Design and development of sulfonylurea derivatives as zinc metalloenzyme modulators

Article abstract of DOI:10.1039/c5ra27341b

Sulfonamide derivatives are an important class of zinc metalloenzyme inhibitors. While the sulfonylurea group is a bioisoster of sulfonamide, their effect on the modulation of metalloenzymes has never been studied. In the present work we synthesize and screen new sulfonylurea derivatives towards the zinc metalloenzymes, human Carbonic Anhydrase II (hCA II) and histone deacetylase 1 (HDAC 1). Specific sulfonylurea derivatives are found to inhibit hCA II with IC₅₀ in the nano molar to micro molar range. Docking studies indicate the binding of the inhibitors to the mouth of the active site cavity thereby blocking access to the enzyme. Surprisingly sulfonylurea derivatives exhibit activation of HDAC 1 rather than inhibition. The activation of HDAC 1 is not uniform across the derivatives tested suggesting a specific mode that depends on structural features of the compounds. Extensive research has been performed on HDAC inhibitors due to their potential as anti-cancer agents, however relatively little has been reported in terms of HDAC activation. In this work, we present the distinctly divergent behavior of the same class of molecules namely sulfonylurea derivatives with respect to hCA II and HDAC 1 and attempt to provide an understanding of the same.

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Design and Development of Sulfonylurea Derivatives as Zinc
Metalloenzyme Modulators
Received 00th January 20xx,
Accepted 00th January 20xx
Murtuza Hadianawalaa, Bhaskar Dattaa
DOI: 10.1039/x0xx00000x
www.rsc.org/
Sulfonamide derivatives are an important class of zinc of zinc metalloenzyme inhibitor especially for HDAC6 and carbonic
metalloenzyme inhibitors. While the sulfonylurea group is
anhydrase.7 While the sulfonylurea group is a bioisostere of
a
bioisostere of sulfonamide, their effect on the modulation of sulfonamide, their effect on the modulation of metalloenzymes has
metalloenzymes has never been studied. In the present work we never been studied to the best of our knowledge. In this work, we
synthesize and screen new sulfonylurea derivatives towards the investigate the ability of sulfonylurea derivatives to modulate the
zinc metalloenzymes, human carbonic anhydrase II (hCA II) and activity of zinc metalloenzymes histone deacetylase and carbonic
histone deacetylase
1 (HDAC 1). Surprisingly sulfonylurea anhydrase.
derivatives exhibit activation of HDAC 1 rather than inhibition. The
activation of HDAC 1 is not uniform across the derivatives tested
suggesting a specific mode that depends on structural features of
the compounds. Specific sulfonylurea derivatives are found to
inhibit hCA II with IC50 in the nano molar to micro molar range.
Docking studies indicate the binding of the inhibitors to the mouth
of the active site cavity thereby blocking access to the enzyme.
Histone deacetylase (HDAC) is a prominent example of zinc-
containing enzymes that have emerged as possessing significant
clinical relevance. By catalyzing the reversible acetylation of
histones, these enzymes affect chromatin structure and ultimately
play a crucial role in gene regulation.8 The covalent modification
effected by HDACs is not limited to histones alone and non-histone
proteins such as transcription factors can also undergo modification
thereby permitting further regulation of gene expression.9
Inhibitors of HDACs (also called histone deacetylase Inhibitors or
HDACIs) have been the subject of intense research as they have
been found to cause growth arrest, apoptosis or differentiation of
tumor cells.10 The beneficial role of an HDAC activator in the
treatment of chronic obstructive pulmonary disease (COPD) has
also been explored.11 The rational design of HDAC modulators
continues to hold promise not only in the context of anti-tumor
agents but also for enhancing the understanding of HDAC-mediated
gene regulation and its implication in various disease conditions.
