基于NAG-thiazoline的84家族糖基水解酶特异性抑制剂的设计
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- 英文论文题名：Design of selective GH84 family inhibitors based on NAG-thiazoline
- 论文作者：陈威 ; 孔涵楚 ; 张建军 ; 杨青
- 英文论文作者：Wei Chen ; Hanchu Kong ; Jianjun Zhang ; Qing Yang ; School of Life Science and Biotechnology ; Dalian University of Technology ; Department of Applied Chemistry ; China Agricultural University
- 年：2016
- 作者机构：大连理工大学生命科学与技术学院;中国农业大学应用化学系;
- 论文关键词：β-N-乙酰葡萄糖胺水解酶 ; 抑制剂 ; NAG-Thiazoline衍生物 ; 合成
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十八分会：化学生物学
- 语种：中文
- 分类号：TQ460.1
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十八分会 ; 化学生物学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：299k
- 原文格式：D
- 会议级别：全国
摘要
细胞质和细胞核蛋白的O-GlcNAc翻译后修饰作为一种胞内营养和压力的感应器与多种疾病相关联,包括癌症、糖尿病,心血管疾病和神经退行性疾病等。O-GlcNAc修饰的水解通过β-N-乙酰葡萄糖胺水解酶(OGA)完成。OGA属于糖基水解酶84家族,采用底物辅助的催化机理将GlcNAc从蛋白质上移除。OGA的抑制剂已经作为一种实用的工具广泛用于调控O-GlcNAc循环和相关疾病的研究中。NAG-thiazoline是OGA的一个高效的抑制剂(K_i=70 nM),但是缺乏选择性,对于GH20家族的酶也具有相同的抑制效果。因此,本研究在NAG-Thiazoline的关键结合位点引入芳香类和三唑类取代基,设计并合成了14个NAG-Thiazoline衍生物,大部分的化合物都表现出了对于GH84的选择性,其中化合物5e同时具有高效性和选择性。
The post-translational modification of nucleocytoplasmic proteins with O-linked β-N-acetylglucosamine(O-GlcNAc) serves as a nutrient and stress sensor implicated in multiple diseases including cancers,diabetes,cardiovascular diseases and neurodegenerative disorders.The enzyme β-N-acetylglucosaminidase(OGA),which belongs to GH84 family,catalyzes the cleavage of O-GlcNAc from modified proteins using substrate-assisted catalysis mechanism.OGA inhibitors have been a useful tool to regulate O-GlcNAc cycling and related diseases researches.NAG-thiazoline is a well-known inhibitor against OGA(K_i=70 nM),but it lacks selectivity between GH84 and GH20.In this report,14 new NAG-Thiazoline derivatives were synthesized by cyclization and click reaction using D-glucosamine hydrochloride as the starting material.Most of the compounds synthesized exhibit selective inhibition of GH84 β-N-acetyl-D-hexosaminidase.Among the compounds tested,compound 5e proved to be a highly selective and potent inhibitor
The post-translational modification of nucleocytoplasmic proteins with O-linked β-N-acetylglucosamine(O-GlcNAc) serves as a nutrient and stress sensor implicated in multiple diseases including cancers,diabetes,cardiovascular diseases and neurodegenerative disorders.The enzyme β-N-acetylglucosaminidase(OGA),which belongs to GH84 family,catalyzes the cleavage of O-GlcNAc from modified proteins using substrate-assisted catalysis mechanism.OGA inhibitors have been a useful tool to regulate O-GlcNAc cycling and related diseases researches.NAG-thiazoline is a well-known inhibitor against OGA(K_i=70 nM),but it lacks selectivity between GH84 and GH20.In this report,14 new NAG-Thiazoline derivatives were synthesized by cyclization and click reaction using D-glucosamine hydrochloride as the starting material.Most of the compounds synthesized exhibit selective inhibition of GH84 β-N-acetyl-D-hexosaminidase.Among the compounds tested,compound 5e proved to be a highly selective and potent inhibitor
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