Scientific Paper

5248 J. Med. Chem. 2010, 53, 5248–5255 DOI: 10.1021/jm100198t

Click Chemistry Approach to New N-Substituted Aminocyclitols as Potential Pharmacological Chaperones for Gaucher Disease†
Lucı´ a Dı´ az,‡ Jordi Bujons, Josefina Casas,§ Amadeu Llebaria,§ and Antonio Delgado*,‡,§
Facultat de Farmcia, Unitat de Quı´mica Farmacutica (Unitat Associada al CSIC), Universitat de Barcelona, Avda. JoanXXIII, s/n, a e 08028 Barcelona, Spain, §Research Unit on Bioactive Molecules (RUBAM), Departament de Quı´mica Biomdica, Institut de Quı´mica Avancada de e Catalunya (IQAC-CSIC, Spanish National Research Council), Jordi Girona 18-26, 08034 Barcelona, Spain, and Department de Quı´mica Biolgica i Modelitzaci Molecular, Institut de Quı´mica Avancada de Catalunya (IQAC-CSIC, Spanish NationalResearch Council), Jordi Girona o o 18-26, 08034 Barcelona, Spain Received February 15, 2010
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New N-alkylaminocyclitols bearing a 1,2,3-triazole system at different positions of the alkyl chain have been prepared as potential GCase pharmacological chaperones using click chemistry approaches. Among them, compounds 1d and 1e, with the shorter spacer (n = 1) between the alkyltriazolyl system and theaminocyclitol core, were the most active ones as GCase inhibitors, revealing a determinant effect of the location of the triazole ring on the activity. Furthermore, SAR data and computational docking models indicate a correlation between lipophilicity and enzyme inhibition and suggest “extended” and “bent” potential binding modes for the compounds. In the “bent” mode, the most active compoundscould establish a hydrogen-bond interaction between the triazole moiety and enzyme residue Q284. Such an interaction would be precluded in compounds with a longer spacer between the triazole and the aminocyclitol core.

Introduction Gaucher disease is one of the most prevalent lysosomal storage disorders characterized by the accumulation of the sphingolipid glucosylceramide in the lysosomes. Thedisease is caused by the deficient activity elicited by several mutated forms of the enzyme glucocerebrosidase (GCase a), the β-glucosidase that hydrolyzes glucosylceramide into glucose and ceramide.1 Cellular levels of the mutated, misfolded enzyme are abnormally low because of its premature degradation by specific cytosolic endoproteases in the endoplasmic reticulum. Several therapeuticstrategies for Gaucher disease have been developed over the past years.2 Among them, the use of pharmacological chaperones, competitive inhibitors of the target enzyme that assist the proper folding of the defective protein at subinhibitory concentrations,3-5 is an active field of research.6 In this context, several iminosugars and aminocyclitols have been reported in the literature (Figure 1). To date, anumber of GCase structures in its native state7 with different degrees of glycosylation,8-10 under different pH conditions,11,12 or as a complex with different inhibitors13-16 have been reported. All these structures show a very similar 3D-arrangement for the protein with four loops (L1-L4) located at the entrance to the catalytic site that control open
† Dedicated to Prof. Pelayo Camps on theoccasion of his 65th anniversary. *To whom correspondence should be addressed. Phone: þ34934006108. Fax: þ34-932045904. E-mail: adelgado@cid.csic.es. a Abbreviations: A-C10, N-decylaminocyclitol; CC50, cytotoxic concentration for 50% of the cell population under study; clogP, calculated logarithm of the partition coeficient; GCase, β-glucocerebrosidase; IFG, isofagomine; NBDNJ,N-butyldeoxynojirimycin; NNDNJ, N-nonyldeoxynojirimycin ; NOV, N-octylvalienamine; SAR, structure-activity relationship.

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Figure 1. Aminocyclitols reported in this study (1-3), together with representative iminosugars and aminocyclitols reported as GCase inhibitors.

and closed conformations (see below). Differences on the surface topology of GCase close to the entrance to the active site have been observed...