Zinc containing metalloenzymes are implicated in a wide array of
functions such as regulation of blood pH, digestion and
transcription regulation.1 Defects in zinc metalloenzymes or
shortcomings in the modulation of their activity have been
associated with clinical conditions such as cancer, glaucoma, heart
diseases and HIV.2-4 Zinc metalloenzymes like carbonic anhydrase
(CA), angiotensin converting enzyme (ACE), and histone deacetylase
(HDAC) are prominent pharmaceutical targets for the treatment of
specific disease conditions.5 Inhibitors and activators that target
zinc metalloenzymes associated with the above disorders could be
used for the treatment of the corresponding conditions. Notable
zinc metalloenzyme inhibitors that have been developed for specific
targets include Acetazolamide as carbonic anhydrase inhibitor (CAI),
suberoylanilide hydroxamic acid (SAHA or Vorinostat) as histone
deacetylase inhibitor (HDACI) and Captopril as Angiotensin
Converting Enzyme Inhibitor (ACEI) (see Fig. 1).
The structure activity relationship (SAR) study of HDACIs has
suggested a modular architecture comprising a ZBG to chelate zinc
ion, a cap to sit at the mouth of a tunnel shaped cavity and a linker
to connect a ZBG and cap (see Fig. 2). Further, the shape of the
active site places an emphasis on the length of the linker. A shorter
chain keeps the ZBG group hanging above the zinc ion in the active
site while a longer chain restricts the cap to sit on the mouth of the
tunnel shaped cavity.12
We have designed a series of novel molecules with sulfonylurea
positioned as a ZBG, along with an alkyl linker and phenyl cap (see
Fig. 2). Notably, the ZBGs that have been explored previously have
Fig. 1 Zinc Metalloenzyme Inhibitors
resided at
a terminal section of the molecule. Since the
sulfonylureas used in present work are substituted at both ends,
the size of the groups presented in the terminal part of the
molecule is expected to play an important role. Analyses of crystal
These inhibitors generally comprise of two main parts, a zinc
binding group (ZBG) and a backbone. Hydroxamic acid is the most
common ZBG followed by carboxylic acids, thiols, phosphonates
and sulfonamides.5 Sulfonamide derivatives are an important class
structure of HDAC (mainly class I HDACs) suggests the constrained
14
nature of space near the zinc ion in the active site.13,
Thus,
a.Department of Chemistry, Indian Institute of Technology Gandhinagar, VGEC
Complex Chandkheda, Ahmedabad 382424 India. Telephone: 079-3245-9902;
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J. Name., 2013, 00, 1-3 | 1
Electronic Supplementary Information (ESI) available: Experimental procedures, full
spectroscopic data and 1H and 13C NMR spectra, DOI: 10.1039/x0xx00000x
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presence of a bulky group adjacent to the ZBG may lead to steric of scaffold to sulfonylurea.11 While all the compounds display
problems for the prospective enzyme modulators. The linker length significant percentage of activation, compound 6 appears to be an
was designed to possess four carbons so as to mimic the natural exception. Compound 1 with the smallest R group in the form of a
substrate of HDAC namely N-acetylated lysine in which a chain of methyl shows greatest activation. Increase in length of R group as
four carbons occupies the tunnel.
present in compounds 2, 3 and 4 results in decrease in activation of
HDAC. Presence of aromatic R group in compounds 6, 7, 8, 9 and 10
results in a lower percentage activation of HDAC. Docking studies
were performed to obtain an insight into the binding mode of
sulfonylurea derivatives with HDAC. Lack of crystal structures of
HDAC1 led us to use HDAC2 for the docking studies with nearly 80%
20
similarity in the structure and activity of the two isoforms.19,
Docking of 1 clearly indicates interaction of the sulfonylurea group
with the active site zinc ion of HDAC2. In addition to interactions of
1 with Gly 154 and Tyr 308, the terminal phenyl ring acts as a cap
and sits at the entrance of the cavity. These features appear to
facilitate occupation of the enzyme cavity by 1 (see Fig. 3). The
variation in activation by the sulfonylureas is interesting and is
Fig.
