Abstract
Sialic acid is the natural substrate for sialidases and its chemical modification has been a useful approach to generate potent and selective inhibitors. Aiming at advancing the discovery of selective Trypanosoma cruzi trans-sialidase (TcTS) inhibitors, we have synthesised a small series of anomeric 1,2,3-triazole-linked sialic acid derivatives in good yields and high purity via copper-catalysed azide–alkyne cycloaddition (CuAAC, click chemistry) and evaluated their activity towards TcTS and neuraminidase. Surprisingly, the compounds showed practically no TcTS inhibition, whereas ca. 70% inhibition was observed for neuraminidase in relation to the analogues bearing hydrophobic substituents and ca. 5% for more polar substituents. These results suggest that polarity changes are less tolerated by neuraminidase due to the big difference in impact of hydrophobicity upon inhibition, thus indicating a simple approach to differentiate both enzymes. Moreover, such selectivity might be reasoned based on a possible steric hindrance caused by a bulky hydrophobic loop that sits over the TcTS active site and may prevent the hydrophobic inhibitors from binding. The present study is a step forward in exploiting subtle structural differences in sialidases that need to be addressed in order to achieve selective inhibition.
Highlights
Amongst the diversity of glycans present in living organisms, N-acetylneuraminic acid (Neu5Ac, sialic acid) is typically found as a terminal unit of surface glycoconjugates and is crucial to various cellular recognition events in both physiological and pathological processes [1]
Amongst the vast number of reported procedures, the 1,3dipolar cycloaddition was performed with 20 mol % excess of the terminal alkynes in a mixture of solvents (DMF/H2O 4:1) at 60 °C and Cu(I) generated in situ [33], but in catalytic amount. This approach resulted in the synthesis of eight 1,4-disubstituted 1,2,3-triazole derivatives (2a–h) in good yields (45–78%) and high purity
A small series of anomeric 1,2,3-triazole-linked sialic acid derivatives was synthesised in good yields and high purity via CuAAC click chemistry and evaluated for their potential inhibitory activity towards Trypanosoma cruzi trans-sialidase (TcTS) and neuraminidase
Summary
Amongst the diversity of glycans present in living organisms, N-acetylneuraminic acid (Neu5Ac, sialic acid) is typically found as a terminal unit of surface glycoconjugates and is crucial to various cellular recognition events in both physiological and pathological processes [1]. In the context of mimicking the terminal sugars α-ᴅ-Neu5Ac(2,3)-β-ᴅ-Gal of Trypanosoma cruzi mucins to obtain potent TcTS inhibitors, our group previously synthesised a small series of C-2-modified sialic acid bearing a monosaccharide tethered via 1,2,3-triazole ring (sialylmimetic neoglycoconjugates) [19] that showed 67–91% inhibitory activity at 1 mM.
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