannosidase. An explanation of this different inhibition based on preferential recognition of different configurations of mannose by the different forms of alpha-mannosidase is postulated. All derivatives of 6-epicastanospermine also have the minimum structural feature for the inhibition of alpha-L-fucosidase, but those with a beta-anomeric substituent do not inhibit the enzyme, or do so very weakly. 1-Deoxy-6,8a-diepicastanospermine, which has four chiral centres identical with alpha-L-fucose, is, however, a potent inhibitor of alpha-L-fucosidase (Ki 1.3 microM).
已合成一系列栗精胺的差向异构体和脱氧衍生物，以研究不同手性中心对抑制人肝脏糖苷酶的特异性和效力的贡献。栗精胺可抑制所有形式的α-和β-D-葡萄糖苷酶，但栗精胺中五个手性中心中的任何一个发生改变都会显著降低抑制作用。6-表栗精胺与D-吡喃甘露糖的关系，与栗精胺与D-吡喃葡萄糖的关系相同，它不抑制溶酶体（酸性）α-甘露糖苷酶，但却是胞质或中性α-甘露糖苷酶的良好抑制剂。相反，1-脱氧-6-表栗精胺强烈抑制酸性α-甘露糖苷酶，但不抑制中性α-甘露糖苷酶。基于不同形式的α-甘露糖苷酶对甘露糖不同构型的优先识别，对这种不同的抑制作用提出了一种解释。6-表栗精胺的所有衍生物也具有抑制α-L-岩藻糖苷酶的最小结构特征，但具有β-异头取代基的衍生物不抑制该酶，或抑制作用非常微弱。然而，1-脱氧-6,8a-二表栗精胺有四个与α-L-岩藻糖相同的手性中心，是α-L-岩藻糖苷酶的有效抑制剂（Ki为1.3 microM）。