2
Comparison of designed molecules with general
pharmacophore for HDACIs
Synthesis of sulfonylureas with aliphatic sidechains is challenging currently being investigated in our lab along with a mechanistic
owing to the limited literature on the subject.15, 16 Our attempts to
study of activation performed by compound 1. Since our designed
use common methods for the synthesis of sulfonylureas, namely molecules contained a four-carbon linker by way of mimicking a
lysine substrate, we performed docking studies and calculated
conversion of sulfonamide into their carbamate derivatives MMGBSA based binding energy to evaluate the effect of linker
length on interaction with HDAC. Compounds designed with 1-3
treatment of sulfonamide with isocyanate in presence of base or
followed by treatment with amines, did not yield desired aliphatic
sulfonylureas. The synthesis of sulfonylurea by treatment of carbon linker lengths displayed significantly lower docking scores
sulfonyl chloride with amine in presence of cyanate has been and poor binding energy compared to compound 1. While the
18
reported previously.17,
We achieved synthesis of designed
binding pose of these shorter-linker compounds suggest proximity
and interaction of the sulfonylurea group with active site zinc ion,
the poor docking score is attributed to their ineffective capping
ability owing to the shorter linker lengths (see Supporting
Information, Table S1 and Fig S1).
aliphatic sulfonylureas by treatment of the corresponding sulfonyl
chloride with sodium cyanate in presence of base followed by
addition of amine to yield the desired compounds (Scheme 1). The
same principle has been suitably modified to generate a series of
novel aromatic sulfonylurea (Scheme 1). All the synthesized
compounds reported in Table 1 (except Compound 6) are novel.
The compounds listed in Table 1 were screened for their inhibitory
activity for histone deacetylase 1 (HDAC1) (using HDAC1 inhibitor
assay kit from Cayman Chemicals). Test compounds were first
incubated with enzyme and substrate followed by the addition of
developer. Fluorescence was recorded using excitation wavelength
of 350 nm and emission wavelength at 450 nm according to
manufacturer instructions. Surprisingly all the compounds exhibit
higher fluorescence compared to a negative control (with buffer)
while a positive control (with SAHA) shows nearly complete
inhibition of enzyme. The percentage increase in HDAC activity for
the synthesized compounds at 10 uM and 100 uM concentrations
are listed in Table 1. In order to verify that the increase in
fluorescence was not due to non-specific interference with the
screening assay, we tested our compounds against the developer,
substrate and buffer. The results obtained from these tests were in
the same range as that of other negative controls (wells with
fluorescent developer, substrate and buffer) nullifying the chance
of increase in fluorescence due to either the compound itself or
interaction of compound with fluorescent substrate. Further, the
observed variation in percentage activation for each compound
points towards he specific interaction of the compounds with
enzyme. We have located only one previous report on HDAC
activators and the compounds described therein have a similar type
Fig. 3 Binding mode of compound 1 in active site of HDAC2
2 | J. Name., 2012, 00, 1-3
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multiple isoforms is well established in several disease conditions
such as oedema,22 glaucoma,23 obesity,24 cancer,25 epilepsy and
osteoporosis.26 carbonic anhydrase inhibitors (CAIs) have been used
clinically for the treatment of glaucoma and as a diuretics drug.27
Association of membrane bound CA isoforms IX and XII to tumours
has been well established and selective inhibitors of these CA
isozymes could be potential clinical candidates for the treatment of
cancer.4 CAIs developed so far mainly comprise of sulphonamide or
its bioisostere such as sulfamates and sulfamides. These bind in
their deprotonated state to zinc metal ion present inside the active
site of CA. Recently a new class of coumarin based natural products
Fig. 4 General structure of compounds 1-10
Table 1 List of compounds synthesized and their percentage
activation of HDAC-1 at 10 uM & 100 uM concentration.
%
%
were reported as CA Inhibitors.28 These compounds show
a
%
Activation
Activation completely new mode of inhibition by binding to residues at the
of HDAC 1 entrance of active site thereby resulting in its blockage.29
(100 uM)a
Compound
R
Yield of HDAC 1
(10 uM)a
A few reports on modulation of CA activity discuss the coupling of
sulfonylurea mainly as a backbone with either sulphonamide or
coumarin (as ZBG) group. The inhibitory activity of such compounds
1
18
57
83
has been primarily attributed to binding of the sulphonamide group
with active site zinc ion.30 To the best of our knowledge there is no
report describing modulation of CA activity by sulfonylurea
2
3
14
16
22
23
31
derivatives alone.
