Glycosidase Inhibition with Fullerene Iminosugar Balls: A Dramatic Multivalent Effect

Abstract

Superball! A dodecavalent iminosugar derivative with a fullerene core (see picture) shows a binding enhancement of up to three orders of magnitude over the corresponding monovalent ligand in glycosidase inhibition assays. This is the first evidence of a significant multivalent effect in glycosidase inhibition.

A study towards the regioselective synthesis of the e,e,e trisadduct of C60 via the [4+2] Diels-Alder reaction with tethers bearing ortho-quinodimethane precursors

“…Apart from their unique architecture, hexakis adducts derived from the functionalization of the six e double bonds of C 60 are very attractive structures in the synthesis of functional fullerene materials. [45][46][47][48][49][50] The results of the present study lead to the conclusion that the [4+2] cycloaddition of orthoquinodimethanes with the C 60 is a kinetically controlled reaction. The in situ thermal generation of ortho-quinodimethanes from the corresponding 1,2-bis(bromomethyl)benzene precursors requires high temperatures (110 o C) and is followed by the fast, irreversible [4+2] cycloaddition reaction with C 60 to afford thermally stable products.…”

The Inhibition of Liposaccharide Heptosyltransferase WaaC with Multivalent Glycosylated Fullerenes: A New Mode of Glycosyltransferase Inhibition

“…[36] More recently, Compain and Nierengarten described a fullerene iminosugar ball that was assayed against a range of glycosidases and displayed a relative inhibition potency of 179 compared with the monomeric structure, also against Jack bean a-mannosidase. [9] These literature data clearly indicate that all enzymes are not prone to multivalent inhibition and that the nature of both the central core structure and the spacer unit tethering the inhibitory monomers play critical roles in the inhibition process. The inhibition data presented in this study demonstrate that heptosyltransferase WaaC is the second enzyme ever reported for which significant levels of multivalent inhibition have been measured.…”

“…[9] Specifically, multivalent effects have been observed with isomaltase of bakers yeast and a-mannosidase of Jack bean with K i values improved by two and three orders of magnitude, respectively, over the corresponding monomeric iminosugar. This first evidence of dramatic multivalent effects in glycosidase inhibition not only opens a new field of research, but also reveals that the multivalent approach may be an appealing tool for innovative drug discoveries.…”

The Impact of Copper‐Catalyzed Alkyne–Azide 1,3‐Dipolar Cycloaddition in Fullerene Chemistry

“…[70][71][72] For example, the inhibition profile of fullerene hexakis-adduct 54, decorated with 12 iminosugar residues, was systematically evaluated towards various glycosidases. [70] Remarkably, significant multivalent effects were evidenced for the first time.…”