C-6 fluorinated casuarines as highly potent and selective amyloglucosidase inhibitors: Synthesis and structure-activity relationship study

• Published in: European journal of medicinal chemistry 2022-12, Vol.244, p.114852-114852, Article 114852
• Main Authors: Li, Yi-Xian, Wang, Jun-Zhe, Shimadate, Yuna, Kise, Maki, Kato, Atsushi, Jia, Yue-Mei, Fleet, George W.J., Yu, Chu-Yi
• Format: Article
• Language: English
• Subjects: Casuarine; Fluorination; Glycosidase inhibition; Iminosugar; Molecular docking; Structure-activity relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114852

A series of C-6 fluorinated casuarine derivatives have been synthesized via organocatalytic stereoselective α-fluorination of iminosugar-based aldehydes or direct nucleophilic fluorination of polyhydroxylated pyrrolizidines. Glycosidase assays against various glycosidases allowed systematic structure-activity relationship (SAR) study using molecular docking calculations. Introduction of fluorine atom(s) at C-6 position removed the trehalase and maltase inhibitory activities of all casuarine derivatives, and greatly increased their specificity towards amyloglucosidase. Inhibition of the fluorinated casuarines depended on the configuration of C-6 fluorine, of which 6-deoxy-6-epi-6-fluoro-casuarine (24) was found approximately 40-fold potent than its parent compound 6-epi-casuarine (2) as a potent and specific inhibitor of amyloglucosidase. Molecular docking calculations showed that replacement of the C-6 hydroxyls by fluorine atom(s) removed the original interactions with trehalase, but helped to reinforce the binding with amyloglucosidase via newly established fluorine related hydrogen bonding or untypical anion-π interactions. To further investigate the quantitative SARs of casuarine derivatives, the CoMFA and CoMSIA models on amyloglucosidase were established, indicating the dominating effect of electrostatic field in amyloglucosidase inhibition. The 3D-QSAR models were validated to be reliable and can be used for further optimization of casuarine-related iminosugars, as well as design and development of anti-diabetic and immunomodulatory drugs. [Display omitted] •Organocatalytic stereoselective α-fluorination as key synthetic step.•A compound library comprising all configurations of C-6 fluorinated casuarines.•Fluorinated iminosugars with rare greatly improved glycosidase inhibitions.•The first report of very potent and specific inhibitor toward amyloglucosidase.•Systematic SAR study of casuarines by docking simulations and 3D QSAR analysis.