A 16 × 8 Focused Compound Library Comprising All Configurational Isomers of the Archetypal Iminosugar, 1-Deoxynojirimycin.

Deoxynojirimycin is the archetypal iminosugar, from which many structural and configurational isosteres have been derived and studied in past decades. In total, 16 configurational isomers of deoxynojirimycin exist, but these have not yet been collected in a single library. This paper describes the assembly of such a library with each configurational isomer present in eight N-substituted forms. Screening of this library against the three glucosylceramide processing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA1), and nonlysosomal glucosylceramidase (GBA2), confirms earlier data that appropriately substituted D-Glc, D-Gal, and L-Ido deoxynojirimycins are most effective in dually inhibiting GCS and GBA2. In contrast to our expectations, we found that the same holds true for the L-alt isomer. We believe that our comprehensive library, as reported here, could prove valuable in drug discovery endeavors targeting cancer, infectious diseases, and inherited glycosphingolipidoses.