Sugar hydrazide imides: A new family of glycosidase inhibitors

Article abstract of DOI:10.1039/c7ob01673e

The preparation of a novel type of iminosugar including a hydrazide imide moiety is described. The sugar hydrazide imides (3S,4S,5R,6R)-1-amino-3,4,5-trihydroxy-6-(hydroxymethyl)-2-iminopiperidine acetate and (3S,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethy

Full text of DOI:10.1039/c7ob01673e

View Article Online
View Journal
Organic &
Biomol ec ular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: E. Lindbäck, O.
Lopez, Å. Tobiesen, J. G. Fernandez-Bolanos and M. O. Sydnes, Org. Biomol. Chem., 2017, DOI:
1
0.1039/C7OB01673E.
Volume 14 Number
1
7
January 2016 Pages 1–372
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB01673E
OH
NH2
NH2
HO
HO
N
OH
\
-glucosidase inhibitor
OH
NHMe
N
HO
HO
NH2
OH
selective -glucosidase inhibitor
We present a new type of glycosidase inhibitors including a unique hydrazide imide moiety,
which display inhibition in the low micromolar range.

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C7OB01673E
Journal Name
COMMUNICATION
Sugar hydrazide imides: a new family of glycosidase inhibitors
a*
b*
a
b
Emil Lindbäck, Óscar Lopéz, Ådne Tobiesen, José G. Fernández‐Bolaños, and Magne O.
Sydnes
a*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
and lysosomal storage disorders.8 Whereby, iminosugars
The preparation of a novel type of iminosugars including a represent attractive synthetic targets.2b,8,9
hydrazide imide moiety is described. The sugar hydrazide imides It has been found that the transition state of glycosidase
(
3
S
,4
iminopiperidine acetate and (3
hydroxymethyl)‐1‐(methylamino)‐2‐iminopiperidine acetate
S
,5
R
,6
R
)‐1‐amino‐3,4,5‐trihydroxy‐6‐(hydroxymethyl)‐2‐
catalysed cleavage of glycosidic bonds resembles both the
S
,4 ,5 ,6 )‐3,4,5‐trihydroxy‐6‐
S
R
R
10
shape and charge of the oxocarbenium ion
2 (Figure 1).
(
Indeed, such intermediate has recently been observed by NMR
presented behave as inhibitors of α/β‐glucosidases in the low
micromolar concentration range. The former inhibitor displays a
pH‐dependent inhibition of β‐glucosidase. The N‐methylated
counterpart behaves as an anomer‐selective competitive
micromolar inhibitor of α‐glucosidase.
upon treatment of per‐O‐acetylated 2‐deoxy and 2‐
11
bromoglucopyranose with super acids. Thus, a compound that
mimics the oxocarbenium ion should also behave as a potent
glycosidase inhibitor.12 In its N‐protonated state, 1‐
deoxynojirimycin ( ) constitutes a charged analogue of the
oxocarbenium ion
.12 However, it is anticipated to be in a chair
conformation rather than in the flatten anomeric conformation
2
1
2
Introduction
13
of the oxocarbenium ion
2
.
At the same time, a pH
Iminosugars, exemplified by naturally occurring 1‐
deoxynojirimycin (1
) (Figure 1),1 represent carbohydrate
dependence analysis of 1/K
i
for binding of 1‐deoxynoririmycin
(
1) to β‐glucosidase (almonds) could not conclude whether 1‐
mimetics in which the endocyclic oxygen atom has been
replaced by a nitrogen atom. This group of compounds
resembles carbohydrates and can therefore interact with
carbohydrate‐processing enzymes, however, they are dissimilar
enough from carbohydrates in order not to undergo
metabolization mediated processing by such enzymes. These
properties among others have highlighted iminosugars as lead
compounds in the hunt for new pharmaceuticals.2 Indeed,
many iminosugars inhibit carbohydrate‐handling enzymes,3
deoxynojirimycin ( ) binds to the enzyme in its protonated or
1
1
4
unprotonated form. In fact, a basic fluorescence labelled
iminosugar has been demonstrated to bind β‐glucosidase in its
unprotonated form.15 However, in this context, it should be
4
mentioned that compound
1
behaves as a ca 10 times more
14
potent inhibitor of β‐glucosidase than does glucose, strongly
indicating that the basic nitrogen atom of participates in
1
favourable interactions with the enzyme.1
2,14
D‐Gluconolactone
(3) (Figure 1) also displays significant glycosidase inhibitory
which make them attractive candidates for treatment of
diseases such as diabetes, cancer, HIV, Alzheimer’s disease,
4
5
6
7
activity in spite of the absence of a formal positive charge. Its
activity was attributed to its shape analogy to the oxocarbenium
1
6
ion
2
.
