Shen Shengqiang, Dong Lili, Chen Wei, Wu Renjie, Lu Huizhe, Yang Qing, Zhang Jianjun
Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, China.
Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.
Front Chem. 2019 Jul 25;7:533. doi: 10.3389/fchem.2019.00533. eCollection 2019.
β-N-acetylhexosaminidases represent an important class of exoglycosidases and have emerged as the promising targets for drug and pesticide discovery. Among these, human O-GlcNAcase (hOGA) has been reported to be closely linked to several diseases such as Alzheimer's disease, diabetes, and cancer. Potent hOGA inhibitors with high selectivity are therefore of great significance for the regulation of the corresponding physiological processes. In this study, several classes of novel and readily available thioglycosyl-naphthalimides bearing the amide linker were designed and synthesized. To investigate their potency and selectivity, the inhibitory efficiencies toward hOGA and human β-N-acetylhexosaminidase B (HsHexB) were assayed. Especially, compounds ( = 0.61 μM) and ( = 0.72 μM) exhibited excellent inhibitory potency against hOGA and high selectivity (HsHexB, > 100 μM). In addition, during the preparation of these thioglycosyl-naphthalimides, a new practical method was developed for the synthesis of ureido glycosides from trichloroethyl carbamates at room temperature and normal pressure without catalyst. Furthermore, the possible binding modes of hOGA with , , and were studied using molecular docking and molecular dynamics simulations to explore the molecular basis for the potency of these thioglycosides. This work present here provides useful clues for the further structural optimization toward hOGA.
β-N-乙酰己糖胺酶是一类重要的外切糖苷酶，已成为药物和农药研发的有前景的靶点。其中，据报道人类O-连接N-乙酰葡糖胺酶（hOGA）与阿尔茨海默病、糖尿病和癌症等多种疾病密切相关。因此，具有高选择性的强效hOGA抑制剂对于调节相应的生理过程具有重要意义。在本研究中，设计并合成了几类带有酰胺连接基的新型且易于获得的硫代糖基萘二甲酰亚胺。为了研究它们的效力和选择性，测定了它们对hOGA和人类β-N-乙酰己糖胺酶B（HsHexB）的抑制效率。特别是，化合物（IC50 = 0.61 μM）和（IC50 = 0.72 μM）对hOGA表现出优异的抑制效力和高选择性（对HsHexB，IC50 > 100 μM）。此外，在制备这些硫代糖基萘二甲酰亚胺的过程中，开发了一种新的实用方法，即在室温、常压且无催化剂的条件下由三氯乙基氨基甲酸酯合成脲基糖苷。此外，利用分子对接和分子动力学模拟研究了hOGA与、和的可能结合模式，以探索这些硫代糖苷效力的分子基础。本文的这项工作为hOGA的进一步结构优化提供了有用的线索。
