Inhibition of glycosidases by substituted amidines

N‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II

“…All potent dGMII inhibitors have to bind properly to the bottom of the active site by interaction with Zn 2+ and neighboring amino acid residues otherwise the potency of the inhibitor is dropped dramatically. [9a, 9b, 9e, 9f, 9i-k, 10c, 12] The critical role of Zn 2+ ion and aspartic acid residues of the catalytic subsite for the interactions with the dGMII inhibitors was recently confirmed by quantum mechanics calculations. [13] From crystal structures of available fruit fly dGMII[5b, 11a] and bovine bLMan[8a] it is evident that the active site of both enzymes are structurally and chemically almost identical in radius of 10 Å around Zn 2+ ion co-factor.…”

“…This is one of reasons why structurally small potent GMII inhibitors like swainsonine inhibit both enzymes effectively with no significant selectivity observed. Thus, our strategy in the design of a selective GMII inhibitor was based on a previous proposal,[5a, 12c] and consists of two basic points: (i) design of the core unit of the inhibitor (key interactions with catalytic subsite which is identical in both dGMII and bLMan); and (ii) design of structural linker (specific interactions with holding or anchor subsites of dGMII which are missing in bLMan). [5a, 8a, 11a] For these purposes, polyhydroxypyrrolidines with N -substitution were prepared.…”

Evaluating N-benzylgalactonoamidines as putative transition state analogs for β-galactoside hydrolysis

“…Likewise, no evidence for compound decomposition was observed by HPLC assays relying on a carbohydrate-discriminating Na + -RMN column as stationary phase and nanopure water as eluent, when exposing 1d to acetate buffer at 30°C for the same amount of time. However, the glyconoamidine stability under alkaline conditions is debated in the literature 9–14 , and insufficient stability of 1d in conditions previously used for the preparation of microgels, i.e. 50 mM CAPS buffer at pH 10.5 and 72°C, was noted.…”

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

“…[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.…”