Pioneering work by Ganem and co‐workers, brought the
and the shape
charge resemblance from compound
1
a.
Faculty of Science and Technology, Department of Mathematics and Natural
Science, University of Stavanger, NO‐4036 Stavanger, Norway
resemblance from lactone
3
with the oxocarbenium ion
2
into
7
b.
one single species, namely amidine
amidine
micromolar range of a wide range of glycosidases. The
4
(Figure 1).1 Indeed,
Department of Organic Chemistry, University of Seville, Professor García González
, 41012 Seville, Spain
Electronic Supplementary Information (ESI) available: Synthetic details for the
preparation of compounds and their NMR spectra. See DOI: 10.1039/x0xx00000x.
1
4
was found to behave as a potent inhibitor in the low
†
Financial supports from the University of Stavanger, Dirección General de innovative work by Ganem and co‐workers encouraged others
Investigación of Spain (CTQ2016‐78703‐P), the Junta de Andalucía (FQM134), and
to engage in the synthesis of sugar amidines and evaluate them
the European Regional Development Fund (FEDER) are gratefully acknowledged.
Thanks are also due to Dr. Bjarte Holmelid, University of Bergen, for conducting MS as glycosidase inhibitors.18 However, to the best of our
analysis, and Servicio de Resonancia Magnética Nuclear, CITIUS (University of
Seville) for the performance of some NMR spectra.
knowledge, there are no examples in the literature in which the
endocyclic nitrogen of amidines of type 4 has been armed with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 6
View Article Online
DOI: 10.1039/C7OB01673E
COMMUNICATION
Journal Name
1
a substituent that is not synchronously connected to the reaction by H‐NMR using CDCl
3
as solvent. In this context, it is
exocyclic nitrogen atom. The absence of that type of worth mentioning that when the reaction scale exceeded 20 mg
compounds appears surprising since the functionalization of the of 10 or 11 yield was lowered and the by‐products formed were
nitrogen atom in compound
two approved drugs for the treatment of Gaucher’s disease
and type II diabetes;19 namely, miglustat (N‐butyl‐ underwent global debenzylation upon palladium‐catalysed
deoxynojirimycin) and miglitol (N‐(2‐ hydrogenolysis to provide the unprotected counterparts
hydroxyethyl)deoxynojirimycin), respectively. In addition, a 16, and 17 as the acetate salts after silica gel column
vast array of derivatives of 1‐deoxynojirimycin ( ) carrying chromatography (eluent; MeCN:25% aqueous AcOH).
various types of N‐substituents have been prepared and found In CD OD, the ‐gluco‐configuration of 14 was concluded by H‐
1 with alkyl groups has provided problematic to remove upon silica gel column chromatography.
2
a
In the final step, the protected sugar hydrazide imides 12‐15
5, 6,
1
1
3
D
to display interesting inhibitory activities towards NMR analysis, which gave the coupling constants J3,4 7.6 Hz, J4,5
carbohydrate‐processing enzymes.8
,13,20
4.0 Hz, and J5,6 2.9 Hz. The small coupling constants J4,5 and J5,6
Thus, in this paper, we address an empty entry of glycosidase along with a larger coupling constant J3,4 mirror a
D
‐gluco‐
inhibitor science by presenting the arming of the endocyclic configuration in a 3 B‐conformation for 14. In DMSO‐d
nitrogen atom of amidine
group to obtain the hitherto unknown hydrazide imides
Figure 1), respectively. In addition, as a sugar amidrazone that addition, the small coupling constant J5,6 5.6 Hz suggests the
,6
24
, H‐
1
6
4
with an amino‐ and methylamino‐ NMR analysis of 15 provided the large coupling constants J3,4 7.4
5
H
4
‐conformation.24 In
5
and
6
Hz and J4,5 9.1, which indicates a
(
L
‐
is electronically similar to our addressed compounds
possesses a pK
and . Thereby, according to our design, compounds
5
and
6
5
6
ido‐configuration of compound 15. 1H‐NMR analysis of
provided the coupling constants J3,4 9.8 Hz, J4,5 9.8 Hz, and J5,6
4
7.8 Hz, indicating ‐gluco‐configuration in ‐
5H
2
5 in D O
of 8.7,21 we envisage a similar pKa value of
a
6
5
and
a
D
a
2
4
should have the potential to form strong ionic interactions with conformation. The coupling constants J3,4 and J4,5 for the 6‐
the enzyme. We also present the screening of compounds
5
and epimer of 5, namely 16, remained large (8.1 Hz and 10.0 Hz,
respectively). However, the coupling constant J5,6 decreased to
6
as inhibitors against a panel of glycosidases.
