An Efficient Combinatorial Method for the Discovery of Glycosidase Inhibitors The concept and part of the text of this work were presented at the XIth Eurocarb Conference in Lisbon on September 7, 2001, under the title “An Efficient Combinatorial Method for the Discovery of Glycosidase Inhibitors. Imines Equilibrating with (2R,3R,4S)-2-Aminomethyl pyrrolidine-3,4-diol and Aldehydes are Inhibitors of α-Mannosidases and Models for the Inhibitory Activity of Corresponding Amines”.

Abstract

A dynamic imine library formed in solution provides a fast route to drug discovery. Imine formation from diamine 4 and a sublibrary of aldehydes can be used for the efficient discovery of glycosidase inhibitors through a new combinatorial approach. When the equilibrium shown is reached rapidly under dilute conditions, a mixture of imines is produced and can be screened by the glycosidase, which binds preferentially to the best inhibitor.

Synthesis, glycosidase activity and X-ray crystallography of 3-amino-sugars

“…Library synthesis is a key tool of medicinal chemistry, but simple methods for synthesising libraries of analogous potential glycosidase inhibitors are quite rare. The chemistry available to assemble such libraries is limited to amide coupling, 5 simple imine formation 6 and an approach using a sugar aldehyde in the Strecker reaction. 7 Moreover, the structures of glycosidase inhibitors are often based on iminosugars or aminocyclopentitols, which require several synthetic steps to prepare.…”

Determining the Role of the Aromatic Ring of N‐Arylmethyl ent‐conduramine F‐1 in their Interactions with α‐Glucosidases by Saturation Transfer Difference NMR Spectroscopy Experiments

“…In conclusion, introduction of aromatic moieties on iminosugars and their analogues might decrease24, 25 or increase26 their inhibitory activity against different glycosidases. In the case of (+)‐ ent ‐conduramine F‐1 ( 1 ), which is a moderate inhibitor of α‐1,4‐glucosidases, N‐benzylation gives a derivative with significantly increased inhibitory activity.…”

Dynamic mixtures and combinatorial libraries: imines as probes for molecular evolution at the interface between chemistry and biology

“…21 A successful dynamic combinatorial approach for the discovery of enzyme inhibitors requires that, under the high dilution conditions of the enzyme assay to be performed at a given pH, sufficient amounts of imines are generated in the equilibrium. 17, 22 Despite the fact that the equilibrium constants for reversible imine formation might be relatively small, 4 was discovered as an a-mannosidase inhibitor, by evaluating the Schiff base formation of a series of about 40 aliphatic and aromatic aldehydes with the corresponding amine. 22 In the present case no use was made of the adaptive dynamic potential of DCC since the compounds were not evaluated as a mixture, but individually on multi-well plates, which avoided the need for reduction of the DCL to identify the most active species.…”

“…17, 22 Despite the fact that the equilibrium constants for reversible imine formation might be relatively small, 4 was discovered as an a-mannosidase inhibitor, by evaluating the Schiff base formation of a series of about 40 aliphatic and aromatic aldehydes with the corresponding amine. 22 In the present case no use was made of the adaptive dynamic potential of DCC since the compounds were not evaluated as a mixture, but individually on multi-well plates, which avoided the need for reduction of the DCL to identify the most active species. Another possibility for avoiding chemical reduction of the Schiff base selectively bound to the enzyme has been described for an imine reductase of anaerobic bacteria (Acetobacterium woodii), which selectively reduced the most active enzyme binders selected from a small DCL of imines.…”