Fluorescence sensing and glycosidase inhibition effect of multivalent glycosidase inhibitors based on Naphthalimide-deoxynojirimycin conjugates

• Published in: Bioorganic chemistry Vol. 132; p. 106373
• Main Authors: Wang, Guang-Yuan, Wei, Wen-Tong, Rong, Rui-Xue, Su, Shan-Shan, Yan, Dong-Xiao, Yin, Fang-Qian, Li, Xiao-Liu, Wang, Ke-Rang
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.03.2023; Elsevier
• Subjects: alpha-Mannosidase; Animals; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Enzyme Inhibitors - chemistry; Fluorescence; Fluorescence sensing; Glycoside Hydrolases - metabolism; Hypoglycemic effect; Iminosugar; Life Sciences & Biomedicine; Mice; Multivalent glycosidase inhibitor; Naphthalimides - pharmacology; Physical Sciences; Science & Technology; Self-assembly; Fluorescence sensing; Iminosugar; Self-assembly; Multivalent glycosidase inhibitor; Hypoglycemic effect; MECHANISM; IMINOSUGAR CLUSTERS; ALPHA-GLUCOSIDASE; PROBES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106373

[Display omitted] •The strong binding interactions of multivalent glycosidase inhibitors with enzymes were related to the efficient inhibitory activity against glycosidase.•The lengths of the chain between DNJ moieties and the triazole ring for the naphthalimide-DNJ conjugates influenced the self-assembly properties, binding interactions and glycosidase inhibition activities.•Detection of multivalent glycosidase inhibition effect by a fluorescent sensing method was developed.•Multivalency was a strategy to improve glycosidase inhibition activity. Synthetic glycoconjugates as chemical probes have been widely developed for the detection of glycosidase enzymes. However, the binding interactions between iminosugar derivatives and glycosidases were limited, especially for the binding interactions between multivalent glycosidase inhibitors and α-glycosidases. In this paper, three naphthalimide-DNJ conjugates were synthesized. Furthermore, the binding interactions and glycosidase inhibition effects of them were investigated. It was found that the strong binding interactions of multivalent glycosidase inhibitors with enzymes were related to the efficient inhibitory activity against glycosidase. Moreover, the lengths of the chain between DNJ moieties and the triazole ring for the naphthalimide-DNJ conjugates influenced the self-assembly properties, binding interactions and glycosidase inhibition activities with multisource glycosidases. Compound 13 with six carbons between the DNJ moiety and triazole ring showed the stronger binding interactions and better glycosidase inhibition activities against α-mannosidase (jack bean) and α-glucosidase (aspergillus niger). In addition, compound 13 showed an effective PBG inhibition effect in mice with 51.18 % decrease in blood glucose at 30 min. This result opens a way for detection of multivalent glycosidase inhibition effect by a fluorescent sensing method.