Abstract
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 10a (Ki = 0.61 μM) and 16l (Ki = 0.72 μM) exhibited excellent inhibitory potency against hOGA and high selectivity (HsHexB, Ki > 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 10a, 10d, and 16j 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.
Highlights
These results suggest that enlargement of the substituent at the 2-position of the glycosyl moiety of Nagstatin leads to an increase of both the inhibitory efficiency and selectivity toward human O-GlcNAcase (hOGA)
The results showed that the 4-substituted group on the naphthalimide moiety significantly influenced the potency of thioglycosyl–naphthalimides against hOGA
Considering that hOGA has a larger catalytic pocket than HsHex and can accommodate more bulky groups near the 2-acetamide of related substrates (Dorfmueller et al, 2009; Igual et al, 2019), we focused on investigating the effect of 2-substituents at the glycosyl moiety on the inhibitory activity of hOGA
Summary
Β-N-acetylhexosaminidases (EC 3.2.1.52) are responsible for catalyzing the hydrolysis of β-linked N-acetyl-D-hexosamine unit from non-reducing ends of glycans, glycoproteins, and glycolipids (Henrissat and Davies, 1997; Liu et al, 2012). GlcNAcstatin C, bearing the 2-isobutyramido on the glycosyl moiety and phenemyl on the iminazole group was found to be an extremely potent hOGA inhibititor (Ki = 4.4 nM) with 164fold selectivity compared to HsHex (Ki = 550 nM) (Dorfmueller et al, 2009) (Figure 1) These results suggest that enlargement of the substituent at the 2-position of the glycosyl moiety of Nagstatin leads to an increase of both the inhibitory efficiency and selectivity toward hOGA. Modification of the 4-substituent group at the naphthalimide of 15b led to the synthesis of 13r (3, Ki = 0.6 μM against hOGA; Ki >100 μM against HsHexB), bearing a 4-piperidylnaphthalimide moiety, which exhibited higher potency and selectivity toward hOGA (Shen et al, 2018b) (Figure 1). Several classes of thioglycosyl–naphthalimides bearing amide linkers were synthesized and their inhibitory activities against hOGA and HsHexB were evaluated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
