Synthesis of iminoalditol analogues of galactofuranosides and their activities against glycosidases

doi:10.1016/j.carres.2008.07.013

Carbohydrate Research

Volume 343, Issue 17, 24 November 2008, Pages 2878-2886

Dedicated to Professor Yongzheng Hui on the occasion of his 70th birthday

https://doi.org/10.1016/j.carres.2008.07.013 Get rights and content

Abstract

Iminoalditol analogues of galactofuranosides were synthesized from 1-C-(2′-oxo-propyl)-1,4-dideoxy-1,4-imino-d-galactosides and different amines by reductive amination, followed by removal of protecting groups. The activity of these compounds against galactosidases and other glycosidases was investigated. The best inhibitor against β-galactosidase (bovine liver) is a diastereomeric mixture of an iminoalditol (10h), which contains a hydrophobic hexadecyl aglycon (R = C₁₆H₃₃), whereas no significant inhibitory activity was observed with compounds having a hydrophilic aglycon. Surprisingly, activation of α-galactosidase (coffee bean) by 10h was also observed. Because these results were obtained from a mixture of iminoalditols, the inhibition and activation of glycosidases could result from different diastereomers.

Graphical abstract

Introduction

Iminosugars as potent glyco-processing enzyme inhibitors have been clinically applied to the treatment of diabetes and glycosidase-deficient diseases.¹ For example, Miglitol (N-hydroxyethyldeoxynojirimycin), a α-glucosidase inhibitor, is used for blood glucose control. Miglustat (N-butyldeoxynojirimycin), a glucosylceramide synthase inhibitor, is one of the therapeutics for type 1 Gaucher disease. The therapeutic applications of iminosugars could be expanded if better inhibition specificity against α- or β-glycosidases can be obtained. There have been examples suggesting that homoiminosugars and 1-C-alkyl iminosugars are more selective inhibitors, particularly against α-glycosidases.² The improved selectivity was attributed to the defined anomeric configuration and additional interaction between the aglycon and the lipophilic domain of glycosidases.³

In addition, iminosugars can also be utilized at subinhibitory concentrations as chemical chaperons that resurrect misfolded enzymes in the ER/Golgi from degradation and facilitate the transportation to lysosome, where lower pH stabilizes the enzyme.⁴ This chemical chaperon approach has been explored for the treatment of both Gaucher⁵ and Fabry⁶ diseases with lysosomal β-glucocerebrosidase and α-galactosidase A deficiency. Other glycosidase deficiency diseases, such as GM1-gangliosidosis and Morquio B disease, have also been investigated in the animal model using glycosidase inhibitors as chemical chaperons.⁷

Previously, we have synthesized various 2-keto-iminoalditols with the aim of using them for diversity-oriented synthesis.⁸ For example, by conjugation with various amines by reductive amination we will be able to obtain an array of diverse iminoalditols that can be tested against glycosidases. In this report, we describe the synthesis of various iminoalditol analogues of galactofuranosides and their activities against glycosidases, particularly, α- and β-galactosidases.

Section snippets

Results and discussion

Five-membered iminosugar derivatives, containing a pyrrolidine core, demonstrated inhibitory potency against various glycosidases because of their ability to mimic transition states.⁹ The core structure of this study is an iminoalditol analogue of the galactofuranoside ring, which was derivatized through the 2-keto group via reductive amination with different amines. We first synthesized 5 as a key intermediate following a procedure similar to that used for the synthesis of similar iminosugar

General methods

¹H and ¹³C NMR spectra were recorded at 400 MHz and 100 MHz, respectively, with a Varian instrument at 293 K. Chemical shifts were given in ppm downfield to the signal of internal TMS, and were assigned on the basis of 2D ¹H–¹H COSY and ¹H–¹³C chemical-shift-correlated experiments. For high resolution mass spectroscopic analysis, samples in CH₂Cl₂–MeOH 1:1 were mixed with Agilent ES tuning mix for internal mass calibration and infused into an AB/MDS-Sciex (Concord, ON) QSTAR mass spectrometer at a

Acknowledgments

This is NRC-CNRC publication No. 42527. We thank Ken Chan and Jacek Stupak for MS analysis and Nam Khieu for the assistance in NMR analysis.

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Synthesis of iminoalditol analogues of galactofuranosides and their activities against glycosidases

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

General methods

Acknowledgments

Bioorg. Med. Chem. Lett.

Nat. Med.

FEBS J.

Tetrahedron

Carbohydr. Res.

Tetrahedron Lett.

J. Org. Chem.

J. Org. Chem.

Carbohydr. Res.

J. Org. Chem.

Synthesis

J. Org. Chem.

Bioorg. Med. Chem.

Iminosugars as Glycosidase Inhibitors

Curr. Top. Med. Chem.

Tetrahedron: Asymmetry

Chem. Rev.

Curr. Top. Med. Chem.

Phytochemistry

Carbohydr. Res.

Bioorg. Med. Chem.

Toward Azaglycoside Mimics: Aza-C-glycosyl Compounds and Homoazaglycosides