Gluco-1 H -imidazole: A New Class of Azole-Type β-Glucosidase Inhibitor

Article abstract of DOI:10.1021/jacs.8b02399

Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1H-imidazoles. Here, we present gluco-1H-imidazole, a gluco-azole bearing a 1H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.

Full text of DOI:10.1021/jacs.8b02399

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Gluco-1H-imidazole: a new class of azole-type #-glucosidase inhibitor
Sybrin P Schröder, Liang Wu, Marta Artola, Thomas Hansen, Wendy A.
Offen, Maria J. Ferraz, Kah-Yee Li, Johannes M.F.G. Aerts, Gijsbert A. van
der Marel, Jeroen D. C. Codée, Gideon J. Davies, and Herman S. Overkleeft
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02399 • Publication Date (Web): 30 Mar 2018
Downloaded from http://pubs.acs.org on March 30, 2018
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Gluco-1H-imidazole: a new class of azole-type β-glucosidase inhibi-
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tor
Sybrin P. Schröder,† Liang Wu,§ Marta Artola,† Thomas Hansen,† Wendy A. Offen,§ Maria J. Ferraz,‡
Kah-Yee Li,† Johannes M. F. G. Aerts,‡ Gijsbert A. van der Marel,† Jeroen D. C. Codée,† Gideon J. Da-
vies§ and Herman S. Overkleeft†*
†Department of Bioorganic Synthesis and ‡Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden Uni-
versity, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
§Department of Chemistry, York Structural Biology Laboratory, University of York, Heslington, York, YO10 5DD, U.K.
Supporting Information Placeholder
al isomers would be attractive alternatives to the reported gluco-
ABSTRACT: Gluco-azoles competitively inhibit glucosidases
azoles. Herein, we report on the synthesis and biochemical eval-
uation of gluco-1H-imidazole 6 and its analogues 7-9 as concep-
tually new retaining β-glucosidase inhibitors (Figure 1b).
by transition-state mimicry and their ability to interact with cata-
lytic acid residues in glucosidase active sites. We noted that no
azole-type inhibitors described, to date, possess a protic nitrogen
characteristic for 1H-imidazoles. Here, we present gluco-1H-
imidazole, a gluco-azole bearing a 1H-imidazole fused to a gluco-
pyranose-configured cyclitol core, and three close analogues as
new glucosidase inhibitors. All compounds inhibit human retain-
ing β-glucosidase, GBA1, with the most potent ones inhibiting
this enzyme (deficient in Gaucher disease) on a par with glucoim-
idazole. None inhibit glucosylceramide synthase, cytosolic β-
glucosidase GBA2 or α-glucosidase GAA. Structural, physical
and computational studies provide first insights into the binding
mode of this conceptually new class of retaining β-glucosidase
inhibitors.
Figure 1. (a) Known cyclitol-azole type glycosidase inhibitors
and their inhibitory potencies against porcine NAG (1)3 and sweet
almond β-glucosidase (2-5).4–7 (b) 1H-Imidazoles subject of this
study.
Glycosidases catalyze the hydrolysis of interglycosidic linkag-
es, and glycosidase inhibitors are widely regarded as promising
therapeutic entities.1 Azole-containing glycopyranoside mimics
are a major class of competitive glycosidase inhibitors.2 The
The synthesis of gluco-1H-imidazole 6 commenced with cyclo-
hexene 10,15 which was transformed into the vicinal diamine
following a modified procedure from Llebaria.16 Rapid conver-
sion of 10 was accomplished using RuCl3/NaIO4, affording a
separable, near equimolar mixture of 1,2-cis-dihydroxy isomers
11a (S,S) and 11b (R,R).17 Bismesylation and subsequent azide
substitution afforded diazido cyclitols 12a,b. Platinum oxide
catalyzed hydrogenolysis afforded diamino cyclitols 13a,b, which
were condensed with trimethyl orthoformate in hexafluoroisopro-
panol (HFIP) to afford imidazolines 14a,b.18 Protected 1H-
imidazole 15 was obtained by oxidation of either isomer of 14
with IBX/DMSO,19 and final hydrogenolysis afforded gluco-1H-
imidazole 6. Derivatization of the imidazole ring of gluco-1H-
imidazoles was achieved by variation of the trimethyl orthoester
employed. Thus, reaction of 13a,b with trimethyl orthovalerate
followed by oxidation and deprotection furnished 2-butyl-1H-
imidazole 7 via 16a,b and 17. Utilizing tetrabenzyl myo-
diaminocyclitol16 as starting material yielded conduritol B-1H-
imidazoles 8 and 9 (see Supporting Information (SI)).
natural product, nagstatin (1), is
a potent N-acetyl-β-D-
glucosaminidase (NAG) inhibitor.3 Glucopyranose mimics bear-
ing tetrazole (2), triazole (3, 4) and imidazole (5) moieties have
been conceived as β-glucosidase inhibitors by Tatsuta and
Vasella, with inhibitory potencies against sweet almond β-
glucosidase ranging from low nanomolar (5) to high micromolar
(4, Figure 1a).4–7 The reaction itinerary followed by many β-
glucosidases proceeds via a 4H3 transition state conformation,8
matching one of the thermodynamically most favored confor-
4
mations of gluco-azoles (local minima calculated for 5 are H3
3
and H4).9 This conformational transition state mimicry contrib-
utes considerably to the inhibitory potency of gluco-azoles.
