Design and synthesis of iso- allo-DNJ and L-isoDALDP derivatives: pursuit of potent and selective inhibitors of α-glucosidase

Lin-Feng Yang; Ming Zhang; Yuna Shimadate; Atsushi Kato; Tian-Yang Liu Hou; Yi-Xian Li; Yue-Mei Jia; George W J Fleet; Chu-Yi Yu

doi:10.1039/d3ob00404j

Design and synthesis of iso- allo-DNJ and L-isoDALDP derivatives: pursuit of potent and selective inhibitors of α-glucosidase

Org Biomol Chem. 2023 Apr 26;21(16):3453-3464. doi: 10.1039/d3ob00404j.

Authors

Lin-Feng Yang^{1

2}, Ming Zhang^{1

3}, Yuna Shimadate⁴, Atsushi Kato⁴, Tian-Yang Liu Hou^{1

3}, Yi-Xian Li^{1

3}, Yue-Mei Jia^{1

3}, George W J Fleet⁵, Chu-Yi Yu^{1

3}

Affiliations

¹ Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. yucy@iccas.ac.cn.
² High School Attached to Beijing University of Technology, Beijing 100022, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp.
⁵ Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.

PMID: 37039337
DOI: 10.1039/d3ob00404j

Abstract

A series of iso-allo-DNJ and L-isoDALDP derivatives were synthesized from dithioacetal 16 with sequential and highly diastereoselective Ho and Henry reactions, and aziridinium intermediate-mediated ring rearrangement as key steps. Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compound 30 showed more potent α-glucosidase inhibition (IC₅₀ = 9.3 μM) than the others. Molecular docking study revealed different docking modes of the iso-allo-DNJ and L-isoDALDP derivatives from their parent compounds, and also the similarity of compound 30 to isofagomine.

Publication types

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

MeSH terms

Glycoside Hydrolase Inhibitors* / pharmacology
Glycoside Hydrolases
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
alpha-Glucosidases* / metabolism

Substances

alpha-Glucosidases
Glycoside Hydrolase Inhibitors
Glycoside Hydrolases