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NC
9
H
19
H
N
H
N
O
O
N
S
NR
HO
S
HN
7
HO
X
N
HO
N
HO
OH
N
HO
H
HO
O
OH
HO
HO
HO
HO
OH
OH
46
47
48
49
X = O
50
X = NH
Fig. 14 Structures of castanospermine analogues 46-50.
OH
OH
HO
HO
HO
HO
HO
HO
HO
NH
NH
NH
HO
HO
HO
35
51
52
Fig. 15 Structures of calystegine B
2
35, noeuromycin 51 and noeurostegin 52.
(Fig. 14).
68
The authors reasoned that introduction of a sulfamide group
could favor dipole-dipole and/or hydrogen bond interactions with protein
residues located nearby the two oxygen atoms of the tetrahedral sulfa-
mide. Of high interest are also the cyclitols 49 and 50 bearing an isourea
or a guanidine moiety respectively developed by Llebaria displaying
nanomolar inhibition of recombinant b-glucocerebrosidase.
69
Calystegine analogues. The naturally occurring calystegines, that can
be seen as conformationally locked analogues of noeuromycin 51, a non-
natural submicromolar b-glucosidase inhibitor,
70
are nor-tropane alkal-
oids that also act as potent b-glucosidase inhibitors.
71
The two carbon
atoms bridge allows introduction of a chemically stable and stereo-
defined OH group at C2.
72
In order to perfectly mimic the hydroxyl pat-
tern of noeuromycin, a CH
2
OH group was introduced at C5 in the
synthetic noeurostegin 52 that proved to be a potent b-glucosidase in-
hibitor (Fig. 15).
73
These findings and the glycosidase inhibition profile
of calystegines have stimulated the search for more potent derivatives.
Garc´a Fern´ndez and co-workers have reported the synthesis of
1-deoxy-6-oxacalystegine B
2
analogues featuring thiourea, urea and car-
bamate functionalities by replacing the ring sp
3
nitrogen atom with a
pseudoamide type sp
2
-like nitrogen. It allowed access to a series of de-
rivatives (53-56) having an axially oriented pseudoanomeric oxygen atom
and displaying different alkyl and aryl substituents at the exocyclic
nitrogen atom.
74
High selectivity and potency towards bovine liver b-
glucosidase was recorded for the analogues with aromatic substituents
whilst pseudodisaccharides such as 54 were only weak inhibitors. In
parallel, they synthesized 6-oxacalystegine analogues
75
having all pos-
sible hydroxylation pattern leading to calystegines B
2
,B
3
,B
4
and 3-epi-B
2
mimics that showed poor glycosidase inhibition profiles.
76
Additionally,
the N-octyl thiourea 55 was designed to probe the molecular basis of
b-glucosidase inhibition by the ring-modified calystegine analogues.
77
Structural, thermodynamic and kinetic analyses of its binding to a
b-glucosidase from Thermotoga maritima (TmGH1) and recombinant
human b-glucocerebrosidase (GCase) demonstrated potent inhibition
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