Vasella concluded, from extensive studies on gluco-azoles (in-
cluding compounds 2-5), that an azole nitrogen at the position
corresponding to the exocyclic oxygen in a β-glucoside substrate
is essential for inhibitory potency, as this ‘exocyclic’ nitrogen
participates in lateral coordination with the catalytic acid/base of
anti-protonating glucosidases.10–14 Remarkably, no azole-type
inhibitors synthesized to date are protic with respect to the azole
ring (such as 1H-imidazoles), and we reasoned that such position-
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Scheme 1. Synthesis of 1H-imidazoles 6 and 7.a
against most β-glucosidases tested, with Ki values ranging from
~3.9 µM against GBA1 to ~69 µM against TxGH116 (Table 1).
Remarkably, given their apparent structural similarity, 1H-
imidazole 6 proved to be a weaker β-glucosidase inhibitor than
glucoimidazole 5, which inhibited β-glucosidases at nanomolar
concentrations. Attachment of a butyl moiety, as in 7, increased
the inhibitory potency of the gluco-1H-imidazole scaffold. Whilst
this increase in potency was modest for TmGH1 and TxGH116, 7
inhibited sweet almond β-glucosidase and GBA1 with nanomolar
potency. Notably, the biological role of GBA1 is breakdown of
amphiphilic glucosylceramide.22 Conduritol-1H-imidazole 8 did
not effectively inhibit any glucosidases tested except for GBA1,
consistent with a loss of interactions at the O6 position, but also
with the fact that GBA1 is effectively inhibited by conduritol B
epoxide (CBE).23 As with the gluco-1H-imidazoles, addition of a
butyl moiety to the conduritol-1H-imidazole scaffold increased
activity against sweet almond β-glucosidase and GBA1, rendering
9 a nanomolar inhibitor of these enzymes. No compounds dis-
played any inhibitory activity against GBA2, GCS or α-
glucosidase GAA under our assay conditions. Competitive, selec-
tive GBA1 inhibitors are considered attractive starting points for
the development of pharmacological chaperones: compounds that
stabilize the fold of mutant, partially malfunctioning GBA1 in
Gaucher patients.24,25 Compounds 7 and 9 (as well as known
glucoimidazole 5) are in our opinion attractive starting points for
this purpose.
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One striking result displayed in Table 1 is that 1H-imidazole 6
is a comparatively much weaker retaining β-glucosidase inhibitor
than glucoimidazole 5. Since the structures are closely related, we
elected to investigate this result in more depth. Literature studies
have shown that the inherent basicity of the azole ring in com-
pounds 2-5 correlates to the inhibitory potency.26 Basicity plays a
negligible role here, since the experimental pKAH values of 5 and
6 are almost identical (5: pKAH 6.2, lit. 6.126; 6: pKAH 6.0; Figure
S1, S2). We also explored the interaction of gluco-1H-imidazoles
with TmGH1 and TxGH116 by isothermal titration calorimetry
(ITC) at pH 5.8 (activity optimum11,21) and pH 6.8 (where 5
shows strongest inhibition)11. In line with the Ki data (Table 1),
ITC titrations at both pH values showed nanomolar binding affini-
ties for 5, and micromolar affinities for 6 and 7 (Table S3). The
enthalpic contributions in active site binding for 1H-azoles are
smaller than those observed for 5, and only partially compensated
for by increased entropic contributions to the binding energy. In
line with what has been reported for 5,11 the presence of a hydro-
phobic moiety in 7 reduced its enthalpy of binding compared to 6,
which was counterbalanced by an increase in favorable entropic
contributions to binding.
aReagents and conditions: a) RuCl3·3H2O (7 mol%), NaIO4,
EtOAc, MeCN, H2O, 0 °C, 90 min, 11a 40%, 11b 32%; b) MsCl,
N-methyl-imidazole, Et3N, CHCl3, rt, 16 h, then NaN3, DMF, 100
°C, 16 h, 12a 74%, 12b 58%; c) PtO2, H2, THF, rt, 16 h, 13a 80%,
13b 96%; d) trimethyl orthoformate, HFIP, rt, 16h, 14a 76%, 14b
87%; or trimethyl orthovalerate, HFIP, rt, 16 h, 16a 74%, 16b
78%; e) For 15: IBX, DMSO, 45 °C, 16 h, 75% from 14a, 71%
from 14b; for 17: (COCl)2, DMSO, DCM, -60 °C, 1h, 76% from
16a; 70% from 16b; f) Pd(OH)2/C, H2, HCl, MeOH, quant. 6;
quant. 7.