5
.6 Hz, providing support for the
L
‐ido‐configuration of
was found to
5
compound 16 in a H
4
‐conformation. Compound
5
favorable position
for substitution
be stable in D
compound decomposed to a complex mixture of products upon
treatment with aqueous NaOH (0.5 ).
2
O for days at room temperature. However, the
OH
OH
OH
X
HO
HO
HO
HO
M
NH2
OH
O
O
HO
HO
O
1
2
OH
3
OH
unexplored position
of substitution
until now
this work
OH
OH
OH
AcO
H
N
AcO
AcO
NH2
NHMe
HO
HO
HO
HO
HO
HO
N
N
NH2
NH2
NH2
OH
OH
OH
4
5
6
Figure 1 Structure of known inhibitors 1, 3, and 4 along with the
oxocarbenium ion 2 and the hydrazide imides 5 and 6 described
herein.
Synthesis
The synthesis of target hydrazide imides
from known ketonitrile (Scheme 1), which can be generated
from methyl α‐ ‐glucopyranoside in five steps following a
literature procedure.22 Thus, compound
underwent reductive
5 and 6 commenced
7
D
7
hydrazidation with t‐butyl carbazate using sodium
cyanoborohydride as the reducing reagent to provide hydrazide
epimers 8 and 9 in 31% and 20% yield, respectively. In a similar
manner, epimers 10 (38%) and 11 (14%) were obtained when t‐
butyl 2‐methylcarbazate was used as the hydrazide source. In
the subsequent step, hydrazides 8 and 9 cyclized smoothly into
hydrazide imide 12 and 13, respectively, upon acidic removal of
the Boc‐protection group. In order to obtain hydrazide imides
1
4
and 15 on the other hand, the cyclization was significantly
slower and it was beneficial to follow the progress of the
2
| J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 6
Orga Pn l iec a s& e Bd oi o nmo ot al ed cj uu sl ta mr Ca rhg ei nms istry
View Article Online
DOI: 10.1039/C7OB01673E
Journal Name
COMMUNICATION
OBn
the free enzyme) within the low micromolar range (9.9 µM) at
pH 6.8; the potency was maintained at higher pH, with no
relevant change in the Kia value at pH 8.0.
O
CN
BnO
OBn
Noteworthy, when the testing was extended to β‐glucosidase,
OBn
7
compound
3
8
5
was found to be a moderate inhibitor at pH 6.8 (K
1.3 µM), and a 4.1‐fold increase in activity was observed at pH
.0, leading to a good inhibition of this enzyme (Kia= 7.7 µM).
i
=
1
) BocNRNH2, AcOH
EtOH/THF 1:1, rt
) NaBH3CN, rt
R
OBn
Boc
R
OBn
Boc
Taken as a whole, such behaviour strongly contrasts with parent
amidine , which was found to be a non‐selective inhibitor of β‐
glucosidase and α‐mannosidase (K ’s: 10 and µM,
2
N
N
4
NH
NH
i
9
CN
CN
+
respectively). Furthermore, for the former enzyme, a complete
BnO
OBn
BnO
OBn
independence of the activity on the assay pH was observed for
OBn
: R = H (31%)
OBn
17b
compound 4.
