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Title: A Fluorescent sp2-Iminosugar With Pharmacological Chaperone Activity for Gaucher Disease: Synthesis and Intracellular Distribution Studies
Authors: Luan, Zhuo, Higaki, Katsumi, Aguilar Moncayo, Matilde, Li, Linjing, Ninomiya, Haruaki, Nanba, Eiji, Ohno, Kousaku, García Moreno, María Isabel, Ortiz-Mellet, Carmen, García-Fernández, José Manuel, Suzuki, Yoshiyuki
Keywords: Chaperones
Fluorescent probes
Gaucher disease
Glucosidases
Iminosugars
Issue Date: 9-Nov-2010
Publisher: Wiley-VCH
Abstract: Gaucher disease (GD) is the most prevalent lysosomal-storage disorder, it is caused by mutations of acid β-glucosidase (β-glucocerebrosidase; β-Glu). Recently, we found that bicyclic nojirimycin (NJ) derivatives of the sp2-iminosugar type, including the 6-thio-N′-octyl-(5N,6S)-octyliminomethylidene derivative (6S-NOI-NJ), behaved as very selective competitive inhibitors of the lysosomal β-Glu and exhibited remarkable chaperone activities for several GD mutations. To obtain information about the cellular uptake pathway and intracellular distribution of this family of chaperones, we have synthesized a fluorescent analogue that maintains the fused piperidine–thiazolidine bicyclic skeleton and incorporates a dansyl group in the N′-substituent, namely 6-thio-(5N,6S)-[4-(N′-dansylamino)butyliminomethylidene]nojirimycin (6S-NDI-NJ). This structural modification does not significantly modify the biological activity of the glycomimetic as a chemical chaperone. Our study showed that 6S-NDI-NJ is mainly located in lysosome-related organelles in both normal and GD fibroblasts, and the fluorescent intensity of 6S-NDI-NJ in the lysosome is related to the β-Glu concentration level. 6S-NDI-NJ also can enter cultured neuronal cells and act as a chaperone. Competitive inhibition studies of 6S-NDI-NJ uptake in fibroblasts showed that high concentrations of D-glucose have no effect on chaperone internalization, suggesting that it enters the cells through glucose-transporter-independent mechanisms.
Description: 12 páginas
Publisher version (URL): http://dx.doi.org/10.1002/cbic.201000323
URI: http://hdl.handle.net/10261/36521
ISSN: 1429-4227
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Citation: ChemBioChem 11(17): 2453-2464 (2010)
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