2-Arylidene Hydrazinecarbodithioates as Potent, Selective Inhibitors of Cystathionine γ-Lyase (CSE)

Article abstract of DOI:10.1021/acsmedchemlett.7b00313

Hydrogen sulfide is produced from l-cysteine by the action of both cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) and increasingly has been found to play a profound regulatory role in a range of physiological processes. Mounting evidence suggests that upregulation of hydrogen sulfide biosynthesis occurs in several disease states, including rheumatoid arthritis, hypertension, ischemic injury, and sleep-disordered breathing. In addition to being critical tools in our understanding of hydrogen sulfide biology, inhibitors of CSE hold therapeutic potential for the treatment of diseases in which increased levels of this gasotransmitter play a role. We describe the discovery and development of a novel series of potent CSE inhibitors that show increased activity over the benchmark inhibitor and, importantly, display high selectivity for CSE versus CBS.

Full text of DOI:10.1021/acsmedchemlett.7b00313

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Letter
2-Arylidene Hydrazinecarbodithioates as Potent,
Selective Inhibitors of #-Cystathionine-Lyase (CSE)
Abir Bhattacharjee, Antara Sinha, Kiira Ratia, Liang Yin, Loruhama Delgado-
Rivera, Pavel A. Petukhov, Gregory RJ Thatcher, and Duncan John Wardrop
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00313 • Publication Date (Web): 21 Nov 2017
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-Arylidene Hydrazinecarbodithioates as Potent, Selective Inhibitors
of Cystathionine-Lyase (CSE)
Abir Bhattacharjee, Antara Sinha, Kiira Ratia, Liang Yin, Loruhama Delgado-Rivera, Pavel A
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†,‡
†,‡
#
#
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#
†
Petukhov, Gregory R. J. Thatcher, and Duncan J. Wardrop*
†Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago, Illinois 60607, United States
#Department of Medicinal Chemistry & Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at
Chicago, 833 S. Wood St., Chicago, IL 60612, United States
KEYWORDS. Cystathionine γ-lyase, cystathionine -synthase, hydrogen sulfide, 2-pyridyl thiosemicarbazones.
ABSTRACT: Hydrogen sulfide is produced from L-cysteine by the action of both cystathionine-lyase (CSE) and cystathionine -
synthase (CBS) and increasingly has been found to play a profound regulatory role in a range of physiological processes. Mounting
evidence suggests that upregulation of hydrogen sulfide biosynthesis occurs in several disease states, including rheumatoid arthritis,
hypertension, ischemic injury, and sleep-disordered breathing. In addition to being critical tools in our understanding of hydrogen
sulfide biology, inhibitors of CSE hold therapeutic potential for the treatment of diseases in which increased levels of this gasotrans-
mitter plays a role. We describe the discovery and development of a novel series of potent CSE inhibitors that show increased activity
over the benchmark inhibitor and, importantly, display high selectivity for CSE versus CBS.
In mammals, the pyridoxal-5-phosphate (PLP)-dependent en-
zyme cystathionine -lyase (CSE) mediates the conversion of
cystathionine to hydrogen sulfide (H S) through the intermedi-
2
acy of L-cysteine (Cys). Together with cystathionine -syn-
thase (CBS) and, to a lesser extent, 3-mercaptopyruvate sul-
furtransferase (3-MST), CSE is the principle source of endog-
2
enous H S which has been found to play an important regula-
tory role in a wide array of physiological processes such as in-
flammation, blood pressure homeostasis, neuromodulation,
1
2
3
4
5
6
7
8
cytoprotection and aging.
Upregulation of CSE and increased H
implicated in several disease states, including inflammatory
joint disease, chronic obstructive pulmonary disease, Alz-
heimer’s disease, and endotoxemia. Reducing H
through inhibition of the enzymes involved in its production has
been found to hold promise as a therapeutic intervention.
Notably, the benchmark CSE inhibitor, L-propargyl glycine (L-
PAG, 1) normalizes breathing and reduces hypoxia induced hy-
pertension in rodent models of sleep-disordered breathing, sug-
2
S biosynthesis has been
Figure 1. Chemical structure and IC50 values of selected inhibitors
of cystathionine γ-lyase (CSE). Compounds 1-3 and 6 show some
degree of selectivity for CSE over cystathionine -synthase (CBS).
