Synthesis and Preliminary Conformational Analysis of 1-Deoxy-L-Idonojirimycin Derivatives as Potential α-L-Iduronidase Modulators.

Herein we present the synthesis of a series of novel 1-deoxy-L-idonojirimycin derivatives exploiting an unexplored synthetic pathway. In recent years this class of piperidines have emerged as promising active-site modulators of the lysosomal glycosidase α-L-iduronidase (IDUA). IDUA deficiency is involved in a neurodegenerative lysosomal disorder known as Mucopolysaccharidosis type I (MPS I). In this context, the proposed synthetic approach led to the successful seven-steps preparation of compound 7 as an analogue of L iduronic acid (Fig. 1).1 Moreover, with the attempt to improve the affinity towards IDUA and investigate conformational features, this synthetic route was expanded for the preparation of compounds 11-14.2 A preliminary computational conformational analysis supported the NMR-based evidence that introducing an acyl- or alkyl- moiety at the nitrogen position can switch the 1C4 chair conformation of compounds 4 and 7 into a 4C1 chair in compounds 11-14. This behaviour suggests that different substitutions at the nitrogen position and the presence of the carboxylic acid at the C6 position can be exploited to modulate the conformation of these small molecules. Furthermore, as a change in conformation of iminosugars has a profound effect on their binding properties towards glycosidases, this strategy could provide preliminary information about the potential biological activity of this class of piperidines.