Original article a-D-Mannose derivatives as models designed for selective inhibition of Golgi a-mannosidase II Monika Poláková a, * , Sergej  Sesták a , Erika Lattová b , Ladislav Petru  s a , Ján Mucha a , Igor Tvaro  ska a , Juraj Kó  na a, ** a Institute of Chemistry, Center for Glycomics, GLYCOMED, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia b University of Manitoba, Department of Chemistry, 144 Dysart Road, Winnipeg, Manitoba R3T 2N2, Canada article info Article history: Received 24 November 2010 Received in revised form 21 December 2010 Accepted 8 January 2011 Available online 15 January 2011 Keywords: Synthetic a-D-mannopyranosides Oxidation Mannopyranosyl sulfones Mannopyranosyl sulfoxides a-Mannosidase inhibitors Molecular modeling abstract Human Golgi a-mannosidase II (hGM) is a pharmaceutical target for the design of inhibitors with anti- tumor activity. Nanomolar inhibitors of hGM exhibit unwanted co-inhibition of the human lysosomal a-mannosidase (hLM). Hence, improving specificity of the inhibitors directed toward hGM is desired in order to use them in cancer chemotherapy. We report on the rapid synthesis of D-mannose derivatives having one of the RS-, R(SO)- or R(SO 2 )- groups at the a-anomeric position. Inhibitory properties of thirteen synthesized a-D-mannopyranosides were tested against the recombinant enzyme Drosophila melanogaster homolog of hGM (dGMIIb) and hLM (dLM408). Derivatives with the sulfonyl [R(SO 2 )-] group exhibited inhibitory activities at the mM level toward both dGMIIb (IC 50 ¼ 1.5e2.5 mM) and dLM408 (IC 50 ¼ 1.0e2.0 mM). Among synthesized, only the benzylsulfonyl derivative showed selectivity toward dGMIIb. Its inhibitory activity was explained based on structural analysis of the built 3-D complexes of the enzyme with the docked compounds. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction The natural indolizidine swainsonine and some related pyrro- lidines (Scheme 1) are nanomolar inhibitors of retaining glycoside hydrolases belonging to the family 38, Golgi a-mannosidase II (GM) (E.C.3.2.1.114) and lysosomal a-mannosidase (LM) (E.C.3.2.1.24) [1]. It was previously shown that treatment of the animals with swai- nsonine induced a strong immunostimulatory activity that resulted in an anti-cancer effect [2] and significantly blocked growing tumor in the lung, liver, and spleen. It was demonstrated that its activity was associated with the modification of N-glycan biosynthesis in which GM is reversibly blocked. However, swainsonine causes a phenocopy of the lysosomal storage disease called a-mannosidosis. This phenomena is caused by the additional targeting of LM by swainsonine, and limits its use in the clinical cancer chemotherapy [3]. Therefore the finding of a selective GM inhibitor with mini- mized unwanted co-inhibition of LM has become challenge for a number of researchers [4e19]. Up to date, dozens of novel swainsonine analogs were proposed and tested [1]. However, most potent inhibitors of GM exhibit negligible or no selectivity. To design an effective selective inhibitor of GM is a major problem, mainly because of the structural simi- larities of the active sites in GM and LM. The both enzymes are from the same family with the almost identical structures in radius 10  A around Zn 2þ ion co-factor, which resides at the bottom of the active site and is essential for catalytic activity of the enzymes as well as for strong binding of the inhibitors [20]. This is the main reason why binding affinities of small organic inhibitors such as swain- sonine are similar for both enzymes with no selectivity observed. Rose and co-workers [21,22] proposed the design for a selective inhibitor which mimics a binding position of non-reducing- terminal N-acetylglucosamine (GlcNAc) residue of the GM subs- trate. Such type of inhibitor would be capable to attach to GM at its binding subsite which is missing in LM. Moreover, this residue is essential for substrate specificity since GM cleaves substrate without terminal GlcNAc 80-fold more slowly. On the other side, Abbreviations: GM, Golgi a-mannosidase II; hGM, human Golgi a-mannosidase II; dGM, Drosophila melanogaster a-mannosidase II; dGMIIb, catalytic domain of Drosophila melanogaster Golgi a-mannosidase II, recombinant enzyme homolog of human Golgi a-mannosidase II; LM, lysosomal a-mannosidase; hLM, human lyso- somal a-mannosidase; bLM, Bos taurus lysosomal a-mannosidase; dLM408, cata- lytic domain of Drosophila melanogaster lysosomal a-mannosidase, recombinant enzyme homolog of human lysosomal a-mannosidase. * Corresponding author. Tel.: þ421 2 59410272; fax: þ421 2 59410222. ** Corresponding author. Tel.: þ421 2 59410203; fax: þ421 2 59410222; E-mail addresses: monika.polakova@savba.sk (M. Poláková), chemkona@savba. sk (J. Kó na). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.01.012 European Journal of Medicinal Chemistry 46 (2011) 944e952