Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors

Abstract

Glucosylceramide metabolism and the enzymes involved have attracted significant interest in medicinal chemistry, because aberrations in the levels of glycolipids that are derived from glucosylceramide are causative in a range of human diseases including lysosomal storage disorders, type 2 diabetes, and neurodegenerative diseases. Selective modulation of one of the glycoprocessing enzymes involved in glucosylceramide metabolism-glucosylceramide synthase (GCS), acid glucosylceramidase (GBA1), or neutral glucosylceramidase (GBA2)-is therefore an attractive research objective. In this study we took two established GCS inhibitors, one based on deoxynojirimycin and the other a ceramide analogue, and merged characteristic features to obtain hybrid compounds. The resulting 39-compound library does not contain new GCS inhibitors; however, a potent (200 nm) GBA1 inhibitor was identified that has little activity toward GBA2 and might therefore serve as a lead for further biomedical development as a selective GBA1 modulator.

Gaucher Disease: A Glance from a Medicinal Chemistry Perspective

“…Several studies have highlighted the ability of HA 14-1 to inhibit Glucosylceramide synthase displaying an IC 50 of 4.5 μM without interfering with off-target enzymes. [133] There is no structural homology between GCS and BCL-2 but some degree of homology in the tertiary structure has been hypothesized, in particular between the GCS active site and the BH3 portion of BCL-2. [132] Thus, several enzyme kinetics experiments have been performed in order to understand the mechanism of inhibition of GCS induced by this molecule, revealing that HA 14-1 acted as a competitive and mixed type inhibitor with respect to C 6 -NBD-Cer and UDP-glucose, respectively, even if it does not share any structural homology with the two substrates.…”

“…It mimics the BH3 domain, crucial for the formation of dimers, of this protein interfering with the dimerization of BCL‐2 and with its interaction with pro‐apoptotic proteins. Several studies have highlighted the ability of HA 14‐1 to inhibit Glucosylceramide synthase displaying an IC 50 of 4.5 μM without interfering with off‐target enzymes [133] . There is no structural homology between GCS and BCL‐2 but some degree of homology in the tertiary structure has been hypothesized, in particular between the GCS active site and the BH3 portion of BCL‐2 [132] …”

“…Several novel compounds have been designed by combining the structural features of iminoglucidic and PDMP ‐related GCS inhibitors. The proposed hybrid derivatives (Figure 27) present the amino alcohol core of PDMP (in black), the iminosugar of Miglustat (in blue) or other secondary cyclic amines, and several acyl chains included the adamantane moiety of AMP‐dNM (in red) [133] . Unfortunately, this approach did not produce any active inhibitor of GCS but allowed the preparation of a potent Glucocerebrosidase inhibitor (derivative G , Figure 27, GCS IC 50 >10 μM, GBA1 IC 50 = 2 μM, GBA2 IC 50 =90 μM) which could be considered a lead compound for the development of novel active molecules for the treatment of other disorders involving this specific enzyme.…”

Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

“…The intrinsic instability of aminoacetal functionalities makes impractical the synthesis of iminosugar O -glycosides or of analogues having other heteroatom substituents at the pseudoanomeric position. Instead, aglycon-like appendages have been incorporated through N -substitution − and C -branching approaches, − which accounts for the two major subclasses of iminosugar derivatives on record.…”