Galacto configured N-aminoaziridines: a new type of irreversible inhibitor of β-galactosidases

Abstract

A new type of galactose mimetics has been synthesized following a straightforward synthetic approach based on cyclohexene olefin aziridination reactions directed by hydroxyl substituents. These enantiomerically pure galacto-configured N-aminoaziridines are potent irreversible inhibitors of Aspergillus oryzae and Escherichia coliβ-galactosidases.

Detection of Active Mammalian GH31 α-Glucosidases in Health and Disease Using In-Class, Broad-Spectrum Activity-Based Probes

“…These probes label, besides lysosomal glucosylceramidase (GBA-the enzyme deficient in Gaucher disease), also neutral glucosylceramidase (GBA2), broad-specificity β-glucosidase (GBA3), and lactase phloridzin hydrolase (LPH). 16 − 21 Based on these findings we hypothesized that the corresponding α-glucopyranose configured, nitrogen-substituted cyclophellitol aziridines ( Figure 1 b) would be effective ABPs for specific labeling of GH31 retaining α-glucosidases, besides GAA also ER α-glucosidase II (GANAB, a crucial enzyme in the quality control of newly formed glycoproteins in the ER) and intestinal α-glucosidases involved in food processing. Here we report the successful development of such in-class GH31 α-glucosidase ABPs.…”

The Synthesis of Cyclophellitol‐Aziridine and Its Configurational and Functional Isomers

“…Expansion of methodology that enables the introduction of an aziridine at various stages of the synthesis is important to access to a wide array of cyclophellitol‐aziridine analogues. Llebaria and co‐workers recently reported direct aziridination of galacto ‐configured cyclohexene 28 (Scheme ). Although the objective of this synthetic study was to obtain N ‐amino‐aziridine 49 , the authors showed that reduction of the N–N bond yields 5‐ epi ‐cyclophellitol‐aziridine ( 31 ) (the structure of which was established after peracetylation to 50 ).…”

“…Although the objective of this synthetic study was to obtain N ‐amino‐aziridine 49 , the authors showed that reduction of the N–N bond yields 5‐ epi ‐cyclophellitol‐aziridine ( 31 ) (the structure of which was established after peracetylation to 50 ). Direct aziridination – either by reaction with aminoquinazolinones or by means of other recently published methodology – will likely evolve to become a complementary method for the synthesis of cyclophellitol‐aziridine analogues, thus expanding the chemical toolbox of covalent, irreversible glycosidase inhibitors and activity‐based glycosidase probes derived thereof.…”

Direct Stereoselective Aziridination of Cyclohexenols with 3‐Amino‐2‐(trifluoromethyl)quinazolin‐4(3H)‐one in the Synthesis of Cyclitol Aziridine Glycosidase Inhibitors

“…Recently, the stereospecific aziridination of a partially protected galacto ‐configured cyclohexene has been described by Llebaria and co‐workers based on the use of 3‐amino‐2‐ethylquinazolin‐4(3 H )‐one (Et‐Q‐NH 2 ) and PhI(OAc) 2 (PIDA). The thus formed β‐ galacto ‐configured acetylated aziridine was employed in this study to produce N ‐aminoaziridine based irreversible inhibitors (Figure D) . Inspired by this work of Llebaria and co‐workers we decided to explore the scope of the direct olefin aziridination reaction by investigating the reactivity of diverse aminoquinalozolin‐4‐ones towards differently configured and functionalized cyclohexenol substrates (Figure E).…”