Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Abstract

Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics

“…Some among the most important examples of iminosugars include polyhydroxylated piperidines Miglitol, Miglustat, and Migalastat ( Figure 1 ), which are FDA-approved drugs for the treatment of type 2 diabetes [ 17 ], Gaucher [ 18 ] and Niemann-Pick type C [ 19 ], and Fabry disease [ 20 ], respectively. Piperidine iminosugars belonging to the unnatural l -series ( l -iminosugars) also exhibit pharmacological properties, such as in the case of l -DGJ [ 21 ], l -NBDNJ [ 22 ] ( Figure 1 ), and its congeners [ 23 , 24 ]. Similarly, iminosugars with a pyrrolidine skeleton (in both enantiomeric series) have been found to hold excellent glycomimetic properties, as in the case of naturally occurring Radicamine A and B [ 25 ], 2,5-dideoxy-2,5-imino- d -mannitol ( d -DMDP), 1,4-dideoxy-1,4-imino- d -arabinitol ( d -DAB-1) ( Figure 1 ), and their structurally related compounds [ 26 , 27 ].…”

The Glucocorticoid PYED-1 Disrupts Mature Biofilms of Candida spp. and Inhibits Hyphal Development in Candida albicans

“…As part of our interest in the synthesis of compounds endowed with pharmacological activity [ 8 , 9 , 10 , 11 , 12 ], we recently developed a novel synthetic route aimed at the preparation of the corticosteroid drug deflazacort (DFZ, Figure 1 ) in order to explore its antimicrobial activity.…”

Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

“…Some iminosugars have also been found to act as chaperones 10 against lysosomal storage disorders, like Gaucher’s 11 and Fabry’s 12 diseases. Iminosugars have also been found to be effective against cystic fibrosis 13 , an autosomal recessive disease-causing severe multi-system organ damage, particularly to the respiratory system. Iminosugars can act as correctors of defective cystic fibrosis transmembrane conductance regulator (CFTR) 14 , 15 , an ABC transporter-class protein that controls the content of ion and water in epithelial cells, or alternatively they can reduce the inflammatory response of pathogens, like P. aeruginosa 16 .…”