9
2
S levels
10,11
Since the discovery of compound 1 as a mechanism-based in-
1
3
14
hibitor (IC50 = 40 M) in 1976, few inhibitors of CSE have
been identified and only a limited number of these display se-
lectivity over CBS. Furthermore, many of these molecules have
significant drawbacks, e.g. compound 1 also acts as an inhibitor
of alanine monotransferase and aspartate aminotransferase at
gesting that inhibition of H
body may be a new approach to treat hypertension in patients
2
S biosynthesis within the carotid
1
2
with sleep apnea (Figure 1). The development of inhibitors
that display selectivity between CSE and CBS is also of im-
portance because expression of these enzymes is more wide-
spread and less tissue specific than once thought. The future de-
lineation of the roles individually played by CSE and CBS will
be dependent on the availability of selective inhibitors.
1
5
the concentrations employed, while -cyanoalanine (BCA, 2)
1
6
is a neurotoxin. The inherent polarity of these amino acids is
an additional drawback to their use since it leads to poor cell
permeability.
The paucity of selective CSE inhibitors is a significant impedi-
ment to the study of H
2
S pathways and has prompted consider-
able recent interest in this area. In 2016, the natural product L-
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-(2-aminoethoxyvinyl)glycine (AVG, 3)17 was reported by
Page 2 of 6

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9
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5
6
Asimakopoulou and Panopoulos, to be a selective inhibitor of
CSE (IC50 = 1.1 M) versus CBS, although its selectivity
against other PLP-dependent enzymes remains to be deter-
1
3
mined. In 2013, high throughput screening (HTS) efforts by
Zu identified iminoquinolinone derivative NSC111041 (4) as
1
8
an inhibitor of CSE (IC50 = 6.3 M), while Pastore
and Caliendo have recently reported the development of N-pro-
1
9
pargyl D-cysteine derivative 5 (IC50 = 30 M). Interestingly
D-penicillamine (6), which has previously been employed clin-
ically to alleviate the symptoms of rheumatoid arthritis, has also
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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9
0
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0
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2
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0
1
2
3
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5
6
7
8
9
0
been reported to selectively inhibit CSE, albeit weakly (IC50
=
20
0
.27 mM).
As part of a program to develop therapeutic agents for sleep-
disordered breathing, we recently initiated a search for small-
molecule inhibitors of CSE that display selectivity over CBS.
In this communication, we report the discovery of a series of -
pyridyl alkylthio(thiocarbonyl)hydrazones that not only po-
tently inhibit CSE, but display high selectivity over CBS. Thi-
osemicarbazones and their metal complexes display a range of
Figure 2. Structural identity of high-throughput screening (HTS)
hit. (a) Reported chemical structure of library hit compound 7. (b)
Revised chemical structure 9, established through synthesis, and
associated data of this cystathionine-lyase (CSE) inhibitor. 2-
Pyridyl thiosemicarbazones can exist in syn (8) and anti (9) iso-
meric forms, which interconvert in protic solvents. The anti-iso-
mers are thermodynamically favored. (c) CSE and CBS activity as-
says, measuring H S production in the presence and absence of
2
compound 9 (40 µM) showing selectivity for CSE over CBS. Using
this AMC assay, IC50 ~1-2 µM for CSE.
2
1
biological activities, including antibacterial and anti-cancer
2
2-24
properties,
terest.
