Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry

Shengqiang Shen¹  Huizhe Lu¹  Lili Dong¹  Jianjun Zhang¹  Wei Chen²  Qing Yang² 

[1]Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, China

[2]School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Chin

关键词: Thioglycosides;    naphthalimide derivatives;    β-N;    O;    inhibitors;   

DOI  :  10.1080/14756366.2017.1419217

来源: publisher

【 摘 要 】

GH20 human β-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these β-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki = 0.91 µM against hsHexB; Ki > 100 µM against hOGA) and compound 15b (Ki = 3.76 µM against hOGA; Ki = 30.42 µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure–activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific β-N-acetylhexosaminidase inhibitors.

【 授权许可】

CC BY