Synthesis of NAG-thiazoline-derived inhibitors for β-N-acetyl-d-hexosaminidases

Hanchu Kong; Wei Chen; Huizhe Lu; Qing Yang; Yanhong Dong; Daoquan Wang; Jianjun Zhang

doi:10.1016/j.carres.2015.06.004

Synthesis of NAG-thiazoline-derived inhibitors for β-N-acetyl-d-hexosaminidases

Carbohydr Res. 2015 Sep 2:413:135-44. doi: 10.1016/j.carres.2015.06.004. Epub 2015 Jun 16.

Authors

Hanchu Kong¹, Wei Chen², Huizhe Lu³, Qing Yang², Yanhong Dong¹, Daoquan Wang¹, Jianjun Zhang⁴

Affiliations

¹ Key Lab of Pesticide Chemistry and Application Technology, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
² School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
³ Key Lab of Pesticide Chemistry and Application Technology, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. Electronic address: luhz@cau.edu.cn.
⁴ Key Lab of Pesticide Chemistry and Application Technology, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. Electronic address: zhangjianjun@cau.edu.cn.

PMID: 26142545
DOI: 10.1016/j.carres.2015.06.004

Abstract

β-N-Acetyl-d-hexosaminidases are responsible for the metabolism of glycoconjugates in diverse physiological processes that are important targets for medicine and pesticide development. Fourteen new NAG-thiazoline derivatives were synthesized by cyclization and click reaction using d-glucosamine hydrochloride as the starting material. All the compounds created were characterized by NMR and HRMS spectra. A preliminary bioassay, using four enzymes from two β-N-acetyl-d-hexosaminidase families, showed that most of the compounds synthesized exhibit selective inhibition of GH84 β-N-acetyl-d-hexosaminidase. Among the compounds tested, compounds 5a (IC50=12.6 μM, hOGA) and 5e (IC50=12.5 μM, OfOGA) proved to be a highly selective and potent inhibitor.

Keywords: NAG-thiazoline derivatives; Selective inhibitors; Synthesis; β-N-Acetyl-d-hexosaminidases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylglucosamine / analogs & derivatives*
Acetylglucosamine / chemical synthesis
Acetylglucosamine / chemistry
Acetylglucosamine / pharmacology
Animals
Chemistry Techniques, Synthetic
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Lepidoptera / enzymology
Substrate Specificity
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology*
beta-N-Acetylhexosaminidases / antagonists & inhibitors*

Substances

Enzyme Inhibitors
Thiazoles
beta-N-Acetylhexosaminidases
N-acetylglucosamine thiazoline
Acetylglucosamine