Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization

Article abstract of DOI:10.1016/j.bmcl.2015.09.062

Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79 ? resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors.

Full text of DOI:10.1016/j.bmcl.2015.09.062

Bioorganic & Medicinal Chemistry Letters 25 (2015) 5232–5236
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Carborane-containing urea-based inhibitors of glutamate
carboxypeptidase II: Synthesis and structural characterization
Sihyun Youn a,y, Kyung Im Kim a,y, Jakub Ptacek b, Kiwon Ok a, Zora Novakova b, YunHye Kim a,
JaeHyung Koo c, Cyril Barinka b, , Youngjoo Byun a,d,
⇑
⇑
a College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea
Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídenská 1083, 14220 Prague 4, Czech Republic
c Department of Brain Science, Daegu Gyeongbuk Institute of Science & Technology, 50-1 Sang-Ri, Hyeonpung-Myeon, Dalseong-Gun, Daegu 711-873, South Korea
d Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, South Korea
b
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2015
Revised 29 August 2015
Accepted 24 September 2015
Available online 26 September 2015
Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which
cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can
decrease glutamate concentration and play a protective role against apoptosis or degradation of brain
neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII
inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing
inhibitor at 1.79 Å resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located
in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further
structurally modified to identify promising lead structures of novel GCPII inhibitors.
Keywords:
Carborane
Glutamate carboxypeptidase II
X-ray crystal structure
Ó 2015 Elsevier Ltd. All rights reserved.
Carboranes are icosahedral clusters consisting of 2 carbon atoms,
10 boron atoms and 12 hydrogen atoms. Due to their unique
physical and chemical properties such as high lipophilicity, thermal
stability and boron content, carboranes have been widely applied in
medical science, material science and physicalscience.1–6 In the field
of medical science, carboranes have been long considered to be
attractive boron-carriers for boron neutron capture therapy (BNCT)
in the treatment of devastating cancers such as glioblastoma, mela-
noma, and head and neck cancer.7–9 Due to high boron content,
resistance to metabolism, and diverse chemical transformations,
carboranes have been conjugated with targeting agents such as
carbohydrates and nucleosides for BNCT.10–16 More recently,
closo-carboranes have been utilized as surrogates of lipophilic
scaffolds for the identification and discovery of novel bioactive
molecules.17–21 The hydrophobic closo-carboranes have successfully
replaced the cyclohexyl or phenyl ring of various nuclear receptor
ligands.22 These include the vitamin D receptor, retinoid receptor,
estrogen receptor, and androgen receptor ligands.23–27 The binding
affinities of carborane-containing ligands for their respective target
proteins were maintained or enhanced when the carborane cluster
was introduced in place of the lipophilic moiety.23–27
Glutamate carboxypeptidase II (GCPII) is a type II zinc-dependent
metalloprotease which catalyzes the cleavage of N-acetylaspartyl
glutamate (NAAG) to produce N-acetylaspartate (NAA) and
glutamate (Glu) in the brain.28 It is also highly expressed in
androgen-independent metastatic prostate cancer and is referred
to as prostate-specific membrane antigen (PSMA). PSMA is now
considered to be an excellent biomarker in the diagnosis of
advanced prostate cancer. For the last two decades, a number of
PSMA-targeted inhibitors have been successfully discovered and
translated into clinical studies for the imaging and therapy of pros-
tate cancer.29–32 However, the obstacles present in the imaging and
therapy of CNS diseases targeting GCPII in the brain due to low
penetration of hydrophilic GCPII inhibitors across the blood–brain
barrier (BBB), still need to be overcome.
To date, there have been very few reports on the X-ray crystal
structure of carborane-containing ligands in complex with the cog-
nate proteins, although the carborane cluster has been widely intro-
duced into pharmacologically active molecules in drug design and
medicinal chemistry.33–37 The determined X-ray crystal structures
of protein–carborane complexes are dihydrofolate reductase (DHFR)
with 2,4-diamino-5-(1-o-carboranylmethyl)-6-methylpyrimidine
(PDB ID: 2C2S),33 HIV protease with cobalt bis(1,2-dicarbollide)
⇑
Corresponding authors. Tel.: +420 296 443 615; fax: +420 296 443 610 (C.B.);
tel.: +82 44 860 1619; fax: +82 44 860 1607 (Y.B.).
E-mail addresses: cyril.barinka@ibt.cas.cz (C. Barinka), yjbyun1@korea.ac.kr
(Y. Byun).
(PDB ID: 1ZTZ),34 vitamin
(S)-stereoisomers of carborane-based ligand (PDB ID: 3VJT),35 and
D receptor (VDR) with (R)- and
y
Equal contribution.
http://dx.doi.org/10.1016/j.bmcl.2015.09.062
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