for which they are the subject of considerable in-
To identify inhibitors, recombinant human CSE was screened
against >100,000 compounds from several commercial collec-
tions, including ChemDiv, Chembridge, Maybridge, and Prest-
wick. The high-throughput primary assay monitored CSE activ-
ity by detecting production of L-cysteine from the cleavage of
L-cystathionine, using the thiol-reactive fluorogenic probe,
Having identified 9 as a promising hit, we now sought to opti-
mize the inhibitory activity of this compound, through chemical
modification, and examine the structure-activity relationships
CPM
(7-diethylamino-3-(4-maleimidylphenyl)-4-methyl-
coumarin). Compounds were screened in duplicate at a concen-
(SAR). Thus, a library of thirty-two analogues (17-55) were
tration of 40 M, and those displaying >30% enzyme inhibition
synthesized following the general strategies outlined in Scheme
(243 compounds) were validated in secondary assays. Remain-
26
1
. Employing the one-pot method of Busch, reaction of carbon
ing positive hits (22 compounds) were repurchased and then as-
sessed for inhibitory activity against CSE- and CBS-catalyzed
H S production, using the hydrogen sulfide selective probe, 7-
2
disulfide, hydrazine hydrate and alkyl halides 10 in the presence
of base, generated the corresponding S-alkyl dithiocarbazates
11, which underwent condensation with aldehydes and ketones
12 to generate hydrazones 15 as single diastereomers. Alterna-
tively, treatment of hydrazones 13 with carbon disulfide gener-
azido-4-methylcoumarin (AzMC) (see Supporting Infor-
25
mation). From this screening effort, one compound, initially
identified as structure 7, which inhibited CSE at 40 M but
showed weak activity against CBS, was selected for further in-
vestigation (Figure 2). This hit was reconfirmed and found to
display dose dependent inhibition of CSE, with an IC50 of 6 M.
We tested the reversibility of this compound by dialysis exper-
iments (see Supporting Information) and found that compound
2
7
ated 1,3,4-thiadiazolidine-2-thiones 14, which underwent
ring-opening and exclusive S-alkylation to generate 15. While
alkylthio(thiocarbonyl)hydrazones can potentially exist in equi-
librium with 2,3-dihydro-1,3,4-thiadiazoles 16, no evidence for
13
the presence of such S,N-acetals was found in the C NMR
spectra of these products, which display characteristic carbodi-
thioate and hydrazone signals at approximately 200 and 150
ppm, respectively. In further regard to the structure of 15, alt-
hough 2-pyridyl thiosemicarbazones can exist as syn and anti-
isomers (8 cf. 9), detailed studies by Venkatachalam and co-
workers have recently shown that in protic solvents, intercon-
7
was a reversible inhibitor of CSE. Our independent synthesis
of this compound (vida infra) indicates that its structure was in-
correctly identified in the commercial library as a cyclic system,
namely 2,3-dihydro-1,3,4-thiadizole 7, rather than Schiff base
9
.
2
8
version takes place and favors the anti-isomers. In all cases,
1
13
the H and C NMR spectra of 15 displayed a set of signals
corresponding to a single diastereomer.
Scheme 1. General Synthetic Scheme for the Preparation of
a
2
-Arylidene Hydrazinecarbodithioates.
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portance of the 2-pyridyl ring at R
1
for activity, finding that sub-
stitution with 3- and 4-pyridyl systems led to an approximately
ten-fold decrease in potency in both cases. Substitution with
1
2
3
4
5
6
7
8
9
1
larger electron-rich N-heterocycles (29, 30) at R proved to be
unproductive, resulting in complete loss of activity. That the in-
troduction of 2-pyridyl isosteres, including piperazine (20), thi-
azoles (21), and pyrazoles (22, 23), at the C-2 position main-
tains activity further validates the structural requirement of a -
1
deficient 2-azaheterocyclic group at R that may act as a hydro-
gen bond acceptor. While the presence of the 2-pyridyl group is
clearly of importance, the influence of substituents on this ring
appears not to be dramatic, as indicated in the series 24-28;
compound 28, derived from 3-fluoropicolinaldehyde proved to
be the most potent member of this group. Interestingly, analogs
such as 19, derived from ketones and consequently bearing non-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
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2
2
2
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0
1
2
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9
0
1
2
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9
0
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2
3
4
5
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0
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0
aReagents and conditions: (a) R
EtOH, rt, 1-3 h; 12, rt, 3 h (60-80%); (b) CS
0%); (c) R -X (10), KOH, acetone, H O, rt, 1 h (60-80%).
-X (10), CS
, NH
, DMF, reflux, 6 h 80-
3
2
2 2 2
NH •H O, KOH,
2
9
3
2
hydrogen groups at R
2
display no significant inhibitory effects
against CSE at concentrations up to 100 M.
