Rational design and synthesis of highly potent pharmacological chaperones for treatment of N370S mutant Gaucher disease

Article abstract of DOI:10.1021/jm801506m

Highly potent N-substituted δ-lactams have been rationally designed and synthesized by a concise route with a one-pot tandem reaction as key step. These iminosugars show weak inhibition of wildtype β-glucocerebrosidase but 3- to 6-fold increases in mutant

Full text of DOI:10.1021/jm801506m

3146
J. Med. Chem. 2009, 52, 3146–3149
pH environment of the ER, and increasing enzyme trafficking
from the ER/Golgi to the lysosome. When the small molecule
chaperones dissociate from GC in the lysosome, the enzyme
remains stable in the low pH environment, which contains high
substrate concentrations, allowing an enhancement of gluco-
sylceramide hydrolysis to glucose and ceramide.13 Since the
X-ray crystal structure of mutant GC is unavailable at present,
most efforts for CMT are focused on screening and modifying
well-known inhibitors of wild-type ꢀ-glucosidase because of
their high affinity to the catalytic domain,7,14 and pharmacologi-
cal chaperones with 2- to 3-fold enhancements to N370S GC
have been identified.15-19 Small molecules that stabilize substrate-
bound conformations of mutant proteins and have suitable
metabolic properties (cell and ER permeability, for example)
have potential therapeutic applications for diseases caused by
protein misfolding and mistrafficking. On the basis of this idea,
a series of novel N-substituted δ-lactams have been rationally
designed and synthesized by a concise route with an expeditious
one-pot tandem reaction as a key step. These iminosugars show
weak inhibition of wild-type GC but 3- to 6-fold increases in
mutant enzyme (N370S) activity.
Rational Design and Synthesis of Highly
Potent Pharmacological Chaperones for
Treatment of N370S Mutant Gaucher Disease
Guan-Nan Wang,† Gabriele Reinkensmeier,‡ Si-Wei Zhang,†
Jian Zhou,† Liang-Ren Zhang,† Li-He Zhang,†
Terry D. Butters,*,‡ and Xin-Shan Ye*,†
State Key Laboratory of Natural and Biomimetic Drugs and School
of Pharmaceutical Sciences, Peking UniVersity, Xue Yuan Road No.
38, Beijing 100191, China, and Department of Biochemistry,
Glycobiology Institute, UniVersity of Oxford, South Parks Road,
Oxford OX1 3QU, U.K.
ReceiVed NoVember 30, 2008
Abstract: Highly potent N-substituted δ-lactams have been rationally
designed and synthesized by a concise route with a one-pot tandem
reaction as key step. These iminosugars show weak inhibition of wild-
type ꢀ-glucocerebrosidase but 3- to 6-fold increases in mutant enzyme
activity (N370S).
A series of N-substituted δ-lactams were designed with a
carbonyl group instead of the hydroxyl methyl group in a
deoxynojirimycin (DNJ) scaffold. The sp2-hybridized carbon
was designed to distort the ring to a half-chair conformation20
and lead the protruding carbonyl group to interact with
surrounding amino acids. To verify our design, N-nonyl-δ-
lactam 6b was flexibly docked into the binding site of GC
(Figure 1, PDB code 2V3E, complexed with N-nonyldeox-
ynojirimycin (NN-DNJ)21). The optimized docking result shows
that the hydrogen bonds between hydroxyl groups and GC are
similar to that in NN-DNJ-GC complex. However, notable
differences are found between carbonyl group of 6b and 6-OH
of NN-DNJ. Whereas a single hydrogen bond is found between
6-OH and N396-Oδ1 in the NN-DNJ-GC complex, the carbonyl
group of 6b forms hydrogen bonds with N396-Nδ2 and S345-
Oγ. Additionally, the carbonyl group induces the interaction
between N396-Nδ2 and the side chain carbonyl group of D127
following energy minimization. Therefore, the replacement of
hydroxyl methyl group with carbonyl group was predicted to
result in additional electrostatic contact with S345 and stabilize