S. Youn et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5232–5236
5233
carbonic anhydrase with 1-(sulfamido)methyl-1,2-dicarba-closo-do-
decaborane analogs (PDB ID: 4MDG).36,37
Since 2-(phosphonomethyl)pentanedioic acid (2-PMPA) was
published as a GCPII inhibitor for the first time in 1996, a great
number of GCPII inhibitors have been reported.42 Based on func-
tional groups that interact with zinc ions in the active site, GCPII
inhibitors are largely classified into phosphonate-, urea-, and
thiol-based subclasses. Among urea-based GCPII inhibitors, DCIBzL
(Fig. 1) exhibited unique binding mode in the active site of GCPII.
The additional S1 accessory pocket with its maximum observed
size of 7 Å ꢀ 8.5 Å ꢀ 9 Å could accommodate the 4-iodophenyl
group of DCIBzL, thus contributing to its extremely high affinity
for GCPII.43 Structural studies suggested that this accessory pocket
can have variable size, that is, defined by the concerted reposition-
ing of the Arg536, Arg534 and Arg463 side chains. At the same
time, it is not clear, whether an even bigger opening of this pocket
is possible, allowing for the accommodation of even larger
hydrophobic moieties. To test this hypothesis as well as to
synthesize more lipophilic GCPII inhibitors than DCIBzL, we
designed and synthesized two novel carborane-based GCPII
inhibitors, where the p-iodobenzene ring of DCIBzL was replaced
with a closo o- or m-carborane cluster.
X-ray structures of GCPII–ligand complexes identified two prin-
cipal specificity pockets that contribute prominently to interac-
tions between the enzyme and its inhibitors/substrates. The S10
(or pharmacophore) pocket serves as a glutamate-recognition site
ensuring high specificity as well as affinity for glutamate-contain-
ing small-molecules that serve as GCPII-specific inhibitors.38,39 The
most prominent feature of the S1 pocket, which is located in the
entrance funnel of GCPII, is the presence of a positively charged
arginine patch and electrostatic interactions between arginine
guanidinium groups and negatively charged P1 functionalities of
inhibitors contribute markedly to their affinity towards GCPII.38,40
In addition, the ‘S1 hydrophobic accessory pocket’ and the
arene-binding site were identified as important structural features
that could be used in the design of high affinity GCPII-specific
probes.41 Here, we determine and analyze the X-ray crystal
structure of GCPII in complex with a carborane-containing ligand,
and further discuss the interaction between the carborane-based
inhibitor and the GCPII protein.
O
O
O
H
O
O
H
O
H
O
O
O
H
N
H
N
H
N
H
N
H
N
H
N
H
O
H
O
H
O
O
O
O
H
O
O
H
O
O
H
O
O
I
HN
HN
HN
: C
O
O
O
: C-H
vertex: B-H
z
D
C
IB L
1
2
Figure 1. Chemical structure of DCIBzL and carborane-containing GCPII inhibitors 1 and 2.
O
O
O
H
N
H
N
O
O
O
O
c
1
HN
a
O
O
O
O
O
H
N
H
N
4
O
O
ref. 44
O
NH3Cl
O
O
O
3 steps
O
O
NH2
b
O
O
H
N
H
N
3
O
O
c
O
O
2
HN
O
5
Scheme 1. Synthesis of carborane-containing GCPII inhibitors. Reagents and conditions: (a) 1,2-dicarba-closo-dodecaborane-1-carboxylic acid, HATU, TEA, DMF, rt, 12 h, 30%;
(b) 1,7-dicarba-closo-dodecaborane-1-carboxylic acid, HATU, TEA, DMF, rt, 12 h, 25%; (c) TFA/CH2Cl2, rt, 4 h, 44% for 1 and 32% for 2.

