6‐Amino‐6‐deoxy‐5,6‐di‐N‐(N′‐octyliminomethylidene)nojirimycin: Synthesis, Biological Evaluation, and Crystal Structure in Complex with Acid β‐Glucosidase

Abstract

Abstract6‐Amino‐6‐deoxy‐5,6‐di‐N‐(N′‐octyliminomethylidene)nojirimycin, a reducing analogue of N‐nonyl‐1‐deoxynojirimycin, proved to be a potent and very selective inhibitor of β‐glucosidases, including human acid β‐glucosidase. Structural studies of the enzyme–inhibitor complex showed a binding mode in which the anomeric hydroxy group is accommodated in the “wrong” α configuration.magnified image

Chaperone Activity of Bicyclic Nojirimycin Analogues for Gaucher Mutations in Comparison with N‐(n‐nonyl)Deoxynojirimycin

“…Formation of the enzyme-inhibitor complex was, however, entropically driven, a thermodynamic signature that is unique for this family of sugar mimics. Further X-ray structural studies on the interaction of the 6-amino-6-deoxy-5,6-di-N-(N'-octyliminomethylidene)nojirimycin analogue (6N-NOI-NJ, 3; Scheme 1) with recombinant human b-glucocerebrosidase confirmed a binding mode analogous to that previously encountered for NN-DNJ, [39] with additional interactions involving the pseudoanomeric hydroxyl group. The rigid bicyclic framework imposes a restricted orientation of the hydrophobic substituent that is probably responsible for the unprecedented anomeric selectivity.…”

“…[49] The remarkable selectivity for b-Glu was ascribed to the rigidity of the bicyclic skeleton. [39] Since the synthesis of sp 2 iminosugars is readily amenable to molecular diversity-oriented strategies and biological activity optimization, evaluation of their potential as chemical chaperones for the treatment of Gaucher disease was very appealing.…”

“…For the preparation of 2-5 the previously reported reaction sequences were followed with slight modification. [37,39] For compound 1, [32] an advantageous route has been developed, while compound 6 has not been previously reported. NN-DNJ was obtained from United States Biological (Marblehead, MA, USA).…”

“…The known 5-azido-5-deoxy-1,2-O-isopropylidene-6-O-tetrahydropyranyl-a-d-glucofuranose (7), [40] readily accessible from commercial d-glucofuranurono-6,3-lactone, was chosen as a pivotal synthetic intermediate from which 1-3 can be obtained in a limited number of steps. [37,39] The optimized reaction sequence leading to 1 is discussed hereinafter to illustrate the methodology because it represents a significant improvement with respect to the previously reported preparation. [32] Reduction of the azido group in 7 by catalytic hydrogenation, coupling of the resulting amine with octyl isocyanate and hydrolysis of the tetrahydropyranyl (THP) group with p-toluenesulfonic acid (PTSA) afforded the N'-octylurea adduct 8 in 93 % overall yield (Scheme 3).…”

1-Deoxynojirimycins with dansyl capped N-substituents as probes for Morbus Gaucher affected cell lines

“…Recently, unusual structures such as bicyclic nojirimycin derivatives 7 and a lipophilic derivative of isofagomine 8 have also been found to exert excellent activities in this context. Other laboratories such as Wong's 9 as well as Aerts and Overkleeft and their co-workers 10 have observed that large, lipophilic N-alkyl substituents, in particular adamantyl-substituted spacer arms, provide excellent interaction between the inhibitor and the lysosomal β-glucosidase.…”