Abstract

Carbasugar sodium-glucose cotransporter 2 (SGLT2) inhibitors are highly promising drug candidates for the treatment of Type 2 diabetes mellitus (T2DM). However, the clinical usage of carbasugar SGLT2 inhibitors has been underexplored, due to the lengthy synthetic routes and the lack of structure-activity relationship (SAR) studies of these compounds. Herein, we report a concise and stereodivergent synthetic route towards some novel carbasugar SGLT2 inhibitors, featuring an underexploited, regioselective, and stereospecific palladium-catalyzed allyl-aryl coupling reaction. This synthetic strategy, together with computational modeling, revealed the unexpected SAR of these carbasugar SGLT2 inhibitors, and enabled the discovery of a highly selective and potent SGLT2 inhibitor.

Details

Title
Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition
Author
Wai-Lung Ng 1   VIAFID ORCID Logo  ; Ho-Chuen, Li 2 ; Kit-Man Lau 3 ; Chan, Anthony K N 4 ; Clara Bik-San Lau 3   VIAFID ORCID Logo  ; Shing, Tony K M 2 

1  Department of Chemistry and Centre of Novel Functional Molecules, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA 
2  Department of Chemistry and Centre of Novel Functional Molecules, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China 
3  Institute of Chinese Medicine and State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China 
4  Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, UK 
Pages
1-8
Publication year
2017
Publication date
Jul 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-017-05895-9
ProQuest document ID
1956123807
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.