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S. Youn et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5232–5236
Table 1
Comparison of hydrogen-bonding distance between GCPII and 1 and DCIBzL
Amino acids
Distance (Å)
DCIBzL
1
Arg210
Asn257
Glu424
Gly518
Asn519
Arg534
Arg536
Tyr552
Lys699
Tyr700
2.72
2.85
3.02
2.91, 3.10
2.92
2.66
2.96
2.92
3.05, 3.03
2.92
2.92
2.91
2.84, 3.01
2.67, 3.13
2.64
2.81, 2.98
2.66, 3.15
2.69
2.62
2.55
Figure 2. In vitro GCPII inhibition of DCIBzL and compounds 1–2.
scaffold 3 was synthesized from commercial protected
L-lysine
and -glutamic acid in 3 steps by applying a previously published
L
method.44 Another starting materials, the carboxylic acids of closo
o-carborane and m-carborane were synthesized in 1 step by using
the reported synthetic procedure (see Supplementary data).45
Briefly, treatment of closo-carborane with n-BuLi, followed by the
addition of dry ice, afforded o-, m-carboranyl acid in 70% and 72%
yield, respectively. Reaction of 3 with o- and m-carboranyl acids
under the traditional peptide coupling conditions (HATU and DIPEA
in DMF) afforded 4 and 5 in moderate yield, respectively. The low
coupling yield in both cases was due to the bulkiness of closo-
carboranyl acid which prevented the carboxylic acid group being
activated by HATU. Deprotection of the t-butyl groups of 4 and 5
was achieved by the treatment of TFA at room temperature for 4 h
to give the corresponding ligands 1 and 2, respectively. The
compounds 1 and 2 were fully analyzed by 1H NMR, 13C NMR, HPLC
and ESI-MS. The ESI-MS spectra for 1 and 2 showed a [MꢁH]ꢁ peak
at 488.3 in the negative mode with the typical isotope distribution
pattern of the carborane cluster (see Supplementary data).
To compare the relative lipophilicity of 1 and 2 with DCIBzL, the
retention time of the compounds were determined by reversed-
phase HPLC with an isocratic mode (65% water/35% acetonitrile,
0.1% formic acid). Compounds 1 and 2 were eluted at 11.37 and
11.38 min, respectively, while DCIBzL was collected at 4.02 min
(see Supplementary data). This result indicated that the closo-carborane
cluster is more lipophilic than the 4-iodobenzene ring, resulting in
Figure 3. Comparison of the binding modes of DCIBzL and 1 in the internal pocket
of human GCPII. Complexes of the GCPII/inhibitor were superimposed on to
corresponding Ca atoms of the enzyme. Inhibitors are in stick representation, with
atoms colored red (oxygen), blue (nitrogen), violet (iodine), and pink (boron).
Carbon atoms are colored green (compound 1) and yellow (DCIBzL). The zinc ions
are shown as orange spheres and selected parts of GCPII are shaded gray.
The synthetic scheme for the preparation of the carborane-
containing GCPII inhibitors is outlined in Scheme 1. Lys-urea-Glu
Figure 4. Interactions between compound 1 and key amino acid residues in the active site of GCPII.

