Worawalai Wisuttaya, Sompornpisut Pornthep, Wacharasindhu Sumrit, Phuwapraisirisan Preecha
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Carbohydr Res. 2016 Jun 24;429:155-62. doi: 10.1016/j.carres.2016.04.014. Epub 2016 Apr 29.
Voglibose, an N-1,3-dihydroxypropylaminocyclitol, has widely been used as an effective α-glucosidase inhibitor for diabetes therapy. Several attempts have been made to synthesize closely related analogues through the coupling of various aminocyclitols and propane-1,3-diol; however, most of them showed weaker or no inhibition. In this communication, we synthesized a pair of new N-1,3-dihydroxypropylaminocyclitols (10 and 11) using (+)-proto-quercitol (1) as a cyclitol core structure. The newly synthesized compounds revealed potent rat intestinal α-glucosidases, particularly against maltase, with IC50 values at submicromolar. Subsequent study on mechanisms underlying the inhibition of 11 indicated the competitive manner towards maltase and sucrase. The potent inhibition of these compounds was elaborated by docking study, in which their binding profiles towards key amino acid residues in the active site were similar to that of voglibose. Therefore, introduction of propane-1,3-diol moiety to suitable cyclohexane core structure such as aminoquercitol would be a potential approach to discover a new series of effective α-glucosidase inhibitors.
伏格列波糖，一种N-1,3-二羟基丙基氨基环糖醇，已被广泛用作治疗糖尿病的有效α-葡萄糖苷酶抑制剂。人们已尝试通过各种氨基环糖醇与1,3-丙二醇的偶联来合成密切相关的类似物；然而，它们中的大多数表现出较弱的抑制作用或无抑制作用。在本论文中，我们以(+)-原栎醇(1)为环糖醇核心结构合成了一对新的N-1,3-二羟基丙基氨基环糖醇(10和11)。新合成的化合物对大鼠肠道α-葡萄糖苷酶显示出强效抑制作用，尤其是对麦芽糖酶，其IC50值处于亚微摩尔水平。随后对11的抑制机制研究表明其对麦芽糖酶和蔗糖酶呈竞争性抑制方式。通过对接研究阐述了这些化合物的强效抑制作用，其中它们与活性位点关键氨基酸残基的结合模式与伏格列波糖相似。因此，将1,3-丙二醇部分引入合适的环己烷核心结构如氨基栎醇中，将是发现一系列新型有效α-葡萄糖苷酶抑制剂的潜在方法。
