- Scalable syntheses of both enantiomers of DNJNAc and DGJNAc from glucuronolactone: The effect of N-alkylation on hexosaminidase inhibition
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The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto- nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of β-GlcNAcases and β-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics. Getting the NAc of it: Scalable syntheses of DGJNAc and DNJNAc from D-glucuronolactone are reported. DGJNAc and its N-alkyl derivatives were inhibitors of α-GalNAcase and both DGJNAc and DNJNAc were potent inhibitors of β-GlcNAcases and β-GalNAcases. Copyright
- Glawar, Andreas F. G.,Best, Daniel,Ayers, Benjamin J.,Miyauchi, Saori,Nakagawa, Shinpei,Aguilar-Moncayo, Matilde,García Fernández, José M.,Ortiz Mellet, Carmen,Crabtree, Elizabeth V.,Butters, Terry D.,Wilson, Francis X.,Kato, Atsushi,Fleet, George W. J.
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p. 9341 - 9359
(2012/09/22)
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- SYNTHESIS OF DGJNAC FROM D-GLUCURONOLACTONE AND USE TO INHIBIT ALPHA-N-ACETYLGALACTOSAMINIDASES
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A convenient and scalable synthesis of DGJNAc ID from D-glucuronolactone in an overall yield of 20% is provided. DGJNAc is the first highly potent and specific competitive inhibitor of GalNAcases. DGJNAc ID is also a competitive inhibitor of -hexosaminida
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- Synthesis of 2-acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc] from d-glucuronolactone: the first sub-micromolar inhibitor of α-N-acetylgalactosaminidases
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2-Acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc], prepared in 20% overall yield from d-glucuronolactone, is the first potent competitive sub-micromolar inhibitor of α-N-acetyl-galactosaminidases (Ki 0.081 μM from chicken liver, Ki 0.136 μM from Charonia lampas). DGJNAc is a good competitive-whereas the enantiomer l-DGJNAc is a very weak but non-competitive-inhibitor of β-hexosaminidases.
- Best, Daniel,Chairatana, Phoom,Glawar, Andreas F.G.,Crabtree, Elizabeth,Butters, Terry D.,Wilson, Francis X.,Yu, Chu-Yi,Wang, Wu-Bao,Jia, Yue-Mei,Adachi, Isao,Kato, Atsushi,Fleet, George W.J.
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scheme or table
p. 2222 - 2224
(2010/05/19)
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