the substrate-bound conformations of GC. By contrast, the
metabolic properties of a single molecule are difficult to predict;
however, it seemed possible to discover pharmacologically
active compounds from a small library of synthetic compounds.
Various modifications of the intramolecular nitrogen atom were
designed to finely adjust the metabolic properties and minimize
cytotoxicity.
Gaucher disease (GDa) is the most prevalent lysosomal
storage disorder and is typically caused by deficient activity of
ꢀ-glucocerebrosidase (GC) resulting in glucosylceramide ac-
cumulation.1 The effective treatment for type 1 GD is enzyme
replacement therapy (ERT);2 however, it is costly and the failure
of enzyme to cross the blood-brain barrier reduces efficacy
for treating neuronopathic forms of the disease. An alternative
to enzyme replacement therapy, substrate reduction therapy
(SRT) works by inhibiting glucosylceramide synthesis with
N-butyldeoxynojirimycin3 (NB-DNJ, miglustat) but has a lower
therapeutic index and results in adverse side effects.4 Chaperon-
mediated therapy (CMT)5 is the current emerging strategy for
GD therapy in which small molecules enable folding of the
mutant GC in the endoplasmic reticulum (ER), thus facilitating
enzyme trafficking to the lysosome.6-8 CMT combines the
specificity of an enzyme-directed approach (such as ERT) with
the oral bioavailability and the potential to cross the blood-brain
barrier of a small-molecule approach (such as SRT).
Numerous point mutations in the GC gene associated with
GD have been characterized.9 N370S GC, which is the most
prevalent amino acid substitution mutation in GD accounts for
77% of the cases among Ashkenazi Jewish patients and about
30% of the cases in the non-Jewish population.10,11 This
mutation does not remove a key catalytic residue in the GC
active site but probably destabilizes the conformation, thereby
rendering the protein more susceptible to mistrafficking and
degradation.12 It was previously demonstrated that pharmaco-
logical chaperones assist mutant GC folding by binding to the
active site, stabilizing the protein conformation in the neutral
Iminosugars continue to be of great synthetic interest because
of the intrinsic pharmacological potential and the need for more
active and selective compounds. Most of studies on δ-lactams
are focused on D-glycono-δ-lactams20,22,23 such as D-glucono-,
D-mannono, and D-galactono-δ-lactams. These D-glycono-δ-
lactams with a carbonyl group on anomeric carbon have a half-
chair geometry to mimic the shape of the transition state.
However, the N-substituted δ-lactams in this study have a
carbonyl group instead of the hydroxyl methyl group in the DNJ
ring. This type of δ-lactam is a new member of the iminosugar
family. To obtain target N-substituted δ-lactams, an expeditious
route has been designed and applied. The synthetic approach is
shown in Scheme 1. The glucose alkene was easily obtained
* To whom correspondence should be addressed. For T.D.B. (bioactivity
assay): phone, 44(0)1865 275725; fax, 44(0)1865 275216; e-mail,
terry.butters@bioch.ox.ac.uk. For X.-S.Y.: phone, (+86)10-62014949; fax,
(+86)10-62014949; e-mail: xinshan@bjmu.edu.cn.
†
Peking University.
University of Oxford.
‡
a Abbreviations: GD, Gaucher disease; GC, ꢀ-glucocerebrosidase; ERT,
enzyme replacement therapy; SRT, substrate reduction therapy; CMT,
chaperon-mediated therapy; ER, endoplasmic reticulum; NB-DNJ, N-
butyldeoxynojirimycin; DNJ, deoxynojirimycin; NN-DNJ, N-nonyldeox-
ynojirimycin; THF, tetrahydrofuran; DMSO, dimethyl sulfoxide; app IC50,
apparent IC50; SD, standard deviation; SEM, standard error of the mean.
10.1021/jm801506m CCC: $40.75
2009 American Chemical Society
Published on Web 04/27/2009