The results of our initial SAR study are summarized in Table
29
1
3
. Retaining the methyl group at R , we first probed the im-
a
Table 1. Structure and Cystathionine -Lyase (CSE) Inhibitory Activity of Compound 8 & Compounds 17-30
Compd
8
R1
R2
H
IC50 (M)
Compd
24
R1
R2
IC50 (M)
6
H
5
N
N
1
1
7
8
H
H
50
40
25
26
27
28
H
H
H
H
6
10
12
5
19
20
Me
H
>100
15
H
N
S
N
Me
S
R1
R2
21
H
7
29
30
H
H
>100
>100
2
2
2
3
H
H
15
6
aIC50 values were obtained as described in the Supporting Information. The values shown are the mean of a single experiment conducted in
triplicate.
now varied aryl substitution. Introduction of alkyl (32, 33) and
The results of our second SAR study are summarized in Table
. Initially retaining the 2-pyridyl group at R , the influence of
the thioether substituent (R ) was now explored. While replace-
alkoxy groups (34) at the C-4 position of the acetanilide proved
to be most productive, leading to a 3-fold increase in potency in
the case of 4-methoxyphenyl acetamide 34. The poor aqueous
solubility of several derivatives (35, 36, 47, 51) prevented anal-
ysis of SAR for these compounds. Prompted by the activity of
-fluoropyridine derivative 28, C-4 acetanilides derivatives 41-
4 where prepared. Of this series, compound 43 proved to be
the most potent CSE inhibitor found during our study with an
2
1
3
ment of the methyl group of initial hit 9 with simple alkyl, allyl
and benzyl substituents ablated all CSE inhibitory activity (data
not shown), introduction of an N-phenylacetamide group (31)
proved to be more productive. Encouraged that this substituent
resulted in equipotent activity with the parent system 9 and pro-
vided another point for introduction of structural diversity, we
2
4
IC50 of 1.2 M. The beneficial influence of the C-4 methoxy
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OMe
group is also apparent with chloropyrazole 54 and thiazole 55,
which have potency close to that found with 2-pyridyl deriva-
tive 34. Interestingly, introduction of N-arylacetamide units at
O
H
N
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
S
N
N
• CSE IC50 = 1.2 µM ± 0.1
• CBS IC50 > 500 µM
• Selectivity > 400:1
H
N
S
R
2
did increase the activity of 3-pyridyl derivatives 48 and 49
H
4
3
relative to their S-Me congener 17.
F
Figure 4. Profile of compound 43, a potent, competitive inhibitor
of cystathionine -lyase (CSE) which displays high selectivity ver-
sus cystathionine -synthase (CBS).
In conclusion, through high throughput screening of commer-
cial libraries and structure-based optimization efforts, we have
identified a series of potent, small molecule inhibitors of cysta-
thionine-lyase (CSE), one of the principle sources of endoge-
By way of example, compound 43 (Figure 4) has potency for
CSE inhibition greater than reported for L-PAG, the most
widely used inhibitor of CSE, and displays at least 400-fold se-
lectivity over inhibition of CBS. As such, it and other members
of the series reported herein are potentially valuable pharmaco-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
nous H S.
2
logical tools for the study of H S signaling.
a
Table 2. Structure and Cystathionine -Lyase (CSE) Inhibitory Activity of Compounds 31-55
Compd IC50 (M) Compd
R1
R2
R1
R2
IC50 (M)
3
3
1
2
6
2
44
45
6.0
10
3
3
3
4
3
46
15
>100b
2
47
48
N
N
35
>100b
25
12
O
H
N
3
3
6
7
>100b
3.5
49
50
S
R2
N
N
H
S
R1
H
40
N
38
39
6
51
52
53
54
>100b
3.0
1.9
2.5
2.0
4
4
0
1
6.0
2.7
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2
3
2.0
1.2
55
2.1
aIC50 values were obtained as described in the Supporting Information. The values shown are the mean of a single experiment conducted
in triplicate. Lack of activity may be due to low solubility.
b
1
1
1
1
1
1
1
1
1
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0
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0
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8
9
0
(6) Wang, Z.; Liu, D. X.; Wang, F. W.; Zhang, Q.; Du, Z. X.; Zhan, J.
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O.; Wallace, J. L. Cytoprotective Effects of Hydrogen Sulfide in Novel
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ASSOCIATED CONTENT
(
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: xxxxx/acsmedchemlett.xxxxx.
Experimental details and characterization data for the reported
compounds, NMR spectra, and biological data. (PDF)
AUTHOR INFORMATION
Corresponding Author
1
(
21, 459-488.
