Cyclic Amidine Sugars as Transition-State Analogue Inhibitors of Glycosidases: Potent Competitive Inhibitors of Mannosidases

Abstract

A series of monocyclic glycoamidines bearing different exocyclic amine, alcohol, or alkyl functionalities and bicyclic amidines derived from D-glucose and D-mannose were synthesized and tested as inhibitors of various glycosidases. All the prepared compounds demonstrated good to excellent inhibition toward glycosidases. In particular, the biscationic D-mannoamidine 9b bearing an exocyclic ethylamine moiety proved to be a selective competitive inhibitor of alpha- and beta-mannosidases (K(i) = 6 nM) making it the most potent inhibitor of these glycosidases reported to date. A favorable B(2,5) boat conformation might explain the selectivity of mannosidase inhibition compared to other glycosidases.

Catalytic Mechanism of Human α-Galactosidase

“…Thus, a new class of inhibitors for ␣-GAL (and other related family 27 glycosidases) might adopt a 4 H 3 half-chair (or the closely related 4 E envelope) conformation of the ring. Transition state mimics have not been developed for ␣-GAL, however, transition state analogues have been developed as selective inhibitors of mannosidases and other glycosidases (45,47,48).…”

Substrate Distortion by a Lichenase Highlights the Different Conformational Itineraries Harnessed by Related Glycoside Hydrolases

“…This leads to the possibility of specific, targeted inhibition of clinically relevant enzymes. In this context, a large number of mannosidase inhibitors have been proposed in recent times with amidines, [25] pyridines [26] and isoquinuclidines, [27] and functionalized mannostatin and aminocyclopentitetrol analogues [21] that are notable for their binding to mannosidases.…”

Multi gram-scale synthesis of galactothionolactam and its transformation into a galactonoamidine

“…Although some procedures for the synthesis of glycosylamidine including aliphatic derivatives of glucoamidine and mannoamidine were reported, 9,12 we found several obstacles in our efforts to adapt this work for a multi gram-scale synthesis of galactothionolactam as a precursor for a galactonoamidine. Particularly, the previously suggested epimerization at C-2 during the synthesis of the glycosylthionolactam intermediate appears questionable for derivatives with the galacto-configuration.…”

“…[3][4][5][6] Gluco-and mannoamidines have been reported previously as potent transition state analogs and competitive inhibitors of corresponding glycosidases. [7][8][9][10][11][12] Comparable entities with the galacto-configuration are not described yet. However, the galactoconfiguration is preferable over a gluco-configuration for its intended use as template due to the structural constraints imposed by the axial hydroxyl group at C-4.…”