Assessment of partially deoxygenated deoxynojirimycin derivatives as glucosylceramide synthase inhibitors

Article abstract of DOI:10.1021/ml200050s

Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those hydrolases that act on glucosylceramide.

Full text of DOI:10.1021/ml200050s

LETTER
pubs.acs.org/acsmedchemlett
Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives
as Glucosylceramide Synthase Inhibitors
†
†
†
‡
Richard J. B. H. N. van den Berg, Tom Wennekes, Amar Ghisaidoobe, Wilma E. Donker-Koopman,
‡
‡
†
,‡
Anneke Strijland, Rolf G. Boot, Gijsbert A. van der Marel, Johannes M. F. G. Aerts,* and
,
†
Herman S. Overkleeft*
†
Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands
‡
S Supporting Information
b
ABSTRACT: Glucosylceramide synthase (GCS) is an ap-
proved drug target for the treatment of Gaucher disease and
is considered as a valid target for combating other human
pathologies, including type 2 diabetes. The clinical drug
N-butyldeoxynojirimycin (Zavesca) is thought to inhibit
through mimicry of its substrate, ceramide. In this work we
demonstrate that, in contrast to what is proposed in this model,
the C2-hydroxyl of the deoxynojirimycin core is important for
GCS inhibition. Here we show that C6-OH appears of less
important, which may set guidelines for the development of
GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those
hydrolases that act on glucosylceramide.
KEYWORDS: Glucosylceramide synthase, iminosugar, Gaucher disease, ceramide, deoxynojirimycin
lucosylceramide synthase (GCS) is a noncanonical glycosyl
transferase in several aspects. Situated at the outer mem-
a therapeutic target in several diseases areas: next to lysosomal
glycolipid storage disorders other than Gaucher, also type 2
diabetes, hepatosteatosis, artherosclerosis, inflammatory dis-
G
brane of the Golgi apparatus, GCS catalyzes the transfer of
glucose from UDP-glucose to ceramide to give glucosylcera-
9
À14
eases, and polycystic kidney disease.
The development of
1
mide. As such, and with the exception of the enzyme O-GlcNAc
GCS inhibitors with improved properties therefore remains a
valid research objective.
2
transferase, GCS is the only mammalian glycosyltransferase
known to act in cytoplasm. GCS appears evolutionary distinct
from most other glycosyltransferases, that all act either in the ER
or the Golgi apparatus. Although little structural data on GCS
exists (the enzyme has, to date, defied attempts to gather
R €o ntgen diffraction data), alignment of the primary sequence
reveals large differences between GCS and other glycosyl
Perhaps most remarkably from an enzymology point of view is
not so much that GCS inhibitors exist but that these include
iminosugar-type piperidines. Iminosugars are widely pursued
and versatile glycosidase inhibitors, and iminosugars acting on
exoglycosidases processing many different glycosides (varying
for instance in preference for the configuration of the substrate
glycoside: glucosidases, mannosidases, galactosidases, etc) are
1
transferases. Perhaps thanks to these differences, potent GCS
15À18
inhibitors of various signatures have been described, whereas for
most other glycosyltransferases no effective inhibitors are avail-
able. In fact, the discovery that GCS is susceptible to inhibition by
small compounds has led to the development of N-butyl-deoxy-
nojirimycin as a drug (Zavesca (1); Figure 1) for the treatment of
known.
In contrast, and with the said exception of GCS,
glycosyltransferases are normally insensitive toward this class of
19,20
compounds.
Deoxynojirimycin-type iminosugars are thought to
inhibit glycosidases through substrate-or-transition state mimi-
cry. In such models, the basic ring nitrogen in its protonated form
is thought to mimic the developing oxocarbenium ion through
which glycoside hydrolysis occurs. The configuration of the
iminosugar emulates that of the parent sugar and guides both
glycosidase inhibitory potency and selectivity. In general, glyco-
sidases are rather particular with respect to their substrate
glycoside. Remarkably, GCS appears much less biased with
3
À5
the lysosomal glycolipid storage disorder Gaucher disease.
Compound 1 is a moderately potent and selective GCS inhibitor.
Treatment of mildly affected type 1 Gaucher patients with this
agent results in sufficient pharmacological lowering of glucosyl-
ceramide to levels that the residual mutant glucosylceramidase
6
(
GBA1) can deal with. We have reported on the development of
much more potent (for instance, 2) and also more selective
with respect to other glycoprocessing enzymes (for instance, 3)
N-alkylated deoxynojirimycin derivatives. Coinciding with
Received: February 19, 2011
Accepted: April 7, 2011
Published: April 07, 2011
7,8
these discoveries, recent studies strongly point toward GCS as
r 2011 American Chemical Society
519
dx.doi.org/10.1021/ml200050s
|ACS Med. Chem. Lett. 2011, 2, 519–522