10) Vandiver, M.; Snyder, S. H. Hydrogen Sulfide: A Gasotransmitter
of Clinical Relevance. J. Mol. Med. 2012, 90, 255-263.
(11) Szabó, C. Hydrogen Sulphide and its Therapeutic Potential. Nat.
Rev. Drug Discov. 2007, 6, 917-935.
*
Tel: 1 312-355-1035. E-mail: wardropd@uic.edu.
Author Contributions
(
12) Yuan, G.; Peng, Y. J.; Khan, S. A.; Nanduri, J.; Singh, A.;
Vasavda, C.; Semenza, G. L.; Kumar, G. K.; Snyder, S. H.; Prabhakar,
N. R. H S Production by Reactive Oxygen Species in the Carotid Body
All authors have given approval to the final version of the manu-
script. ‡These authors contributed equally. A.B, A.S. and D.J.W.
designed and synthesized compounds; K.R., L.Y., and L. D-R
performed bioassays. P.A.P. carried out the docking studies.
D.J.W wrote the paper with input from coauthors.
Notes
2
Triggers Hypertension in a Rodent Model of Sleep Apnea. Sci. Signal-
ing 2016, 9, ra80.
(13) Asimakopoulou, A.; Panopoulos, P.; Chasapis, C. T.; Coletta, C.;
Zhou, Z.; Cirino, G.; Giannis, A.; Szabo, C.; Spyroulias, G. A.; Pa-
papetropoulos, A. Selectivity of Commonly used Pharmacological In-
hibitors for Cystathionine  Synthase (CBS) and Cystathionine  Lyase
(CSEA). Br. J. Pharmacol. 2013, 169, 922-932.
14) Abeles, R. H.; Walsh, C. T. Acetylenic Enzyme Inactivators. In-
activation of -Cystathionase, in Vitro and in Vivo by Propargylgly-
cine. J. Am. Chem. Soc. 1973, 95, 6124-6125.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(
This study was supported by the National Institutes of Health, Na-
tional Heart, Lung, and Blood Institute (1UH2HL123610) and the
UICentre for drug discovery.
(
15) Tanase, S.; Morino, Y. Irreversible Inactivation of Aspartate Ami-
notransferases during Transamination with L-Propargylglycine. Bio-
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ABBREVIATIONS
(
16) Ressler, C.; Nigam, S. N.; Giza, Y. H. Toxic Principle in Vetch.
AVG, aminoethoxyvinylglycine; CBS, cystathionine--synthase;
CSE, cystathionine -lyase; CPM, 7-diethylamino-3-(4-malei-
midylphenyl)-4-methylcoumarin; HTS, high throughput screening;
H S hydrogen sulfide; L-PAG, L-propargyl glycine; PLP, pyri-
2 ,
doxal-5’-phosphate; SAR, structure-activity relationship.
Isolation and Identification of -L-Glutamyl-l-β-cyanoalanine from
Common Vetch Seeds. Distribution in some Legumes. J. Am. Chem.
Soc. 1969, 91, 2758-2765.
(17) Pruess, D. L.; Scannell, J. P.; Kellett, M.; Ax, H. A.; Janecek, J.;
Williams, T. H.; Stempel, A.; Berger, J. Antimetabolites Produced by
Microorganisms. X. L-2-Amino-4-(2-aminoethoxy)-trans-3-butenoic
Acid. J. Antibiot. 1974, 27, 229-233.
(18) Zhou, Y.; Yu, J.; Lei, X.; Wu, J.; Niu, Q.; Zhang, Y.; Liu, H.;
Christen, P.; Gehring, H.; Wu, F. High-Throughput Tandem-Microwell
Assay Identifies Inhibitors of the Hydrogen Sulfide Signaling Pathway.
Chem. Commun. 2013, 49, 11782-11784.
(19) Corvino, A.; Severino, B.; Fiorino, F.; Frecentese, F.; Magli, E.;
Perissutti, E.; Santagada, V.; Bucci, M.; Cirino, G.; Kelly, G.; Servillo,
L.; Popowicz, G.; Pastore, A.; Caliendo, G. Fragment-Based De Novo
Design of a Cystathionine Lyase Selective Inhibitor Blocking Hy-
drogen Sulfide Production. Sci. Rep. 2016, 6, 34398.
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