Letters
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 10 3147
is also a new strategy to make N-substituted 1,5-dideoxy-1,5-
iminoalditols with various biological activities.26,27
Following the synthesis of a small library of 20 N-substituted
δ-lactams, the inhibition of all synthetic compounds toward
human placental GC was determined and the results were
summarized in Table 1. The app IC50 data showed that these
N-substituted δ-lactams are weak inhibitors of human GC
because most of the compounds, except 6a, showed app IC50
greater than 100 µM. Cytotoxicity assays were performed before
performing a cellular assay in Gaucher mutant cells. All of the
compounds, including those with long alkyl chains, had no
apparent cytotoxicity at 100 µM in HL60 cells.
Next, the N-substituted δ-lactams were added to growth
media of N370S GC Gaucher lymphoblasts at 50 µM for 3 days.
Two positive controls were included. The first one was NB-
DNJ, and its activation achieved in our experiments was similar
to published data (1.7 and 2.3, respectively).19 The other positive
control was NN-DNJ, which is also a known stronger pharma-
cological chaperone for GC, and its maximal activation is 2.1
( 0.4 (at 1.0 µM), which is compared favorably with the
published data.15,18
In the assay of N370S GC activation, almost one-third of
the compounds had more than 3-fold increase in enzyme
activity, a significant improvement to published chaperone
activation. Compound 6c demonstrated more than 6-fold
increase in activity, which is one of the best enhancements
observed to date for the N370S mutation. However, when the
carbonyl group of 6c was reduced to provide 12, this activation
property was lost. This observation identifies the importance
of the carbonyl group for stabilizing protein folds in N370S
GC. The optimized docking result demonstrates that the carbonyl
group forms an additional hydrogen bond with S345 and induces
the electrostatic contact between N396 and D127. On the basis
of the crystal structure of isofagomine-GC complex, it has been
hypothesized that the interaction between E349 and D315 will
promote the movement of W312 and Y313, and these changes
in conformation will reduce substrate binding in the N370S GC.6
According to our calculations, the hydrogen bond between
carbonyl group and S345 could stabilize loop 2, which is at the
opening of the GC active site, thus preventing E349 from getting
closer to D315. Moreover, the additional intramolecular action
between N396 and D127 could also fix the complex into a more
stable conformation which could possibly provide benefit to the
destabilized binding pocket in N370S GC. These extra interac-
tions might be not important in the wild-type enzyme, since
there are already many hydrogen bonds between the OH groups
on lactam and residues of enzyme, but be very important to the
mutant enzyme because the extra interactions induced by the
carbonyl group seemed to be relevant to active site and
conformational changes. Therefore, the N-substituted δ-lactams
exhibit excellent activation to N370S mutant GC but provide
only moderate inhibition to wild-type GC.
Figure 1. Optimized docking structure of 6b (purple) bound to the
active site of GC. (a) Hydrogen bonds (green dashed lines) and
hydrophobic interactions involved in stabilizing 6b at the active site
of GC. Donor-acceptor distances of hydrogen bonds are shown in Å
(0.1 nm). Residues of GC are shown in yellow. (b) Superposition of
the crystal structure of NN-DNJ (green) in the active site of 6b complex.
Only the rings of iminosugars are shown, in stick, and not all of the
GC is shown, for clarity. Key residues are represented by lines; loop
1 (residues 312-319) is shown in teal, loop 2 (residues 341-350) in
blue, and loop 3 (residues 393-396) in yellow.
from methyl R-D-glucopyranoside through three brief steps24
or five steps with high overall yield (77%).25 The key step was
a one-pot tandem procedure with lactone as intermediate. When
the ozonolysis was completed at -78 °C, without separation,
the resulting methoxyl acetal lactone was directly treated with
NaCNBH3, amines, and ZnCl2 in the same pot to provide
N-substituted δ-lactams in high yield. It was proposed that
lactone 2 underwent a tandem reaction in which it was first
subjected to methanolysis to provide 3, followed by reductive
amination and cyclization yielding lactams 5a-k. This proposed
mechanism was supported by the observation that 4l was
identified when aniline was used to trap the intermediate 3.
Generally, iminosugar syntheses starting from commercially
available sugars involve the introduction of an amino function
in the sugar skeleton and subsequent aminocyclization to
generate the nitrogen-containing ring. Moreover, to introduce
substituted groups on nitrogen atom, at least one more step is
required. Our approach combined amination, cyclization, and
introduction of N-substituents in one pot. Furthermore, to
confirm whether this synthetic strategy was applicable to other
sugar substrates, other iminosugar analogues such as galactose,
mannose, glucosamine, and ribose type compounds were also
prepared in a similar way in high yields (Scheme 2). Addition-
ally, N-octyl-1,5-dideoxy-1,5-iminoxylitol was prepared by
simple lactam reduction with LiAlH4 to test the function of
carbonyl group (Scheme 3). Generally, the overall yields for
the preparation of these iminosugars were 40-70%. This one-
pot tandem reaction allowed very concise and economical
construction of δ-lactams with various chains on the nitrogen
atom and can be applied to obtain N-substituted δ-lactams with
wide coverage of sugar mimicry. Last but not least, this approach
When different isomers were modified with the N-decyl chain
(7a, 8a, 9a, and 10a), only the galactose type lactam 7a (2.9-
fold increase; see Table 1) had a better enhancement than the
glucose type mimetic 6a (2.1-fold increase). By contrast, the
glucose type lactam had a better enhancement (4.1-fold increase)
than other isomers when the N-hydroxyhexyl chain modified
compounds (6f, 7f, 8f, 9f, 10f) were analyzed for enzyme
enhancement. This indicates that some structural and spatial
features are essential for activation, although there is a certain
redundancy around the C4-OH. In glucose type δ-lactams, the
δ-lactams containing hydrophobic chains such as alkyl and ether
chains (6a, 6c, 6h, etc.) provided greater enzyme enhancement

