title: Synthesis of novel l-rhamnose derived acyclic C-nucleosides with substituted 1,2,3-triazole core as potent sodium-glucose co-transporter (SGLT) inhibitors.
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.
authors.affiliation: Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Siddamal Reddy
authors.initials: SR
authors.lastname: Putapatri
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Kanwal
authors.affiliation: 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.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Banerjee
authors.affiliation: 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.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Kantevari
mesh_terms: D057930:Click Chemistry; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009705:Nucleosides / Q000737:chemistry*; D011485:Protein Binding; D012210:Rhamnose / Q000737:chemistry*; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014230:Triazoles / Q000737:chemistry* / Q000378:metabolism
chemical_list: D009705:Nucleosides; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014230:Triazoles; D005947:Glucose; D012210:Rhamnose
keywords: Click chemistry; Diabetes; Rhamnose; SGLT2 inhibitors; Triazole