Journal
PHARMACEUTICALS
Volume 13, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/ph13110366
Keywords
multivalency; inhibitory multivalent effect; CuAAC; calix[8]arene; alpha-mannosidase
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Funding
- CNRS (UMR 7509)
- University of Strasbourg
- Fondation pour la Recherche en Chimie (FRC Strasbourg)
- University of Salerno
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A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ K-i being at 322 and 188 mu M for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean alpha-mannosidase (JB alpha-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms. Preliminary docking studies were performed to get insights into the preferred binding modes.
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