Selective inhibition of beta-N-acetylhexosaminidases by thioglycosyl-naphthalimide hybrid molecules

文献类型： 外文期刊

第一作者： Yang, Qing

作者： Yang, Qing;Shen, Shengqiang;Dong, Lili;Zhang, Jianjun;Yang, Qing

作者机构：

关键词： beta-N-acetylhexosaminidase;Synthesis;Selective inhibitors;Thioglycosyl-naphthalimide hybrid

期刊名称：BIOORGANIC & MEDICINAL CHEMISTRY （ 影响因子：3.641； 五年影响因子：3.319 ）

ISSN： 0968-0896

年卷期： 2018 年 26 卷 2 期

页码：

收录情况： SCI

摘要： To develop selective inhibitors for beta-N-acetylhexosaminidases which are involved in a myriad of physiological processes, a series of novel thioglycosyl-naphthalimide hybrid inhibitors were designed, synthesized and evaluated for inhibition activity against glycosyl hydrolase family 20 and 84 (GH20 and GH84) beta-N-acetylhexosaminidases. These compounds which incorporate groups with varied sizes and lengths at the linker region between thioglycosyl moiety and naphthalimide moiety are designed to improve the selectivity and stacking interactions. The GH84 human O-GlcNAcase (hOGA) was sensitive to the subtle changes in the linker region and the optimal choice is a small size linker with six atoms length. And the GH20 insect beta-N-acetylhexosaminidase OfHex1 could tolerate compounds with a hydrophobic bulky linker. Especially, the compound 5c (hOGA, K-i = 3.46 mu M; OfHex1, K-i > 200 mu M) and the compound 6f (hOGA, K-i > 200 mu M; OfHex1, K-i = 21.81 mu M) displayed high selectivity. The molecular docking results indicated that the inhibition mechanism was different between the two families due to their different structural characteristics beyond the active sites. These results provide some promising clues to improve selectivity of potent molecules against beta-N-acetylhexosaminidases. (C) 2017 Elsevier Ltd. All rights reserved.

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