We determined competitive kinetic constants and IC50 values
for 1H-imidazoles 6–9 as compared with glucoimidazole 5 for
inhibition of the retaining glucosidases TmGH1 from Thermotoga
maritima,20 TxGH116 from Thermoanaerobacterium xylanolyti-
cum,21 sweet almond β-glucosidase (GH1), human lysosomal acid
β-glucosylceramidase (GBA1, GH30), human cytosolic β-
glucosylceramidase (GBA2, GH116), murine glucosylceramide
synthase (GCS) and human acid α-glucosidase (GAA, GH31).
Gluco-1H-imidazole 6 displayed micromolar inhibitory activity
Table 1. Inhibition constants (Ki) and IC50 values in µM for compounds 5-9.
TmGH1a
TxGH116a
sweet almond
GH1b
GBA1a
GBA2c
GCS c
GAAc
58 ± 1
39 ± 14
>100c
69 ± 12
46 ± 5
>100c
23 ± 1
3.9 ± 2
>100
>100
>100
>100
>100
>50
>50
>50
>50
>50
>100
>100
>100
>100
>100
6
7
8
9
5
0.039 ± 0.006
>100c
0.133 ± 0.040
13.7 ± 6
>100c
>100c
0.221 ± 0.004
0.067 ± 0.004d
0.079 ± 0.001
0.070 ± 0.005
0.026 ± 0.001
0.165 ± 0.006
Values are mean ± SD from triplicate experiments. Assays measured at apH 6.8 using β-
p
-NPG substrate; bpH 5.2 using β-2,4-
DNPG substrate; cApparent IC50. dLit. i = 0.100 µM.6
K
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Figure 3. Interactions of gluco-1H-imidazole 6 and classical
glucoimidazole 5 with the catalytic residues. (a) Prototropic
tautomerism of 6. (b) Positive charge is delocalized onto the
‘apical’ carbon in protonated 6. (c) In 5, positive charge is delo-
calized onto the anomeric equivalent carbon, ideally located for
charge-charge interaction with the nucleophile residue. Mulliken
charges are annotated in red.
Figure 2. (a) Gluco-1H-imidazole 6 in complex with TmGH1,
with direct H-bonding interactions shown. (b) Overlay of 5 (pink)
and 6 (cyan) within the TmGH1 active site (chain B from each
structure). (c) Gluco-1H-imidazole 6 in complex with TxGH116.
(d) Overlay of 5 (salmon) and 6 (blue) within the TxGH116 acti-
ve site. Electron densities are REFMAC maximum-likelihood/σA
weighted 2Fo−Fc contoured to 0.38 (TmGH1) or 0.48 (TxGH116)
e-/Å3.
tained in 6, as observed in its complex with TmGH1 (Figure 2a).
However, and in contrast to 5, 1H-imidazole 6 may undergo
prototropic tautomerism (Figure 3a). Thus, whilst the overall
pKAH values of 5 and 6 are similar, the N2 lone pair of 6 may be
less available for interaction with the glucosidase acid/base, re-
ducing the binding affinity of 6 compared to 5. Protonation of the
imidazole in turn (either in solution or by proton abstraction from
the acid/base residue)28 results in positive charge delocalization.
Resulting charge-charge interactions with enzyme active site
carboxylates are thought to contribute substantially to enzyme
binding energy of azole-type inhibitors.29 We calculated the Mul-
liken charge on all atoms for protonated 5 and 6 by DFT. Protona-
tion of the azole ring in 5 produces a + charge on the ‘anomeric’
carbon, which is ideally located for a charge-charge interaction
with a retaining glucosidase active site nucleophile. Conversely,
protonation of 6 leads to a + charge largely delocalized onto the
‘apical’ carbon atom of the imidazole, with the overall + charge
also being less pronounced (Figure 3b). This apical + charge is
located distal from the catalytic nucleophile and thus poorly posi-
tioned for charge-charge interactions, which may explain the
reduced binding enthalpy observed in ITC for gluco-1H-
imidazoles 6 compared to 5. The small ‘upwards’ shift and in-
creased imidazole B-factors, observed in crystal structure com-
plexes of 6 compared to 5 is also consistent with a weaker charge-
charge interaction of the imidazole portion of 6 with the enzyme
catalytic nucleophile. Interestingly, in contrast to neutral 6, glu-
coimidazole 5 also contains a significant + character (+0.306
Mulliken charge) on the ‘anomeric’ carbon in its neutral state (see
SI).
