Α-Geminal disubstituted pyrrolidine iminosugars and their C-4-fluoro analogues: Synthesis, glycosidase inhibition and molecular docking studies. Issue 19 (1st October 2017)

• Record Type: Journal Article
• Authors: Gavale, Kishor S.; Chavan, Shrawan R.; Kumbhar, Navanath; Kawade, Sonali; Doshi, Pooja; Khan, Ayesha; Dhavale, Dilip D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 19(2017)
• Page Start: 5148
• Page End: 5159
• Publication Date: 2017-10-01
• Subjects: Iminosugars -- Glycosidase inhibitors -- Corey-Link and Jocic-Reeve approach -- Structure activity relationship (SAR) -- Nucleophilic displacement; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.07.026
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A simple strategy for the synthesis of α -geminal disubstituted pyrrolidine iminosugars 3a -c and their C -4 fluorinated derivatives 4a -c has been described from d -glucose. The methodology involves the Corey-Link and Jocic-Reeve reaction with 3-oxo- α -d -glucofuranose and nucleophilic displacement reaction to get the furanose fused pyrrolidine ring skeleton with requisite CH2 OH/CO2 H functionalities at C -3. The fluorine substituent in target molecules was introduced by nucleophilic displacement of - O Tf in 9a /9c with CsF. Appropriate manipulation of the anomeric carbon in the furanose fused pyrrolidine ring skeleton afforded α -geminal disubstituted pyrrolidine iminosugars 3a –c and C -4 fluoro derivatives 4a –c . The pyrrolidine iminosugars 3a and 3c were found to be potent inhibitors of α -galactosidase while, the fluoro derivatives 4a and 4b showed strong inhibition of β -glucosidase and β -galactosidase, respectively. These results were substantiated by in silico molecular docking studies.