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Bioorg Med Chem Lett. 2014 Mar 15;24(6):1528-31. doi: 10.1016/j.bmcl.2014.01.077. Epub 2014 Feb 6.

Synthesis of novel l-rhamnose derived acyclic C-nucleosides with substituted 1,2,3-triazole core as potent sodium-glucose co-transporter (SGLT) inhibitors.

Author information

1
Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
2
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
3
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. Electronic address: skbanerjee@iict.res.in.
4
Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. Electronic address: kantevari@yahoo.com.

Abstract

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 β-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: 125.9nM emerged as the most potent SGLT2 inhibitor. On the other hand compound 7d exhibited best selectivity for inhibition of SGLT2 (IC50: 149.1nM) over SGLT1 (IC50: 693.2nM). The results presented here demonstrated the utility of acyclic C-nucleosides as novel SGLT inhibitors for future investigations.

KEYWORDS:

Click chemistry; Diabetes; Rhamnose; SGLT2 inhibitors; Triazole

PMID:
24556379
DOI:
10.1016/j.bmcl.2014.01.077
[Indexed for MEDLINE]

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