1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor.
1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor.
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DOI：
10.1021/acscentsci.7b00214
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发表时间：
2017-07-26
影响因子：
18.2
通讯作者：
Overkleeft HS
中科院分区：
文献类型：
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作者：
Artola M;Wu L;Ferraz MJ;Kuo CL;Raich L;Breen IZ;Offen WA;Codée JDC;van der Marel GA;Rovira C;Aerts JMFG;Davies GJ;Overkleeft HS
糖苷酶所发挥的重要生物学作用，加上药理学上针对这些酶的多种治疗益处，为新抑制剂类别的开发提供了相当大的动力。环卫醇环氧化物和氮丙啶是最近建立的共价糖苷酶灭活剂。受到环状硫酸酯在有机合成中作为环氧化物的亲电等价物的应用的启发，我们试图测试环苯乙醇环硫酸酯是否会类似地充当不可逆糖苷酶抑制剂。在这里，我们介绍新型 1,6-环苯乙醇环硫酸酯的合成、构象分析和应用。我们发现 1,6-表环苯酚环硫酸酯（α-cyclosulfate）是一种快速反应的 α-葡萄糖苷酶抑制剂，其 4C1 椅构象与 α-葡萄糖苷酶 Michaelis 复合物采用的构象相匹配。 1,6-环苯醇环硫酸酯（β-环硫酸酯）的反应速度较慢，可能反映了其构象限制。选择性糖苷酶抑制剂作为机制探针和治疗剂具有无价的价值，我们建议环苯乙醇环硫酸盐作为一类有价值的新型碳水化合物模拟物，用于这些方向的应用。 1,6-epi-Cyclophellitol cyclosulfate（“α-cyclosulfate”）是一种概念上新的、有效的、选择性的不可逆 α-葡萄糖苷酶抑制剂，通过模拟 α-葡萄糖苷酶米氏复合体 4C1 椅构象发挥作用。
The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6-epi-cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose 4C1 chair conformation matches that adopted by α-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (β-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions. 1,6-epi-Cyclophellitol cyclosulfate (“α-cyclosulfate”) is a conceptually new, potent and selective irreversible α-glucosidase inhibitor that acts through mimicry of the α-glucosidase Michaelis complex 4C1 chair conformation.