Modifying the phenyl group of PUGNAc: reactivity tuning to deliver selective inhibitors for N-acetyl-d-glucosaminidases

Abstract

The synthesis of analogues of the potent N-acetylhexosaminidase inhibitor, PUGNAc, are described. These compounds were assayed against a set of biologically important N-acetyl-d-glucosaminidases and were found to vary in both potency and selectivity.

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

“…These enzymes are classified into three glycosyl hydrolase family (GH3, GH20 and GH84) based on amino acid sequence similarities in the CAZy classification system ( http://www.cazy.org ) 1 , 2 . And they are involved in various physiological functions, such as energy metabolism 3 , cell communication 4 , cell proliferation 5 and inflammation 6 . Among these, the GH20 human β- N -acetylhexosaminidases (hsHex) and GH84 human O -GlcNAcase (hOGA) are the most promising targets for drug development.…”

Synthetic and Crystallographic Insight into Exploiting sp2 Hybridization in the Development of α‐l‐Fucosidase Inhibitors

“…[15] With these points in mind we felt, based on the putative conformational itinerary analysist hat has been described for GH29 a-l-fucosidases, that molecules bearing an sp 2 -hybridized anomeric carbon may act as inhibitors of these enzymes as they could potentially mimic the conformation of the putative transition state( Scheme 1D). [22] Starting from l-fucose 7,p eracetylation under standard conditions followed by selectivedeacetylation at the anomeric position gave the known hemiacetal 8 (Scheme 2). [22] Starting from l-fucose 7,p eracetylation under standard conditions followed by selectivedeacetylation at the anomeric position gave the known hemiacetal 8 (Scheme 2).…”

“…[22] Thus, treatment of 10 Scheme1.A) GH29 fucosidases use ar etainingc atalytic mechanism involvingaglycosyl-enzyme intermediate such that the overall reaction proceeds with net retention of stereochemistry.B)Putative transition state for GH29 fucosidases. [22] Thus, treatment of 10 Scheme1.A) GH29 fucosidases use ar etainingc atalytic mechanism involvingaglycosyl-enzyme intermediate such that the overall reaction proceeds with net retention of stereochemistry.B)Putative transition state for GH29 fucosidases.…”

Back to (non-)Basics: An Update on Neutral and Charge-Balanced Glycosidase Inhibitors

“…Over 75 years since gluconolactone 1 was first discovered to inhibit glucosidases, research into new classes of glycosidase inhibitors continues to flourish. 158,159 This is supported by a broader understanding of the tertiary structures of enzyme targets and the further uncovering of novel mechanisms in this family. 98,160,161 Epoxides such as the natural product cyclophellitol and sulfonium ions like ones found naturally within the salicinol family were both discovered as synthetic classes of glycosidase inhibitor before they were identified in nature.…”