title: Synthesis of NAM-thiazoline derivatives as novel O-GlcNAcase inhibitors.
abstract: Human O-GlcNAcase (GH 84) and human β-N-acetyl-D-hexosaminidase (GH 20) from Homo sapiens are two therapeutic enzyme targets that share the same catalytic mechanism but play different physiological roles in vivo. Selective inhibition toward one of these enzymes is therefore of importance to regulate the corresponding bioprocess. Here ten new NAM-thiazoline derivatives were synthesized and subsequently characterized by NMR and HRMS. A preliminary bioassay showed that most of the synthesized compounds exhibited obvious selective inhibition against human O-GlcNAcase over human β-N-acetyl-D-hexosaminidase. Among the compounds tested, compound 7d (IC50 = 6.4 µM, hOGA; IC50>1 mM, hHex) and 7f (IC50 = 11.9 µM, hOGA; IC50>1 mM, hHex) proved to be a highly selective and potent inhibitor. Structure-activity relationship analysis indicated a correlation between the inhibitory activity and the size of the groups linked to the thiazoline ring.
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
authors.forename: Hanchu
authors.initials: H
authors.lastname: Kong
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
authors.forename: Huizhe
authors.initials: H
authors.lastname: Lu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China. Electronic address: qingyang@dlut.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. Electronic address: zhangjianjun@cau.edu.cn.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D013844:Thiazoles; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine
keywords: NAM-thiazoline derivatives; O-GlcNAcase; Selective inhibitors; β-N-Acetyl-D-hexosaminidases