Abstract:
:This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal β-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human β-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC50 = 8 nM, 30× more potent than 4-epi-isofagomine at pH 7.3) with a high selectivity for this glycosidase whereas the (5aS) epimer was a much weaker inhibitor. In addition, compound 1 showed a remarkable activity as a PC. It significantly enhanced the residual activity of mutant β-galactosidase in 15 patient cell lines out of 23, with enhancement factors greater than 3.5 in 10 cell lines and activity restoration up to 91% of normal. Altogether, these results indicated that (5aR)-5a-C-pentyl-4-epi-isofagomine constitutes a promising PC-based drug candidate for the treatment of GM1-gangliosidosis and Morquio disease type B.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Front S,Biela-Banaś A,Burda P,Ballhausen D,Higaki K,Caciotti A,Morrone A,Charollais-Thoenig J,Gallienne E,Demotz S,Martin ORdoi
10.1016/j.ejmech.2016.09.095subject
Has Abstractpub_date
2017-01-27 00:00:00pages
160-170eissn
0223-5234issn
1768-3254pii
S0223-5234(16)30858-3journal_volume
126pub_type
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