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Article

Synthesis and Biological Evaluation of Glycosidase Inhibitors: gem-Difluoromethylenated Nojirimycin Analogues

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Ruo-Wen Wang,^† Xiao-Long Qiu,^† Mikael Bols,^‡ Fernando Ortega-Caballero,^‡ and Feng-Ling Qing*^†^§

Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China, Institute of Biological Sciences and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China, and Department of Chemistry, University of Aarhus, DK-8000 Aarhus C, Denmark

J. Med. Chem., 2006, 49 (10), pp 2989–2997

DOI: 10.1021/jm060066q

Publication Date (Web): April 13, 2006

†

Shanghai Institute of Organic Chemistry.

‡

Aarhus University.

Corresponding author. Office: 86-21-5492-5187. Fax: 86-21-6416-6128. E-mail: flq@mail.sioc.ac.cn.

Donghua University.

Abstract

In our ongoing program aimed at the design, synthesis, and biological evaluation of novel gem-difluoromethylenated glycosidase inhibitors, gem-4,4-difluoromethylenated iminosugars (5−9) were synthesized. The biological evaluation of these synthetic iminosugars showed that the gem-difluoromethylenyl group generally reduced the inhibition of glycosidases. However, this was not the case at pH 5.0, where the gem-difluoromethylenated iminosugar 6 was a stronger inhibitor than comparable iminosugars 1 and 36, suggesting that the influence of this group is mainly through its effect on the amine. It is proposed that the unprotonated iminosugar is the species preferably bound by β-glucosidase, due to the lower pK_a value of iminosugar 6 than of 1 or 36, leaving iminosugars 1 and 36 mostly protonated at pH 5.0, while iminosugar 6 is not. Iminosugar 6 also displayed good and selective inhibition of β-glucosidase at pH 6.8.

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Published In Issue May 18, 2006
Received January 19, 2006

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Article

Synthesis and Biological Evaluation of Glycosidase Inhibitors: gem-Difluoromethylenated Nojirimycin Analogues

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