Synthesis and evaluation of d-gluco-pyranocyclopropyl amines as potential glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.10.022

In the recent past sugar-derived cyclopropylamines were proposed as structurally new glycosidase inhibitors. In this Letter we report our efforts in the synthesis of a set of α-glucose configured oxabicyclo[4.1.0] heptanes, based on this hypothesis, beari

Full text of DOI:10.1016/j.bmcl.2009.10.022

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6600–6603
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of D-gluco-pyranocyclopropyl amines as potential
glucosidase inhibitors
Martijn D. P. Risseeuw a, Richard J. B. H. N. van den Berg a, Wilma E. Donker-Koopman b,
a,
Gijs A. van der Marel a, Johannes M. F. G. Aerts b, Mark Overhand a, , Herman S. Overkleeft
*
*
a Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA Leiden, The Netherlands
b Academic Medical Centre, Department of Biochemistry, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
In the recent past sugar-derived cyclopropylamines were proposed as structurally new glycosidase inhib-
itors. In this Letter we report our efforts in the synthesis of a set of -glucose configured oxabicyclo[4.1.0]
heptanes, based on this hypothesis, bearing an amine substituent on the propyl ring and reveal that their
inhibitory potential towards a range of mammalian glucosidases is modest.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 28 July 2009
Revised 5 October 2009
Accepted 6 October 2009
Available online 8 October 2009
a
Keywords:
Glucosidase inhibitors
Oxabicyclo[4.1.0] heptanes
Cyclopropylamines
Glycosidase inhibitors continue to be of interest both for funda-
mental and applied biomedical research.1 The importance of glyco-
sidase and glycosyltransferase inhibitors is underscored by the
successful development of ZavescaTM (N-butyldeoxynojirimycin,
1) and MiglitolTM (N-hydroxyethyldeoxynojirimycin, 2) as drugs
for the treatment of Gaucher disease2 and type two diabetes,3
respectively (Fig. 1). We recently found that the lipophilic iminosug-
ar N-adamantanemethyloxypentyl-1-deoxynojirimycin 3 inhibits
both human glucosylceramidase and intestinal glycosidases and
on the basis of these combined actions presents a new lead towards
the development of type two diabetes drugs.4
Despite these and other successes there still is ample room for
the development of conceptually new classes of glycosidase inhib-
itory compounds. A potent inhibitor for a given glycosidase activity
can normally be designed with confidence by tuning substitution
pattern and configuration on a general scaffold, and for this purpose
most literature studies make use of carbohydrate mimetic alka-
loids.5 These include polyhydroxylated pyrrolidines, piperidines
(deoxynojirimycin, azafagomine) and indolizidines (castanosper-
mine, swainsonine). Such inhibitors however are most often not
selective in that multiple glycosidase activities are affected at con-
centrations needed to downregulate the target glycosidase to the
desired level. Interestingly, this also holds true for the glycosidase
inhibitor based drugs Miglitol, the therapeutically relevant prop-
erty of which is based on inhibition of intestinal enzymes but which
impairs the action of several subcellular glycosidases as off targets,
and Zavesca, whose therapeutic activity relies on glucosylceramide
synthase inhibition whereas it also inhibits with considerable
potency most subcellular b-glucosidases as well as several intesti-
nal digestive glycosidases. Therefore, more selective glycosidase
and glycosyl transferase inhibitors should be of interest for the
development of new pharmaceutical leads. It should be noted here
that glycosyl transferases are much more elusive targets for
inhibition by carbohydrate mimetics than their hydrolytic counter-
parts.6 Here it appears that glucosylceramide synthase is the
exception as it is the only glycosyl transferase species for which
clinically relevant inhibitors have been reported.3,4,6 Several scaf-
folds other than carbohydrate mimetic alkaloids are pursued for
the development of new glycosidase inhibitors.7 These include
C-glycosides,8 cyclitols9 (polyhydroxylated cyclopentane or cyclo-
hexane derivatives, including conduritol epoxides10) and function-
alised cyclic thio-ethers.11 In this respect, our attention was drawn
to the
clo[4.1.0]heptane 4 (Fig. 1), which was recently suggested as a
selective inhibitor of retaining
-glycosidases.12 The rationale
behind this idea is the assumption that, upon binding to an
-glucosidase active site, the secondary amine in 4 will point
towards the carboxylic acid residue present in the enzyme active
site on the -face of the molecule. Next to binding due to glucose
a-D-glucose configured amine-functionalised oxabicy-
a
a
a
mimicry added stability is then expected to arise from the forma-
tion of a salt bridge that would be the result of protonation of the
amine by the active site carboxylate. If true, this would then be a
distinguishing feature that should allow the molecule to discrimi-
* Corresponding authors.
E-mail addresses: m.overhand@chem.leidenuniv (M. Overhand), h.s.overkleeft@
chem.leidenuniv.nl (H.S. Overkleeft).
nate between
a-glucosidases and the corresponding retaining
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.022