33
CA is known to possess a 15 Ǻ deep cavity with the zinc ion seated
at the bottom.7 The tosylurido group has been suggested as
conferring isoform specificity and greater affinity.30 We thus
4
15
12
20
-
30
-
incorporate the tosyl group at one end of the designed sulfonylurea
derivatives. Synthesis of all designed compounds was achieved by
using Scheme 2 with p-toulenesulfonyl chloride as one of the
starting materials and by using various amines. Among the amines
tested, the heterocyclic amines like 2-amino benzothiazole and 2-
amino pyrazine were transformed into compounds 11 and 12.
Further, reaction with an aromatic amine such as aniline gives
compound 13, while aliphatic amines such as propyl amine, isobutyl
amine and cyclohexyl amine give compounds 14, 15 and 16,
respectively. Phenylethyl amine is used to prepare compound 17.
The secondary amine piperidine produces the corresponding
sulfonylurea 18. The compounds synthesized along with their
percentage yield are listed in Table 2.
5*
6
7
54
57
55
38
52
06
25
11
28
18
05
43
20
48
23
8
9
Compounds 11 – 18 as well as 1 - 10 were screened for their CA
modulation by monitoring esterase activity using p-nitrophenyl
acetate as a substrate.5 hCA II was selected for studies since it is
the prime target for anti-glaucoma drugs and also a physiologically
abundant isoform.21 All compounds were incubated with human
carbonic anhydrase II (hCA II) at 37 o C for about 10 min followed by
addition of substrate to start the reaction. Absorption was recorded
at 405 nm and percentage inhibition of CA activity by all test
compounds was calculated and listed in Table 2.
10
* Compound not involved in Biological assay. a Average of triplicate
The surprising activation of HDAC by sulfonylurea derivatives
prompted us to investigate the effect of these compounds on
carbonic anhydrase (CA). Carbonic anhydrases (CAs, EC 4.2.1.1) are
zinc metalloenzymes which catalyse the interconversion of carbon
dioxide and bicarbonate ion. This interconversion plays a critical
role in a variety of physiological processes such as CO2/bicarbonate
transport, pH maintenance, CO2 homeostasis, electrolyte secretion
in various tissues, biosynthetic reactions (such as gluconeogenesis,
lipogenesis and ureagenesis), bone resorption, calcification and
tumorigenicity.4 In mammals, 16 different isozymes of CAs have
been reported that show wide variation in their tissue distribution
and subcellular localization.21 Modulation in activity of individual or
Fig. 5 General structure of compounds 11-18
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Table 2 List of compounds synthesized and their percentage IC50 value of compounds showing at least 50% inhibition of hCA II
Inhibition of hCA II at 10 uM concentration and their IC50
activity at 10 uM concentration were calculated and reported in
Table 2. These compounds display a strong dose dependent
response (see Fig. 6).
%
Inhibition
of hCA II
(10 uM)b
IC50
Compound
R’
Yield
(uM)c
Determination of IC50 values of other compounds was attempted
but was unsuccessful due to their poor inhibitory property. It may
be noted that compounds 11 – 18 displayed insignificant activation
of HDAC1 (see Supporting Information, Table S3).The biological
assays highlight sulfonylurea derivatives with specific substituents
as exercising inhibitory action. To get insight into the mode of
binding and inhibition of our sulfonylurea derivatives for hCA II, we
performed a FRET-based assay using dansylsulfonamide. The assay
is based on the formation of a FRET pair between an active site
tryptophan and dansylsulfonamide that binds in the active site.31, 32
First dansylsulfonamide (25 uM) was incubated with hCA II and
FRET was observed by exciting the tryptophan at 280 nm and
recording dansylsulfonamide emission at 470 nm. Addition of
acetazolamide (competitive inhibitor with better potency) is
expected to completely replace dansylsulfonamide from the active
site. The significantly lower FRET upon addition of acetazolamide
agrees with the expected behaviour. Next, the same scheme was
used for testing compounds 12 and 13. Based on the changes in
FRET, compound 13 is able to displace dansylsulfonamide in a
manner comparable to that of acetazolamide. In contrast
11
12
13
41
45
59
10
95
86
NA
0.59 ±
0.02
0.58 ±
0.02
14
15
53
52
48
78
≥50
3.03 ±
0.4
37
21
NA
NA
16
17
18
compound
12
only
shows
partial
displacement
of
59
55
37
79
dansylsulfonamide over a period of time (see Table 3). These results
reflect the differences in ability of the compounds 12 and 13 to bind
the enzyme active site. Notably, compounds 12 and 13 display
similar magnitude of inhibition. Further, while the sulfonylurea
derivatives are likely binding in the active site, their mechanism of
inhibition could be by direct chelation of zinc akin to sulphonamides
or by blocking access to the active site such as that performed by
coumarins.