8
9: R = H (20%)
The R‐stereochemistry in the 6‐position of inhibitor
5 was found
1
0: R = Me (38%)
11: R = Me (14%)
1
) TFA/CH2Cl2 2:3, rt
1) TFA/CH2Cl2 2:3, rt
to be essential for the inhibitory activity, as the 6‐epimer of 5,
2
) CDCl3, rt (only for 10) 2) CDCl3, rt (only for 11)
namely 16, only displayed modest activity towards the
OBn
investigated enzymes. In fact, a similar relationship has been
5
NHR
Cl
NH2
6
1
N
1
3N
NHR
BnO
BnO
found between 1‐deoxynojirimycin
(
1
)
and
L‐ido‐1‐
5
6
3
BnO
Cl
NH2
deoxynojirimycin where the former is a significantly more
4
2
BnO
4
BnO 2
BnO
13: R = H (74%)
15: R = Me (50%)
Pd/C, H2
OBn
25
potent inhibitor. Interestingly, the N‐methyl sugar hydrazide
1
2: R = H (71%)
imide
to inhibitor
hydrazide imide
6
displayed a quite different inhibition profile compared
lacking the N‐methyl group. Indeed, in contrast to
, compound behaved as a competitive
1
4: R = Me (58%)
5
Pd/C, H2
5
6
EtOH/TFA 9:1
EtOH/TFA 9:1
inhibitor of α‐glucosidase in the micromolar concentration
OH
5
range (Kia 32.6 μM). Apart from the inhibition of α‐glucosidase,
5
6
1
N
NHR
AcO
NH2
6
3
1
NHR
AcO
NH2
HO
HO
hydrazide imide
enzymes in the panel of targets, which label compound
selective α‐glucosidase inhibitor. The significantly stronger
inhibition of than against β‐glucosidase may be to the
6
acted as a poor inhibitor for the other
HO
3
N
HO
4
2
6
as a
4
2
HO
OH
OH
5
: R = H (80%)
16: R = H (90%)
17: R = Me (31%)
5
6
6
: R = Me (85%)
additional NH functionality of the former that provide an
additional interaction with a hydrogen bond acceptor in the
enzyme. In agreement with L‐ido‐hydrazide imide 16, the N‐
Scheme 1 Synthetic pathway for hydrazide imides 5, 6, 16, and
17.
methylated counterpart 17 also behaved as a modest inhibitor
of all enzymes included in our biological tests.
Inhibition studies
Conclusions
Hydrazide imides 5, 6, 16, and 17 were evaluated as glycosidase
In conclusion, we have carried out the synthesis of four
inhibitors against a panel of seven commercially available
glycosidases (Table 1). Many of the enzymes in our panel are
routinely used in order to evaluate the inhibition profile of
iminosugars at early stages of the hunt for new drug candidates.
Lineaweaver‐Burk (double reciprocal) plots provided the kinetic
unprecedented sugar hydrazide imides
5, 6, 16, and 17.
Compounds and behave as good α‐ and β‐glucosidase
5
6
inhibitors in the low micromolar concentration range. The type
of iminosugars presented herein, carrying a hydrazide imide
moiety are unique and thus the work presented has the
potential to serve as a platform in the hunt for new
pharmaceutical targets. Indeed, in the search for
pharmacological chaperones for treatment of lysosomal
storage disorders, iminosugars armed with lipophilic N‐groups
parameters that afforded the inhibition constants (K
example, Figure S1 (in supporting information) depicts such a
plot for the inhibition of β‐glucosidase by hydrazide imide at
i
’s); as an
5
pH 8.0. In case Lineaweaver‐Burk did not provide undoubtedly
the inhibition mode, the double Corsnih‐Bowden plot (1/V vs.
8
have appeared as such candidates. Thus, arming of compound
[
I] and [S]/V vs. [I]) was used (see Figure S2 for the inhibition of
β‐glucosidase by at pH 8.0).
Compounds 16, and 17 were found to display very distinct
inhibition profiles of which hydrazide imide proved to be the
5
with various lipophilic N‐groups will provide additional
5
pharmacological chaperone candidates.
5, 6,
5
most potent glycosidase inhibitor of the series. This compound
behaved as a competitive and mixed‐type inhibitor of
glucosidases and mannosidases, respectively, with
predominantly competitive component (Kia
mannosidases. Remarkably, compound
a
for
<
K
ib
)
5
was found to be a
good inhibitor of α‐glucosidase, with Kia value (interaction with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
View Article Online
DOI: 10.1039/C7OB01673E
COMMUNICATION
Journal Name
i
Table 1. Inhibitory constants (K , µM) for hydrazide imides 5, 6, 16, and 17 against a panel of glycosidases.