M. D. P. Risseeuw et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6600–6603
6601
HO
HO
HO
HO
H
H
HO
HO
OH
O
N
N
HO
HO
NH2
OH
OH
OH
1
2
4
HO
O
H
H
HO
HO
O
N
O
HO
HO
NH2
OH
OH
3
5
Figure 1. Structures of Zavesca (1), Miglitol (2), N-adamantanemethyloxypentyl-1-deoxynojirimycin (3), target compound 4 and sugar amino acid 5.
b-glucosidases13 where the carboxylic acid residue resides on the b
zyl-D-glucal 10 is treated with ethyl diazoacetate under the agency
site of its substrate glycosides. It should however be noted that
of rhodium(II) acetate to give cyclopropane adduct 11 in 59% yield
and as the single diastereoisomer, as described in the literature.14
Curtius rearrangement of 11 to tert-butoxycarbonyl(Boc)-pro-
tected amine 12 was effected by applying the two-step procedure
we previously used towards the construction of SAA 5.16 Briefly,
saponification of the ethyl ester (LiOH, THF, H2O, MeOH) was fol-
lowed by addition of diphenylphosphoryl azide and triethylamine
in tert-butyl alcohol at elevated temperature, leading after work-
up to the fully protected cyclopropylamine scaffold 12 in 58% yield
over the two steps. N-Alkylation was effected by deprotonation of
the NHBoc group in 12 with sodium hydride followed by addition
of 1-bromobutane or 5-(adamant-1-yl-methoxy)-1-bromopen-
tane,6 to give fully protected N-butyl derivative 13 and the corre-
sponding adamantanemethoxypentyl derivative 14 in 85% and
73% yield, respectively.
Concomitant deprotection of the benzyl groups and the Boc-
group using palladium-catalysed hydrogenation followed by treat-
ment with neat trifluoroacetic acid gave the target compounds 6
and 7 both in a near quantitative yield over the last two steps.
Applying the same deprotection conditions with compound 12
gave the parent compound 4 in 98% yield. Compound 4 was acyl-
ated with either N-hydroxysuccinimidyl-butyrate 16 to give 6 or
N-hydroxysuccinimidyl-5-(adamantylmethoxy)-pentanoate 17 to
give 7, in 63%, respectively 58% yield.
retaining b-glucosidases do have a carboxylate at the
a site of the
substrate that might coordinate with the amine or ammonium salt
presented by structure 4. In any case, we decided to verify the
hypothesis as put forward by Stick and Stubbs12 by the synthesis
of 4 and some analogues and assessment of their inhibitory poten-
tial against both a-glucosidases and b-glucosidases.
We recently reported14 on the synthesis of glucose-derived oxa-
bicyclo[4.1.0]heptane amino acid (SAA) 5 (Fig. 1) as part of the de-
sign of a new class of conformationally constrained sugar amino
acids. Protected aminocyclopropanes corresponding to 4 featured
as intermediates en route to SAA 5 and we decided to adapt this
route of synthesis to generate 4 and a small number of N-alkylated
(6, 7) and N-acylated (8, 9) derivatives. The alkyl and acyl chains
were selected to arrive at compounds that resemble in substitution
pattern most closely N-butyldeoxynojirimycin 1 and N-adamant-
anemethyloxypentyl-deoxynojirimycin 3.3,4 The acyl substituents
were selected to probe the difference, of the (partially) protonated
cyclopropyl amines and the neutral species on glycosidase inhibi-
tory potential. In this respect, we note that the pKa of unsubstitut-
ed cyclopropylamine (in its protonated form) is about 9.1 and we
expect that our substituted derivatives, although possibly en-
dowed with a slightly lowered pKa due to the electronegative ele-
ments present in the carbohydrate core, are sufficiently basic to be
largely protonated at physiological pH. We have previously estab-
lished the inhibitory potency of several potent but non-selective
glucosylceramide synthase inhibitors, as well as several related
compounds on a broad panel of human glycosidases, including
The inhibitory potency (IC50) of the panel of five aminocyclopro-
panes 4, 6, 7, 8 and 9 against human lysosomal glucosylceramidase
(GBA1), human non-lysosomal glucosylceramidase (GBA2), human
lysosomal-
a-glucosidase, rice
a-glucosidase, Saccharomyces cerevi-
retaining
a
- and b-glucosidases.4,6,15 By comparing this data with
siae -glucosidase, Bacillus stearothermophilus a
a
-glucosidase and
the inhibitory potential of compounds 4 and 6–9 we aimed to
establish whether carbohydrate-derived amino- and amidocyclo-
propanes are useful leads for the development of selective glycosi-
dase inhibitors.
sweet almond b-glucosidase was established using standard assays
in which we included alkylated deoxynojirimycin derivatives 1 and
3 as well as the natural compound deoxynojirimycin (18) for com-
parison.17 None of the newly synthesized compounds inhibit the
The synthesis of the target compounds is depicted in Scheme 1
and proceeds as follows. Commercially available 3,4,6-tri-O-ben-
human lysosomal
limolar (Table 1). This result is in contrast to the inhibitory poten-
a-glucosidase at concentrations of up to one mil-
Table 1
IC50 values in
l
M18–20
Compound
GBA1
GBA2
Human lysosomal
-glucosidase
Rice
sidase
a
-gluco-
Sacch.cer
sidase
a
-gluco-
Bac. Stear.
-gluco-sidase
Sweet almond
b-gluco-sidase
a
a
1
3
4
6
7
8
9
18
400
0.20
0.230
0.001
>1000
>1000
>1000
>1000
>1000
20
0.10
0.40
1
0.13
20
1
20
0.9
1000
100
>1000
>1000
100
>1000
400
>1000
>1000
>1000
>1000
>1000
1.5
>1000
>1000
>1000
>1000
>1000
0.03
>1000
>1000
>1000
>1000
>1000
0.5
>1000
>1000
>1000
>1000
>1000
0.65
>1000
>1000
>1000
>1000
>1000
250
250