Next, the X-ray structure of 6 in complex with TmGH1 was de-
termined to 1.7 Å (PDB: 5OSS), and compared to the structure of
the same enzyme complexed with 5 (PDB: 2CES).11 These struc-
tures revealed the binding mode of both compounds to be similar.
We observed a single molecule of 6 in the active site after ligand
4
soaking, adopting a E conformation, similar to the complex of 5
and TmGH1 (Figure 2a).11 H-bonding interactions made by 6 to
active site residues were identical to those observed with 5, albeit
with a slight ‘upwards’ tilt for 6 compared to 5 (~0.4 or 0.5 Å
‘upward’ shifts at the apical imidazole carbon, compared with
ligands in chains A or B of 2CES respectively; Figure 2b, Figure
S3). Crystal structures in TxGH116 at 2.1 Å resolution (Figure
2c,d) also revealed similar binding modes21 and a ~0.5 Å ‘up-
wards’ tilt for 6 compared to 5 (PDB: 5OST and 5BX4, respec-
tively). For both TmGH1 and TxGH116 complexes, B-factors in
the ‘imidazole’ portion of 6 were markedly higher when com-
pared to the ‘glucose’ portion of the molecule, indicating the
imidazole of 6 was more disordered in the crystal structure and
may be bound less strongly. No strong B-factor trend was ob-
served for complexes with 5 (Figure S3).
The underlying cause for the reduced potency of gluco-1H-
imidazole 6 compared to 5 is most likely the combination of a
number of factors. We propose that repositioning of the N1 atom
(from the bridgehead position in 5 to the position in 6) brings two
major consequences that together reduce the binding affinity of 6
compared to 5. Firstly, considering the situation where the imid-
azole is in a neutral state28: the free lone pair of the N2 atom in 5
can laterally coordinate to the acid/base residue of the bound
glucosidase in typical anti-protonating glucosidases14 (although
TxGH116 lacks this interaction due to the unusual placement of
its acid/base residue21). This lateral positioning of N2 is main-
In conclusion, we have described a new class of competitive β-
glucosidase inhibitors: the 1H-gluco-azoles. The synthetic route is
flexible regarding substituents on the imidazole ring, and can
likely be transferred to configurational isomers by applying this
route to configurational isomers of cyclohexene 10.30 Our com-
pounds resemble to some extent the 1H-imidazoles reported by Li
and Byers31, and Field et al.,32 whose simple, achiral molecules
inhibit several glucosidases as well, though likely by a different
mode of action. 1H-Imidazole 6 appeared a poorer inhibitor than
compound 5, and we hypothesize this is caused by delocalization
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T. D. Heightman, M. Locatelli, A. Vasella, Helv. Chim. Acta
of the lone pair on the nitrogen atom due to tautomerism and/or
impaired + charge development at the anomeric center. Introduc-
tion of an alkyl substituent on the 1H-imidazole ring (as in 7) as
well as ‘deletion’ of the methylene carbon (as in 9) yielded potent
competitive inhibitors of the human lysosomal glucosylcerami-
dase GBA1, selective over human cytosolic GBA2 and GCS.
These and related compounds we believe have potential to be
developed into pharmacological chaperone candidates for Gau-
cher disease and perhaps also neuropathological disorders (in
particular, Parkinsonism) that are characterized by partial defi-
ciency in GBA.33,34
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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Experimental data and procedures, enzyme kinetics, DFT calcula-
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AUTHOR INFORMATION
S. Khaksar, A. Heydari, M. Tajbakhsh, S. M. Vahdat, J. Fluor.
Corresponding Author
* h.s.overkleeft@lic.leidenuniv.nl
K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, J. Am.
L. Liu, Z. Zeng, G. Zeng, M. Chen, Y. Zhang, J. Zhang, X.
Notes
R. Charoenwattanasatien, S. Pengthaisong, I. Breen, R. Mutoh,
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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We thank the Netherlands Organization for Scientific Research
(NWO-CW ChemThem grant to JMFGA and HSO), the European
Research Council (ERC-2011-AdG-290836 ‘Chembiosphing’ to
HSO, and ERC-2012-AdG-322942 ‘Glycopoise’ to GJD), Sanofi
Genzyme (research grant to JMFGA and HSO and postdoctoral
contract to MA) and Diamond Light Source (beamline I03, propo-
sal number mx-13587) for provision of data collection facilities.
GJD thanks the Royal Society for the Ken Murray Research Pro-
fessorship.
G. A. Grabowski, K. Osiecki-Newman, T. Dinur, D. Fabbro,
A. R. Sawkar, W.-C. Cheng, E. Beutler, C.-H. Wong, W. E.
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