S. Youn et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5232–5236
5235
Figure 5. Fo-Fc electron density map of compound 1 in the active site of GCPII.
the delayed retention time of 1 and 2 as compared with DCIBzL.
With the aim of characterizing compounds 1 and 2 as surrogates
of DCIBzL, the interaction pattern between the closo-carborane cage
and the residues lining the entrance funnel of GCPII was investi-
gated. This data could in turn be used for the rational design of
carborane-based bioactive molecules. To this end, we first deter-
mined inhibition constants for the carborane-containing inhibitors
using a fluorescence polarization assay46 and the acquired data are
shown in Figure 2. The IC50 values for compounds 1 and 2 were
20.5 nM and 15.6 nM, respectively, while the IC50 for DCIBzL as a
control was determined to be below 1 nM which is the detection
limit of the assay. In fact, earlier studies using a fluorescence- or
radiometry-based assay reported the IC50 value for DCIBzL to be
0.04 nM.43
linker and the carborane cluster of 1 adopt several alternate
conformations within the GCPII entrance funnel. The Fo-Fc map
for this part of the inhibitor is somewhat weaker compared
with the urea-glutamate part, implying the higher flexibility of
the former (Fig. 5). This observation is further supported by the
substantial increase in temperature factors for atoms of the
hexanoyl-carborane fragment. Combined data clearly showed that
the carborane cluster cannot engage the S1 accessory pocket
similarly to the p-iodophenyl group of DCIBzL due to the steric
bulkiness of the carborane cluster. Apparently, the polyhedral
shape of the carborane cluster with a diameter of approximately
7.1 Å is too big to fit into the S1 accessory pocket, and the size of
the pocket observed in the GCPII/DCIBzL complex is likely close
to its maximum volume and cannot be further enlarged to
In order to provide a mechanistic explanation for carborane-
based inhibitors, we determined the X-ray structure of the
GCPII/compound 1 complex at a resolution of 1.79 Å (PDB ID:
4OME) and compared it to the structure of the GCPII/DCIBzL com-
plex reported previously (PDB ID: 3D7H).43 The common denomi-
nators of both inhibitors are the presence of the P10 glutamate
connected to the P1-hexanoyl linker via a urea function serving
as a zinc-binding group (ZBG). Unsurprisingly, the positioning of
the urea-glutamate part of inhibitors is identical for both struc-
tures and follows the ‘canonical’ interaction pattern within the
S10 pocket and the vicinity of the active-site zinc ions (Fig. 3).
Additionally, the P1 carboxylate present in both inhibitors
forms an identical set of hydrogen bonds with the guanidinium
groups of Arg536 (2.8 Å and 3.0 Å), Arg534 (2.9 Å), and the amido
group of the Asn519 side chain (2.9 Å) as shown in Figure 4 and
summarized in Table 1. The positioning of the remaining distal
parts of both inhibitors, however, differs markedly. In the case of
DCIBzL, the hexanoyl linker connecting the terminal p-iodophenyl
group to the ureido function was fully visible in the electron den-
sity map, as its conformational space is restricted by the ureido/P1
carboxylate at one side and the p-iodophenyl group inserted into
the S1 accessory pocket at the other side, respectively.
accommodate bigger functionalities. The absence of cation–p
stacking interactions between the carborane cage and the GCPII
residues in the S1 accessory pocket thus explains the decreased
affinity of compound 1 compared with DCIBzL. However, the major
advantage of the carborane cluster not being buried within the
GCPII structure is the fact that its positioning and orientation
enables the cage to be further modified to the halogenated cluster
labelled with 76Br, 125I, or 131I for imaging or therapy.47
In summary, we designed and synthesized novel carborane-
containing urea-based inhibitors of GCPII. The X-ray crystal struc-
ture of GCPII in complex with the carborane-based inhibitor was
determined at 1.79 Å resolution. As the bulky closo-carborane
cluster is located in the spacious entrance funnel region of GCPII,
the current carborane-containing compounds can be further
structurally modified to identify promising lead structures of novel
GCPII inhibitors.
Acknowledgements
We thank J. Cerny and G. Murshudov for their help with
the preparation of coordinate and restrains library files. C.B.
acknowledges support from the Czech Science Foundation (Grant
No 301/12/1513). Z.N. acknowledges support from the program
‘‘Biotechnological expert in structural biology and gene
expression” (Reg #: CZ.1.07/2.3.00/30.0045). The use of MX 14.2
was in part funded by the Helmholtz-Zentrum Berlin and
In fact, it is the intimate contact between the terminal
p-iodophenyl group and the residues shaping the S1 accessory
pocket that contributes to the increased affinity of DCIBzL for GCPII.
Conversely, the structure of GCPII/1 suggests that the hexanoyl

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S. Youn et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5232–5236
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Supplementary data
Supplementary data (experimental procedures and analytical
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