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A Fluorescent sp2-Iminosugar With Pharmacological Chaperone Activity for Gaucher Disease: Synthesis and Intracellular Distribution Studies

AuthorsLuan, 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
Fluorescent probes
Gaucher disease
Issue Date9-Nov-2010
CitationChemBioChem 11(17): 2453-2464 (2010)
AbstractGaucher 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.
Description12 páginas
Publisher version (URL)http://dx.doi.org/10.1002/cbic.201000323
Appears in Collections:(IIQ) Artículos
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