6602
M. D. P. Risseeuw et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6600–6603
H
H
H
O
H
O
Boc
R
vi, vii
HO
HO
BnO
BnO
N
R
N
H
OH
OBn
13
14
R = n-Bu
R = C5H10OCH2Ada
6
7
R = n-Bu
R = C5H10OCH2Ada
iv or v
H
H
O
O
O
O
BnO
BnO
i
BnO
ii,iii
BnO
BnO
NHBoc
OEt
ref 16.
BnO
H
H
OBn
OBn
OBn
10
12
11
vi
O
H
H
H
H
H
H
O
O
O
R
HO
HO
viii or ix HO
HO
vii
HO
HO
NH
NH2TFA
NHBoc
OH
OH
OH
8
9
4
15
R = n-Pr
R = C4H8OCH2Ada
O
O
O
O
N
O
N
O
O
O
O
16
17
Scheme 1. Synthesis of cyclopropylamines and -amides 4, 6, 7, 8 and 9. Reagents and conditions: (i) Rh2OAc4, ethyldiazoacetate, CH2Cl2, 59%; (ii) 4 M LiOH, THF, MeOH; (iii)
diphenylphosphorylazide, Et3N, tBuOH, 4 Å molecular sieves, , 58%; (iv) 1-bromobutane, NaH, DMF, 85%; (v) 5-(adamant-1-yl-methoxy)-1-bromopentane, NaH, DMF, 73%;
(vi) Pd/C, H2, MeOH, HOAc (98%); (vii) TFA, CH2Cl2, (quant.); (viii) 16, DMF, DIPEA, 63%; (ix) 17, DMF, DIPEA, 58%.
D
tial of the known derivatives 1, 3 and 18 which have IC50 values
ranging from nanomolar to low micromolar. Interestingly, com-
pounds 7 and 9 exert moderate inhibitory activity towards the
lysosomal glucosylceramidase GBA1. This retaining b-glucosidase
is inhibited at concentrations in the same range of those observed
for deoxynojirimycin 18 and N-butyldeoxynojirimycin 1, with the
adamantane derivative 7 being slightly more active and selective
for GBA1 in this experiment.
Supplementary data
Supplementary data (experimental procedures and analytical
data for all compounds and enzyme assays) associated with this ar-
ticle can be found, in the online version, at doi:10.1016/
j.bmcl.2009.10.022.
References and notes
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more thorough assessment of the inhibitory activities of these
types of compounds towards -glycosidases from other sources
a-glucosidase. This means that the hypothesis
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Acknowledgments
This research was financed by the Leiden Institute of Chemistry.
We thank Kees Erkelens and Fons Leberer for NMR assistance.

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