ACS Medicinal Chemistry Letters
LETTER
Figure 1. Known glucosylceramide synthase inhibitors (1À3) and the target compounds discussed in this study.
respect to the configuration of the (N-alkylated) iminosugar. We,
and others, have demonstrated that at least three configurational
deoxynojirimycin isomers are recognized by GCS: next to the
D-gluco- and L-ido configurations (as in 2 and 3, respectively), also
up to 20 μM. This result stands in contrast to the strong (IC50
0.1À0.2 μM) inhibitory potency as exerted by lead compounds 2
and 3 toward the target enzyme. While these results do not
necessarily negate the proposed mode of action by which N-
butyldeoxynojirimycin inhibits GCS, they do indicate that one
should take care in using the model as a guideline for designing
new GCS inhibitors. It should be noted that one might see
differences when comparing compounds from the series at
higher (millimolar) concentrations; however, we decided to
refrain from these studies for the dual reason that such measure-
ments are complicated and that millimolar inhibitors hold no
therapeutic value. When looking at the two glucosylceramidases,
it is immediately apparent that removing both C2-OH and
C3-OH, as in series A and B, is detrimental for all activity
irrespective of the configuration of the remaining chiral carbon
centers. Selected compounds from the C sublibrary, however,
retain some activity toward GBA1 or GBA2, especially in those
cases where R is adamantanemethyloxypentyl. For instance, D-
gluco-configured derivative 30 inhibits GBA2 at an IC of 1 μM,
2,21À24
the D-galacto configuration.
The relative lack of configurational specificity of GCS toward
iminosugars invites the hypothesis that N-alkylated deoxynojir-
imycin derivatives act not by glucose (or UDP-glucose) mimicry
but by another molecular mechanism. Indeed, Butters and co-
workers in their work on the development of Zavesca proposed a
model in which N-butyldeoxynojirimycin binds to GCS as a
25
mimic of its other substrate, namely, ceramide. In this model
the ring-nitrogen in 1 superimposes the ceramide nitrogen, with
the alkyl (butyl) chain situated at the ceramide N-acyl side. The
piperidine O3 and O4 and possibly O6 (glucopyranose number-
ing) would occupy the positions occupied by the primary and
secondary hydroxyls of the ceramide structure. The experimental
finding that compound 1 is competitive for ceramide but not
25
UDP-glucose, binding to GCS, supports this model. However,
no structural evidence for the model has been obtained yet. We
decided to put the model to the test in an attempt to design new
and potentially selective GCS inhibitors. The model as proposed
by Butters and co-workers suggests that, of the deoxynojirimycin
substituents, C3-OH and C4-OH and possibly C6-OH are
important contributors to GCS binding, whereas the presence
of C2-OH is not required. In other words, 2-deoxy-DNM
derivatives C should potentially inhibit GCS whereas 2,3-dideoxy
derivatives B should not. In order to validate this reasoning, we
set out to synthesize all configurational isomers of scaffolds B and
C. We either left the secondary nitrogen unmodified (to obtain
the respective deoxygenated analogues of the natural product,
deoxynojirimycin), introduced a butyl group (enabling compar-
ison with the clinically applied drug, Zavesca), or introduced an
adamantanemethyloxypentyl group (to allow a head-to-head
comparison with our lead structures, 2 and 3). The synthetic
schemes through which the compounds are prepared follow well-
established literature procedures (see the experimental section
5
0
whereas its L-ido-congerer 39 does so at 0.5 μM (IC ); this
5
0
compound, in fact, appears to be a rather selective GBA2
inhibitor that may find application as such. In general, how-
ever, deoxygenation at C2 appears to considerably impair
inhibitory potency of deoxynojirimycin-type iminosugars, also
against glycosidases.
Returning to the original research objective, our results
strongly suggest that C2-OH does contribute to a large extent
to GCS inhibition, this in contrast to the model proposed by
25
Butters. As a preliminary study, we probed the importance of
the C6-hydroxyl to GCS inhibitory potency. To this end, we
prepared both 6-deoxy-N-(adamantanemethoxyethyl)deoxyno-
jiimycin 52 and its xylo-congener (lacking the C5-hydroxymethyl
substituent, 53) and established their IC50 values against the
same panel of enzymes. Interestingly, the 6-deoxy-compound
turned out to be a quite potent (IC 0.8 μM) GCS inhibitor, in fact,
5
0
only 4-fold less potent than our lead compounds. It thus appears that
the C6-OH is less important than C3-OH and C4-OH, which is
suggested by the ceramide mimic model. Compound 53 retains
some inhibitory potency against GBA1 and GBA2 as well, which is
unfortunate when considering the need for selective GCS inhibitors.
A substituent at C5 does appear of importance, as xylo-piperidine 53
turned out to have no GCS inhibitory activity.
In conclusion, we have added to the growing list of iminosugar
inhibitor studies through the preparation and evaluation of a
comprehensive library of N-alkyl C2-deoxy- and C2/C3-dideoxy
deoxynojirimycin derivatives. We focused our inhibitory studies
on enzymes involved in mammalian glucosylceramide metabolism
26À30
for full experimental and analytical details
). These routes
proceed through partially unsaturated piperidine intermediates,
and we capitalized on this by also preparing piperidine derivatives
A. In all, we assembled a 48 compound library, which we assessed
3
1
32
on inhibitory potential against GCS, GBA1, the nonlyso-
3
3
somal glucosylceramidase GBA2, as well as a selection of
2
4
intestinal glycosidases. The results are summarized in the
below Table.
As can be seen (Table 1), none of the 48 compounds
possessed any inhibitory potency against GCS at concentrations
5
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dx.doi.org/10.1021/ml200050s |ACS Med. Chem. Lett. 2011, 2, 519–522