3148 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 10
Scheme 1. Synthesis of N-Substituted Glucose-Type δ-Lactams
Letters
Table 1. Results of Inhibition and Activation Assays
Scheme 2. Other Types of N-Substituted δ-Lactams from
app IC50 (µM)a
cytotoxicity, % deadb
fold increased
Galactose, Mannose, Glucosamine, and Ribose
compd
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
7a
8a
9a
10a
7f
8f
46 ( 1
102 ( 4
5.19
4.71
3.51
2.78
3.46
3.75
2.95
4.33
2.39
3.45
2.77
10.22
11.20
7.58
6.69
3.23
3.44
2.90
3.57
3.55
2.69
2.1 ( 0.2
2.0 ( 0.3
6.2 ( 0.3
NDe
3.4 ( 0.3
4.1 ( 0.3
NDe
3.6 ( 0.4
3.8 ( 0.4
3.9 ( 0.4
NDe
2.9 ( 0.3
2.0 ( 0.3
NDe
1.5 ( 0.1
2.5 ( 0.2
1.8 ( 0.2
1.3 ( 0.1
1.8 ( 0.2
NDe
1.7 ( 0.2
2.1 ( 0.4f
1
175 ( 44
>0.5 mM
>0.5 mM
>0.5 mM
>0.5 mM
127 ( 24
>0.5 mM
253 ( 29
>0.5 mM
463 ( 52
295 ( 1
>0.5 mM
285 ( 13
>0.5 mM
>0.5 mM
>0.5 mM
>0.5 mM
>0.5 mM
259 ( 22
Scheme 3. Reduction of N-Octyl-δ-lactam 5ca
9f
10f
12
NB-DNJ
NN-DNJ
control
2.32 (4.24)c
a The app IC50 values were determined with human placental GC (Km
for 4-MU-ꢀ-glucoside, 1.9 ( 0.3 mM). Experiments were performed in
triplicate, and the mean ( SD is shown. b HL60 cells were treated with
100 µM compounds for 3 days, and the cytotoxicity was evaluated as
described in the experimental procedures. c Control cells (no compound
addition) were analyzed following addition of water or 0.01% DMSO.
d Gaucher lymphoblasts (N370S) were cultured in the presence of com-
pounds (50 µM) for 3 days before GC activity was measured. The fold
increase in enzyme activity is compared to untreated cells, i.e., normalized
value ) 1. The mean ( SEM obtained from three separate experiments is
shown. e ND ) not determined. f Gaucher lymphoblasts (N370S) were
cultured in the presence of various concentrations of NN-DNJ for 3 days
before GC activity was measured. The maximal fold increase as shown in
the table appeared at 1 µM (see Supporting Information). The fold increase
in enzyme activity is compared to untreated cells, i.e., normalized value )
1, and shown as relative enzyme activity. Experiments were performed in
triplicate, and the mean ( SD is shown.
a (a) LiAlH4, 92%; (b) Pd/C, H2, THF/H2O/CH3COOH, 98%.
than hydrophilic chain compounds (6g). This result is consistent
with the “hydrophobic-hydrophilic two substrate-binding sites”
theory.16 However, the chain length had a limited effect, since
6c was much better than 6a and 6b. The reason for difference
in activation provided by an additional carbon atom is not known
but may be due to differences in metabolic properties.28 Since
6f, 6h, 6i, and 6j have chains with similar polarity, they all
showed similar levels of enzyme activation.
In summary, novel N-substituted δ-lactams have been
rationally designed and synthesized by a concise route with the
one-pot tandem reaction as key step. These iminosugars show
weak inhibition to wild-type GC but improved enhancement
for N370S GC. This enhancement could be provided by an
additional hydrogen bond between the carbonyl group and S345
and an intramolecular interaction between N396 and D127,
which accounts for substrate-bound conformations of the mutant
enzyme becoming more stabilized. These results suggest that
small molecules that stabilize substrate-bound conformations
of mutant enzymes and have suitable metabolic properties may
yield potentially active chaperones for the treatment of GD.
Acknowledgment. This work was financially supported by
the National Natural Science Foundation of China, Grants “973”
and “863” from the Ministry of Science and Technology of
China. This work was also supported by funding from the
Oxford Glycobiology Institute.

Letters
Supporting Information Available: Full experimental proce-
dures and characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 10 3149
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