Metalloglycosidase Mimics: Oxidative Cleavage of Saccharides Promoted by Multinuclear Copper Complexes under Physiological Conditions

Abstract

Degradation of saccharides is relevant to the design of catalytic therapeutics, the production of biofuels, inhibition of biofilms, as well as other applications in chemical biology. Herein, we report the design of multinuclear Cu complexes that enable cleavage of saccharides under physiological conditions. Reactivity studies with para-nitrophenyl (pNP)-conjugated carbohydrates show that dinuclear Cu complexes exhibit a synergistic effect and promote faster and more robust cleavage of saccharide substrates, relative to the mononuclear Cu complex, while no further enhancement is observed for the tetranuclear Cu complex. The use of scavengers for reactive oxygen species confirms that saccharide cleavage is promoted by the formation of superoxide and hydroxyl radicals through CuII/I redox chemistry, similar to that observed for native copper-containing lytic polysaccharide monooxygenases (LMPOs). Differences in selectivity for di- and tetranuclear Cu complexes are modest. However, these are the first reported small multinuclear Cu complexes that show selectivity and reactivity against mono- and disaccharide substrates and form a basis for further development of metalloglycosidases for applications in chemical biology.

Cellulose Depolymerization with LPMO‐inspired Cu Complexes

“…Two model systems containing a mixed imidazole/pyridylamine‐based donor set, [8] and the bis(benzimidazole)amine‐based 2BB [9] (Scheme 1), provide examples of confirmed oxidative degradation of model substrates. The more recently reported systems based on 2‐pyridyl/diazepane, [10] bis(imidazole)amine, [11] and bis(2‐picolyl)amine [12] ligands degrade p ‐nitrophenolate‐derivatized glucose and/or disaccharides, with the p ‐nitrophenolate leaving group quantified as the end product by UV‐vis spectroscopy. In the first two cases, D‐allose was also identified as product, instead of the expected gluconic acid upon hydrolysis of the initially formed gluconolactone; in the latter, the saccharide byproducts were not identified.…”

Oxidation of hexacyanoferrate(II) ion by hydrogen peroxide: evidence of free radical intermediacy

“…Although the main chemical agents able to reduce hydrogen peroxide to hydroxyl radical under physiological conditions are thought to be transition-metal ions in their lower oxidation states [11], especially Fe(II) and Cu(I) in their protein-bounded forms [12][13][14], some authors (belonging to the field of chemistry rather than to that of biology) have openly opposed this interpretation, favoring either an Fe(IV) or a Cu(III) non-radical mechanism instead [15][16][17][18][19][20][21][22][23][24][25][26]. This has resulted in a certain polemic, since other authors favor the hydroxyl-based mechanism [27][28][29][30][31][32][33].…”

Oxidative Cleavage of Glycosidic Bonds by Synthetic Mimics of Lytic Polysaccharide Monooxygenases

“…2,3 Indeed, 3c-Cu and MINP(2a) together at 1 mol % level cleaved substrate 1 in a 53% yield, with H 2 O 2 as the oxidant and ascorbic acid (ASC) to reduce Cu(II) to the catalytically active Cu(I) to start the reaction, under similar conditions used in other copper systems. 6,7 Liquid chromatography-mass spectrometry (LC-MS) analysis showed the main product as Dgluconic acid δ-lactone 1P (Figure S5), confirming the anomeric carbon being oxidized. Control experiments indicated that the copper complex, H 2 O 2 , ASC, and the MINP must all be present for significant cleavage to occur (Figure S6).…”

“…Its catalytic efficiency (k cat /K m = 155 M −1 min −1 ) is 1−2 orders of magnitude smaller than those of reported multinuclear copper complexes, although more active p-nitrophenyl glycosides were used in the latter. 7 In addition to 1, MINP(2a)−3c-Cu cleaved a range of glycosides and disaccharides (Figure 1). For these reactions, a 1:2 ratio between the copper cofactor and the MINP was used, which improved the yield.…”