Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 24, Issue 6, Pages 1528-1531Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.01.077
Keywords
Triazole; Rhamnose; Diabetes; Click chemistry; SGLT2 inhibitors
Categories
Funding
- CSIR 12th FYP Network (ORIGIN) [CSC0108, CSC0205, CSC 0110, MLP 0002]
- Department of Biotechnology (DBT)
- DBT [BT/Indo-Aus/07/06/2013, BT/PR13768/MED/30/300/2010]
- CSIR
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Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of therapeutic agents for the treatment of type 2 diabetes by preventing renal glucose reabsorption. In our efforts to identify novel inhibitors of SGLT, we synthesized a series of L-rhamnose derived acyclic C-nucleosides with 1,2,3-triazole core. The key beta-ketoester building block 4 prepared from L-rhamnose in five steps, was reacted with various aryl azides to produce the respective 1,2,3-triazole derivatives in excellent yields. Deprotection of acetonide group gave the desired acyclic C-nucleosides 7a-o. All the new compounds were screened for their sodium-glucose co-transporters (SGLT1 and SGLT2) inhibition activity using recently developed cell-based nonradioactive fluorescence glucose uptake assay. Among them, 7m with IC50: 125.9 nM emerged as the most potent SGLT2 inhibitor. On the other hand compound 7d exhibited best selectivity for inhibition of SGLT2 (IC50: 149.1 nM) over SGLT1 (IC50: 693.2 nM). The results presented here demonstrated the utility of acyclic C-nucleosides as novel SGLT inhibitors for future investigations. (C) 2014 Elsevier Ltd. All rights reserved.
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