Pharmaceutical chaperones (PCs) are small compounds able to bind and stabilize misfolded proteins, allowing them to recover their native folding and thus their biological activity. In particular, lysosomal storage disorders (LSDs), a class of metabolic disorders due to genetic mutations that result in misfolded lysosomal enzymes, can strongly benefit from the use of PCs able to facilitate their translocation to the lysosomes. This results in a recovery of their catalytic activity. No PC for the GCase enzyme (lysosomal acid-β-glucosidase, or glucocerebrosidase) has reached the market yet, despite the importance of this enzyme not only for Gaucher disease, the most common LSD, but also for neurological disorders, such as Parkinson’s disease. This review aims to describe the efforts made by the scientific community in the last 7 years (since 2015) in order to identify new PCs for the GCase enzyme, which have been mainly identified among glycomimetic-based compounds.
We report a straightforward
synthetic strategy for the preparation
of trihydroxypiperidine azasugars decorated with lipophilic chains
at both the nitrogen and the adjacent carbon as potential inhibitors
of the lysosomal enzyme glucocerebrosidase (GCase), which is involved
in Gaucher disease. The procedure relies on the preparation of
C
-erythrosyl
N
-alkylated nitrones
10
through reaction of aldehyde
8
and primary
amines
13
followed by oxidation of the imines formed
in situ
with the methyltrioxorhenium catalyst and urea hydrogen
peroxide. The addition of octylMgBr to nitrone
10e
provided
access to both epimeric hydroxylamines
21
and
22
with opposite configuration at the newly created stereocenter in
a stereodivergent and completely stereoselective way, depending on
the absence or presence of BF
3
·Et
2
O. Final
reductive amination and acetonide deprotection provided compounds
14
and
15
from low-cost
d
-mannose in
remarkable 43 and 32% overall yields, respectively, over eight steps.
The C-2
R
-configured bis-alkylated trihydroxypiperidine
15
was the best ligand for GCase (IC
50
= 15 μM),
in agreement with MD simulations that allowed us to identify the chair
conformation corresponding to the best binding affinity.
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