Enzyme
α‐Glucosidase
9.9±2.2 (12.3)a
Competitive
3667
Competitive
32±8 (25)a
Competitive
>
250b
(
Saccharomyces cerevisiae)
3
1±4 (15)a
c
Competitive
5
42 (537)a
β‐Glucosidase (almonds)
>250b
>250b
>250b
Competitive
7
.7 ±1.8 (7.9)a
d
Competitive
K
K
ia= 62±27
ib= 398±27
α‐Mannosidase
>
250b
>250b
e
(
Jack beans)
Mixed
K
K
ia= 211
ib= 1245
K
ib = 2991
β‐Mannosidase (Helix pomatia)e
>250b
850
>250b
708
Uncompetitive
Mixed
>250
b
>250b
α‐Galactosidase
(
green coffee beans)
b
b
b
b
β‐Galactosidase (Asp. oryzae)
β‐Galactosidase (E.coli)
>250
>250
>250
>250
b
b
b
b
>250
>250
>250
>250
aIC50 values (µM); Maximum inhibitor concentration tested; At pH 6.8; At pH 8.0; At pH 5.6
b
c
d
e
Biology, Elsevier, 2007, pp 815‐884; (c) P. Compain, V.
Chagnault and O. R. Martin, Tetrahedron: Asymmetry, 2009,
20, 672; (d) Ó. López, P. Merino‐Montiel, S. Martos and A.
González‐Benjumea, Carbohydr. Chem., 2012, 38, 215.
0 (a) D. L. Zechel and S. G. Withers, Acc. Chem. Res., 2000, 33
Notes and references
1
2
3
4
(a) H. He and Y. H. Lu, J. Agric. Food Chem., 2013, 61, 8110;
b) S. Onose, R. Ikeda, K. Nakagawa, T. Kimura, K. Yamagishi,
1
1
,
(
1
2
1; (b) G. J. Davies, A. Planas and C. Rovira, Acc. Chem. Res.,
O. Higuchi and T. Miyazawa, Food Chem., 2013, 138, 516.
(a) G. Horne, F. X. Wilson, J. Tinsley, D. H. Williams and R.
Storer, Drug Discovery Today, 2011, 16, 107; (b) V. K. Harit
012, 45, 308.
1 A. Martin, A. Arda, J. Désiré, A. Martin‐Mingot, N. Probst, P.
Sinaÿ, J. Jiménez‐Barbero, S. Thibaudeau and Y. Blériot, Nat.
and N. G. Ramesh, RSC Adv., 2016, 6, 109528.
Chem., 2016, 8, 186.
P. Compain and O. Martin, Iminosugars: From synthesis to
therapeutic applications; John Wiley & sons Ltd, Chichester,
1
1
2 M. Bols, Acc. Chem. Res., 1998, 31, 1.
3 N. Asano, H. Kizu, K. Oseki, E. Tomioka, K. Matsui, M.
Okamoto and M. Baba, J. Med. Chem., 1995, 38, 2349.
4 M. P. Dale, H. E. Ensley, K. Kern, K. A. R. Sastry and L. D. Byers,
Biochemistry, 1985, 24, 3530.
2
007.
A. T. Ghisaidoobe, R. J. B. H. N. van den Berg, S. S. Butt, A.
Strijland, W. E. Donker‐Koopman, S. Scheij, A. M. C. H. van den
Nieuwendijk, G. J. Koomen, A. van Loevezijn, M. Leemhuis, T.
Wennekes, M. van der Stelt, G. A. van der Marel, C. A. A. van
Boeckel, J. M. F. G. Aerts and H. S. Overkleeft, J. Med. Chem.,
1
1
5 E. Lindbäck, B. W. Laursen, J. C. Navarro Poulsen, K. Kilså, C.
M. Pedersen and M. Bols, Org. Biomol. Chem., 2015, 13, 6562.
6 D. H. Leaback, Biochem. Biophys. Res. Commun., 1968, 32, 1025.
7 (a) M. K. Tong, G. Papandreou and B. Ganem, J. Am. Chem.
Soc., 1990, 112, 6137; (b) G. Papandreou, M. K. Tong and B.
Ganem, J. Am. Chem. Soc., 1993, 115, 11682.
8 (a) Y. Blériot, T. Dintinger, N. Guillo and C. Tellier,
Tetrahedron Lett., 1995, 36, 5175; (b) G. Legler, M.‐T. Finken
and S. Felsch, Carbohydr. Res., 1996, 292, 91; (c) M. P. Heck,
S. P. Vincent, B. W. Murray, F. Bellamy, C. H. Wong and C.
Mioskowski, J. Am. Chem. Soc., 2004, 126, 1971; (d) R. Kanso
and S. Striegler, Carbohydr. Res., 2011, 346, 897; (e) E.
