Spirocyclopropyl pyrrolidines as a new series of a-L -fucosidase inhibitors Christophe Laroche, a Jean-Bernard Behr, a, * Jan Szymoniak, a Philippe Bertus, a Catherine Schu ¨tz, b Pierre Vogel b and Richard Plantier-Royon a, * a Laboratoire ‘Re ´actions Se ´ lectives et Applications,’ Universite ´ de Reims Champagne-Ardenne, UMR URCA/CNRS 6519, UFR Sciences, BP 1039, F-51687 Reims Cedex 2, France b Laboratoire de Glycochimie et Synthe `se Asyme ´trique, Ecole Polytechnique Fe ´de ´rale de Lausanne (EPFL), BCH CH-1015 Lausanne, Switzerland Received 14 December 2005; revised 24 January 2006; accepted 3 February 2006 Available online 20 February 2006 Abstract—Polyhydroxy 4-azaspiro[2.4]heptane derivatives (spirocyclopropyl iminosugars) were prepared in four to six steps from readily available protected aldoses. The key step of the reaction sequence involves a titanium-mediated aminocyclopropanation of glycononitriles with subsequent cyclization. Five new polyhydroxypyrrolidines so-obtained have been evaluated for their ability to inhibit 16 glycosidases. One of them exhibits selective inhibition of a-L-fucosidase from bovine kidney (K i = 1.6 lM, competitive). Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Fucosyltransferases and a-L-fucosidases are involved in the processing of fucosylated glycoconjugates. 1–3 Owing to the great variety of physiological and pathological events relevant to fucose-containing oligosaccharides, 4–6 increasing attention has been drawn to the mode of ac- tion and inhibition of these enzymes. For instance, hu- man a-1,3-fucosyltransferase, responsible for the production of sialyl Le x , 7,8 is a potential target for the development of antiinflammatory agents. 9 On the other hand, high activity and aberrant distribution of a-fuco- sidases have been observed in cancer cells. 10,11 Conse- quently, fucosidases have been recognized as diagnostic markers for the early detection of colorectal and hepato- cellular cancers. Moreover, a-fucosidase inhibitors have also been found to reduce HIV-infection, certainly by altering the glycosylation pattern of viral glycoproteins responsible for host cell surface binding. 12–14 Much effort has been devoted towards the synthesis and biological evaluation of fucosyltransferase and fucosi- dase inhibitors. Nitrogen-containing fucose analogues such as 1,5-dideoxy-1,5-iminoalditols like deoxyfuconoj- irimycin 1, or 1,4-dideoxy-1,4-iminoalditols 2–11 were shown to interfere with the fucose-processing enzymes (Fig. 1). It is usually postulated that these iminosugars compete with the natural substrate (a fucose glycoside or fucose-GDP) by mimicking its charge distribution and hydroxyl group topography at the transition state of the biocatalytic reaction. 15–17 Thus, deoxyfuconojiri- mycin 1 is the most potent inhibitor of a-L-fucosidase known so far (K i = 5 nM). 18 The five-membered-ring iminosugars featuring a methyl group at C-5 also displayed potent fucosidase inhibition properties (K i = 8 nM for 4 and K i = 10 nM for 2; K i in the micromolar range for other structures). A variety of configurations have been encountered in the pyrrolidine series (Fig. 1). 19–23 Moreover, Wong et al. have reported a synergistic inhibition of fucosyltransferase by imino- sugar 7 in combination with GDP. 24 Other iminosugar- based fucosyltransferase inhibitors have been described since then. 25,26 Finally, the protected iminosugar 11 dis- played a pronounced anti-HIV activity (50% reduction of virus yield in infected cells at 20 lM). 13 We have recently explored the aminocyclopropanation of protected carbohydrates, 27 with the aim of synthesiz- ing new cyclopropane-containing sugar analogues. 28 0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2006.02.005 Keywords: Azasugars; Glycosidases; Inhibition; Spiro compounds. * Corresponding authors. Tel.: +33 326 91 32 38; fax: +33 326 91 31 66 (J.-B.B.); tel.: +33 326 91 33 08; fax: +33 326 91 31 66 (R.P.R.); e-mail addresses: jb.behr@univ-reims.fr; richard.plantier-royon@ univ-reims.fr Bioorganic & Medicinal Chemistry 14 (2006) 4047–4054