Medicinal scientific study based on imiosugar C-glycosides mimics

基于亚咪糖C-糖苷模拟物的药用科学研究

• 批准号: 22590104
• 负责人: TAKAHATA Hiroki
• 金额: $ 2.91万
• 依托单位: Tohoku Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590104/
• 关键词: イミノ糖; α-グリコシダーゼ阻害剤; 糖尿病; L型糖; C-グリコシドミミック; リソソーム蓄積症; α-グリコシダーゼ阻害; β-グリコシダーゼ阻害; ケミカルシャペロン; L糖; sp^3-sp^3カップリング

Glycosidases and glycosyltransferases are involved in a wide range of anabolic and catabolic process, including digestion, the lysosomal catabolism of glycoconjugates, glycoprotein biosynthesis. Hence, modifying or blocking these processes in vivo using inhibitors is a topic of great interest from the therapeutic point of view. Iminosugars are sugars in which the endocyclic oxygen is replaced by a basic nitrogen atom. They are regarded as transition state mimics in certain types of enzyme reactions. This makes the field of iminosugars as carbohydrate mimics an exciting area of research. The asymmetric synthesis of α-1-C-alkyl-arabinoiminofuranoses was achieved by asymmetric allylic alkylation, RCM, and Negishi cross coupling as key reactions. Surprisingly, the L-forms showed a quite potent inhibitory activity toward rat intestinal maltase, while the activities of the D-forms were much weaker. Some of the prepared L-forms showed potent inhibitory activities towards intestinal maltase, with IC50 values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity towards intestinal sucrase of α-1-C-L-butylarabinoiminofuranose was quite strong towards intestinal sucrase compared to the above commercial drugs.

糖苷酶和糖基转移酶参与广泛的合成代谢和分解代谢过程，包括消化、糖缀合物的溶酶体催化、糖蛋白生物合成。因此，从治疗的角度来看，使用抑制剂在体内修饰或阻断这些过程是一个非常感兴趣的话题。亚氨基糖是其中内环氧被碱性氮原子取代的糖。它们被认为是某些类型的酶反应中的过渡态模拟物。这使得作为碳水化合物模拟物的亚氨基糖领域成为一个令人兴奋的研究领域。以不对称烯丙基烷基化、RCM和Negishi交叉偶联为关键反应，实现了α-1-C-烷基阿拉伯亚氨基呋喃糖的不对称合成。令人惊讶的是，L-型对大鼠肠道麦芽糖酶显示出相当强的抑制活性，而D-型的活性要弱得多。一些制备的L-形式对肠道麦芽糖酶表现出强效抑制活性，IC 50值与用于治疗2型糖尿病的阿卡波糖、伏格列波糖和米格列醇等商业药物相当。其中，α-1-C-L-丁酰氨基呋喃糖对肠道蔗糖酶的抑制活性较上述市售药物强。

项目成果

C1位に4-アリールブチル基を導入したL-アラビノイミノ糖誘導体の触媒的不斉合成

C1位引入4-芳基丁基的L-阿拉伯亚氨基糖衍生物的催化不对称合成

• 发表时间: 2012
• 作者: 名取良浩;今堀龍志;吉村祐一;中川進平;加藤 敦;足立伊佐雄;高畑廣紀
• 通讯作者: 高畑廣紀

Synthesis of p-Chloroazacalix[5]arene Pentamethyl Ether: Ring Size-Dependent Desorption of N-Benzyl Groups

对氯氮杂萼[5]芳烃五甲醚的合成：N-苄基的环尺寸依赖性解吸

• DOI: 10.3987/com-12-s
• 发表时间: 2012
• 期刊: Heterocycles
• 影响因子: 0.6
• 作者: T. Kushida;C. Camacho;A. Shuto;S. Irle;M. Muramatsu;T. Katayama;S. Ito;Y. Nagasawa;H. Miyasaka;E. Sakuda;N. Kitamura;Z. Zhou;A. Wakamiya;S. Yamaguchi;Hirohito Tsue
• 通讯作者: Hirohito Tsue

Synthesis of 1-C-Substituted-L-arabinoiminofuranoses and Evaluation of Biological Activities as Novel Class of a-Glucosidase Inhibitors

1-C-取代的-L-阿拉伯亚氨基呋喃糖的合成及其作为新型α-葡萄糖苷酶抑制剂的生物活性评价

• 发表时间: 2012
• 作者: Natori;Y.; Yoshimura;Y.; Kato;A.; Adachi;I.; Hirono;S.; Takahata;H
• 通讯作者: H

Docking and SAR studies of D- and L-isofagomine isomers as human β-glucocerebrosidase inhibitors.

• DOI: 10.1016/j.bmc.2011.04.011
• 发表时间: 2011-06
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: A. Kato;Saori Miyauchi;N. Kato;R. Nash;Y. Yoshimura;I. Nakagome;S. Hirono;H. Takahata;I. Adachi

Cl位に4-アリールブチル基を組み込んだL-アラビノイミノフラノースの触媒的不斉合成と生物活性評価

Cl位带有4-芳基丁基的L-阿拉伯亚氨基呋喃糖的催化不对称合成及生物活性评价

• 发表时间: 2012
• 作者: 名取良浩;吉村祐一;高畑廣紀;嶋田陽介;加藤敦;足立伊佐雄
• 通讯作者: 足立伊佐雄