Lindbäck, Ó. Lopéz, J. G. Fernández‐Bolaños, S. P. A. Sauer
and M. Bols, Org. Lett., 2011, 13, 2908; (f) Q. H. Fan, K. A.
Claunch and S. Striegler, J. Med. Chem., 2014, 57, 8999.
9 L. K. Campbell, D. E. Baker, R. K. Campbell. Ann.
Pharmacother., 2000, 34, 1291.
1
1
2
014, 57, 9096.
5
6
M. Guerrera and S. Ladisch, Cancer Lett., 2003, 201, 31.
S. Pollock, R. A. Dwek, D. R. Burton and N. Zitzmann, AIDS, 2008,
2
2, 1961.
1
7
C. Decroocq, F. Stauffert, O. Pamlard, F. Oulaïdi, E. Gallienne,
O. R. Martin, C. Guillou and P. Compain, Bioorg. Med. Chem.
Lett., 2015, 25, 830.
8
9
E. M. Sánchez‐Fernández, J. M. García Fernández and C. Ortiz
Mellet, Chem. Commun., 2016, 52, 5497.
(a) V. H. Lillelund, H. H. Jensen, X. Liang and M. Bols, Chem.
Rev., 2002, 102, 515; (b) M. Bols, Ó. López and F. Ortega‐
Caballero, Glycosidase inhibitors: structure, activity,
synthesis, and medical relevance, in: J.P. Kamerling (Ed.),
Comprehensive Glycoscience From Chemistry to Systems
1
4
| J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 6
Orga Pn l iec a s& e Bd oi o nmo ot al ed cj uu sl ta mr Ca rhg ei nms istry
View Article Online
DOI: 10.1039/C7OB01673E
Journal Name
2
COMMUNICATION
0 (a) H. S. Overkleeft, G. H. Renkema, J. Neele, P. Vianello, I. O.
Hung, A. Strijland, A. M. van der Burg, G. J. Koomen, U. K.
Pandit and J. M. F. G. Aerts, J. Biol. Chem., 1998, 273, 26522;
(
b) T. Wennekes, R. J. B. H. N. van den Berg, W. Donker, G. A.
van der Marel, A. Strijland, J. M. F. G. Aerts and H. S.
Overkleeft, J. Org. Chem., 2007, 72, 1088; (c) J. D. Diot, I.
Garcia Moreno, G. Twigg, C. Ortiz Mellet, K. Haupt, T. D.
Butters, J. Kovensky and S. G. Gouin, J. Org. Chem., 2011, 76
,
7
757; (d) V. Cendret, T. Legigan, A. Mingot, S. Thibaudeau, I.
Adachi, M. Forcella, P. Parenti, J. Bertrand, F. Becq, C. Norez,
J. Désiré, A. Kato and Y. Blériot, Org. Biomol. Chem., 2015,
13, 10734; (e) J. I. Olsen, G. B. Plata, J. M. Padrón, Ó. López,
M. Bols and J. G. Fernández‐Bolaños, Eur. J. Med. Chem.,
2
016, 123, 155; (f) A. Hatano, Y. Kanno, Y. Kondo, Y. Sunaga,
H. Umezawa, M. Okada, H. Yamada, R. Iwaki, A. Kato and K.
Fukui, Bioorg. Med. Chem., 2017, 25, 773.
2
1 B. Ganem and G. Papandreou, J. Am. Chem. Soc., 1991, 113,
8
984.
2
2
2 P. Ermert and A. Vasella, Helv. Chim. Acta., 1991, 74, 2043.
3 L. Amorim, F. Marcelo, J Désiré, M. Sollogoub, J. Jiménez‐
Barbero and Y. Blériot, Carbohydr. Res., 2012, 361, 219.
4 Z. Walaszek, D. Horton and I. Ekiel, Carbohydr. Res., 1982,
2
2
1
06, 193.
5 A. Kato, N. Kato, E. Kano, I. Adachi, K. Ikeda, L. Yu, T.
Okamoto, Y. Banba, H. Ouchi, H. Takahata and N. Asano, J.
Med. Chem., 2005, 48, 2036.

This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
Please do not adjust margins