Efficient stereoselective synthesis of 2-acetamido-1,2- dideoxyallonojirimycin (DAJNAc) and sp2-iminosugar conjugates: Novel hexosaminidase inhibitors with discrimination capabilities between the mature and precursor forms of the enzyme

摘要

Due to their capacity to inhibit hexosaminidases, 2-acetamido-1,2-dideoxy-iminosugars have been\udwidely studied as potential therapeutic agents for various diseases. An efficient stereoselective synthesis\udof 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc), the most potent inhibitor of human placenta b-Nacetylglucosaminidase\ud(b-hexosaminidase) among the epimeric series, is here described. This novel\udprocedure can be easily scaled up, providing enough material for structural modifications and further\udbiological tests. Thus, two series of sp2-iminosugar conjugates derived from DAJNAc have been prepared,\udnamely monocyclic DAJNAc-thioureas and bicyclic 2-iminothiazolidines, and their glycosidase inhibitory\udactivity evaluated. The data evidence the utmost importance of developing diversity-oriented synthetic\udstrategies allowing optimization of electrostatic and hydrophobic interactions to achieve high inhibitory\udpotencies and selectivities among isoenzymes. Notably, strong differences in the inhibition potency of\udthe compounds towards b-hexosaminidase from human placenta (mature) or cultured fibroblasts (precursor\udform) were encountered. The ensemble of data suggests that the ratio between them, and not the\udinhibition potency towards the placenta enzyme, is a good indication of the chaperoning potential of\udTaySachs disease-associated mutant hexosaminidase