New syntheses towards C-glycosyl type glycomimetics

Abstract

Glycomimetics are compounds that resemble carbohydrate molecules in their chemical structure and/or biological effect. A large variety of compounds can be designed and synthesized to get glycomimetics, however, C-glycosyl derivatives represent one of the most frequently studied subgroup. In the present survey syntheses of a range of five- and six membered C-glycopyranosyl heterocycles, anhydro-aldimine type compounds, exo-glycals, C-glycosyl styrenes, carbon-sulfur bonded oligosaccharide mimics are described. Some of the C-glycopyranosyl azoles, namely 1,2,4-triazoles and imidazoles belong to the most efficient glucose analog inhibitors of glycogen phosphorylase known to date. Biological studies revealed the therapeutical potential of such inhibitors. Other synthetic derivatives offer versatile possibilities to get further glycomimetics.

Dual-Target Compounds against Type 2 Diabetes Mellitus: Proof of Concept for Sodium Dependent Glucose Transporter (SGLT) and Glycogen Phosphorylase (GP) Inhibitors

“…The compounds were selected from non-inhibitory ones to low nanomolar GP inhibitors. Former GP inhibition studies revealed the essential role of the heterocyclic linker between the glucose unit and the distal aromatic moiety [ 21 , 55 , 56 ]. With respect to the latter aromatic group, the 2-naphthyl substituted derivatives 21b – 25b surpassed the phenyl substituted ones 21a – 25a by a factor of approx.…”

“…Furthermore, taking into account that the glucosyl biphenyl derivative B also inhibited the SGLTs [ 43 ], the study of compounds D was also envisaged. Since many of the D type derivatives proved to be potent inhibitors of glycogen phosphorylases (GP) [ 21 , 55 , 56 ], another validated target in combatting T2DM, these compounds may prove the dual-target concept for SGLT-GP which, to the best of our knowledge, has never yet been investigated.…”

First representatives of C-glycosyl 1,2,4,5-tetrazines: synthesis of 3-β-d-glucopyranosyl 1,2,4,5-tetrazines and their transformation into 3-β-d-glucopyranosyl pyridazines

“…Previously, we prepared several 2,6-anhydro-aldonic acid derivatives ( e.g. esters, nitriles, amidines) and used them as starting materials for the synthesis of a variety of C -glycopyranosyl azoles 28–30 and pyrimidines. 31–33…”

“…Previously, we prepared several 2,6-anhydro-aldonic acid derivatives (e.g. esters, nitriles, amidines) and used them as starting materials for the synthesis of a variety of C-glycopyranosyl azoles [28][29][30] and pyrimidines. [31][32][33] In the present study, a series of investigations to get C-glucopyranosyl 1,2,4,5-tetrazines (I in Scheme 1) by ring-closing reactions of the above type glucose-based precursors has been envisaged.…”

Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase

“…The most prominent example is perhaps canagliflozin ( 2 , Figure 1 ), first approved for use in clinical practice in 2014 [ 28 ]. Indeed, C -glucopyranosyl derivatives have been comprehensively studied as potential GP inhibitors by Somsák and coworkers [ 29 ], leading to some of the most potent catalytic-site inhibitors known to date [ 26 , 30 ]. Based on our previous research [ 19 , 25 , 31 ], we decided to extend our work into the family of C -glucopyranosyl, nucleoside-type, molecules.…”