2.07 ±
0.35
NA= Not Active. b Average of triplicate. c Values were the average of
three different experiments run in triplicate ± SD.
SAR studies suggest that compounds with a four carbon linker
between the amine N and phenyl ring (Compounds 1-10) do not
show any significant modulation of hCA II activity (see Supporting
Information, Table S2). Variation in linker length between amine N
and phenyl ring shows that compounds with linker length 4 and 2
do not show any significant inhibitory property, while the
compound with no linker group namely 13 exhibits nearly complete
inhibition of hCA II. Steric effects are clearly at play in the inhibition
as evident from the behaviour of compounds 14 and 15. While 14
and 15 have minor differences in structure they exhibit dramatically
different inhibitory activities. Comparison of the activities of
compounds 13, 16 and 18 indicate planarity of the ring to be an
important factor. Loss of partial planarity in compound 18
compared to compound 13 results in a drop in inhibitory activity
which diminishes significantly in case of compound 16.
Table 3 Percentage FRET observed for dansylsulfonamide in presence
of Acetazolamide, Compound 12 and 13
Sl
No
Inhibitor (10
uM)
% FRET
% FRET
% FRET
(0 min)d
(10 min)d
(20 min)d
1
2
-
100
5
100
5
100
5
Acetazolamide
(b)
(a)
3
4
Compound 12
Compound 13
86
8
63
12
57
14
Fig. 6 Screening of compound 12 (a) and compound 13 (b) against
hCA II using its esterase activity at various concentrations.
d Errors are in range of 5-10% from three separate experiments
4 | J. Name., 2012, 00, 1-3
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Molecular docking studies were performed to understand the mode sulfonylurea derivatives were synthesized with tosylurido group as
of binding of sulfonylurea derivatives in the active site of hCA. common scaffold. Screening of sulfonylurea derivatives against CA
Docking studies were performed with compounds 12, 13, 15 and 18 reveals that compounds 12, 13, 15 and 18 exhibit nearly complete
using GLIDE (Schrodinger, LLC, NY, USA). The results show that all inhibition of CA II activity at 10 uM concentration and compound 12
four compounds bind to residues at the entrance of the cavity. This and 13 shows IC50 of approximately 600 nM. FRET based assay using
mode of binding is similar to that of recently reported coumarin dansylsulfonamide indicates that the sulfonylurea derivatives bind
derivatives, albeit the residues involved in the interactions are in the active site region. Molecular docking studies revealed that all
different.29 Binding pose analyses reveals that these compounds active sulfonylurea derivatives bind to residues at the entrance of
form a network of H-bonds with water present inside the cavity the active site thereby blocking access and resulting in enzyme
owing to their multiple hydrophilic residues. They also form H- inhibition. The results presented in this work are promising due to
bonds with residues Gln 92 and Asn 67 (see Fig. 7 and Fig S2-S4). the modular character of the compounds being prepared as well as
Docking results shed light on the inhibitory action of specific indications of their desirable steric and electronic properties.
sulfonylurea derivatives. In particular our results show that Further exploration of the current strategy will enable stronger
sulfonylurea derivatives bind to residues present at the entrance of modulators of the metalloenzymes to be developed.
the active site cavity thereby preventing access of substrate to the
active site. The compounds that fit precisely on the mouth of cavity
exhibit the best inhibition. The sulfonylurea derivatives with bulkier
Gandhinagar for financial support of the work. Experimental
or smaller substituents do not fit into the mouth of the cavity and
thus lack the inhibitory property. This mechanism explains the
acknowledged.
differences in inhibitory activity of various sulfonylurea derivatives
and especially the difference in activity of compounds 14 and 15.
Acknowledgements
B.D. would like to thank the Center for Biomedical Engineering, IIT
assistance provided by Althaf Shaik and Anuji, K.V. is gratefully
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