ACS Medicinal Chemistry Letters
LETTER
Table 1. Enzyme Inhibition Assay Results: Apparent IC50 Values in μM
a
Other enzyme assays are in vitro; AMP = 5-(adamantan-1-yl-methoxy)pentyl.
and did not identify a new attractive lead toward either GCS or
Funding Sources
GBA1. We do note the selectivity of compound 39 toward
The research described was funded by The Netherlands Orga-
nization for Scientific Research (NWO), Leiden University, and
the Academic Medical Center.
34
inhibition of GBA2, which might be of interest for studies in
which the physiological role of this enzyme is questioned.
Moreover, our library encompasses all possible configurational
isomers at C3, C4, and C5 and it is not excluded that individual
compounds possess strong affinity toward glycoprocessing en-
zymes not included in our screening panel. With respect to the
mode of action by which deoxynojirimycin-type iminosugars can
inhibit GCS, we have strong, but indirect, evidence that a C2-OH
is important but that the C6-OH is amenable for modification.
We focus our current research on the development of potent and
selective GCS inhibitors on preparing some configurational
deoxynojirimycin isomers (other than those already known)
and on modifying the nature of the N-alkyl substituent.
’
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*E-mail: J.M.F.G.A., j.m.aerts@amc.uva.nl; H.S.O., h.s.overkleeft@
chem.leidenuniv.nl.
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