Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.12.090

A small library of 36 functionalized benzophenone thiosemicarbazone analogs has been prepared by chemical synthesis and evaluated for their ability to inhibit the cysteine proteases cathepsin L and cathepsin B. Inhibitors of cathepsins L and B have the potential to limit or arrest cancer metastasis. The six most active inhibitors of cathepsin L (IC₅₀ < 85 nM) in this series incorporate a meta-bromo substituent in one aryl ring along with a variety of functional groups in the second aryl ring. These six analogs are selective for their inhibition of cathepsin L versus cathepsin B (IC₅₀ > 10,000 nM). The most active analog in the series, 3-bromophenyl-2′-fluorophenyl thiosemicarbazone 1, also efficiently inhibits cell invasion of the DU-145 human prostate cancer cell line.

Full text of DOI:10.1016/j.bmcl.2009.12.090

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1415–1419
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and biological evaluation of potent thiosemicarbazone
based cathepsin L inhibitors
G. D. Kishore Kumar a, Gustavo E. Chavarria a, Amanda K. Charlton-Sevcik a, Wara M. Arispe a,
Matthew T. MacDonough a, Tracy E. Strecker a, Shen-En Chen a, Bronwyn G. Siim b, David J. Chaplin b,
Mary Lynn Trawick a, Kevin G. Pinney a,
*
a Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, USA
b OXiGENE Inc., Magdalen Center, Robert Robinson Avenue, The Oxford Science Park, OX4 4GA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A small library of 36 functionalized benzophenone thiosemicarbazone analogs has been prepared by
chemical synthesis and evaluated for their ability to inhibit the cysteine proteases cathepsin L and
cathepsin B. Inhibitors of cathepsins L and B have the potential to limit or arrest cancer metastasis.
The six most active inhibitors of cathepsin L (IC50 < 85 nM) in this series incorporate a meta-bromo sub-
stituent in one aryl ring along with a variety of functional groups in the second aryl ring. These six ana-
logs are selective for their inhibition of cathepsin L versus cathepsin B (IC50 > 10,000 nM). The most active
analog in the series, 3-bromophenyl-20-fluorophenyl thiosemicarbazone 1, also efficiently inhibits cell
invasion of the DU-145 human prostate cancer cell line.
Received 2 December 2009
Revised 23 December 2009
Accepted 24 December 2009
Available online 6 January 2010
Keywords:
Inhibitors of cathepsin L
Inhibitors of cathepsin B
Chemical synthesis
Molecular design
Ó 2010 Elsevier Ltd. All rights reserved.
Molecular modeling
The papain family of proteases includes a subfamily of eleven
human lysosomal cysteine peptidases known as the cathepsins
(B, C, F, H, K, L, O, S, V, W and X).1 Although the first cathepsin
was discovered in the 1940s, cathepsin C, these cysteine proteases
have only been more thoroughly characterized structurally and
biologically in the last 10–15 years.2 Several of these proteins are
responsible for the degradation of the extracellular matrix (ECM)
in addition to other physiological processes such as intracellular
protein turnover. Recent studies have shown that specific cysteine
proteases, such as cathepsins B and L, participate in tumor progres-
sion, hyperproliferation, apoptosis, angiogenesis and metastasis by
malignant cells.3 Cathepsins L and B have a broad tissue distribu-
tion and are overexpressed in several human tumors including
breast, prostate, lung, gastrointestinal, and epidermal.4 Therefore,
cysteine proteases are of special interest as targets for the develop-
ment of novel chemotherapeutic drugs.5
Cathepsin L is a globular endosomal cysteine protease that plays
a vital role in biological and physiological processes such as bone
remodeling, cancer metastasis, tumor cell invasion, rheumatoid
and osteo-arthritis.6 Cathepsin L also catalyzes the hydrolytic
cleavage of specific peptide bonds involved in antigen processing,
bone resorption, and turnover of proteins. Cathepsin L activity
has also been reported to be involved in diseases such as Ebola
hemorrhagic fever,7 severe acute respiratory syndrome (SARS),8
and Leishmania.9 Inhibitors of cathepsin L-like cysteine proteases
also have potential utility in the treatment of protozoan infections
such as trypanosomiasis and malaria.10
Cathepsin B is characterized by a dual function as a lysosomal
endopeptidase and as an exopeptidase.11 In addition to facilitating
ECM and basal membrane degradation, cathepsin B also plays an
important role in promoting invasion of certain solid tumors.12
Overexpression of cathepsins L and B contributes to the migration
of cancer cells into surrounding tissue resulting in further
metastasis.13
The thiosemicarbazone moiety has been recognized as a func-
tional group that presumably interacts with the cysteine-25 resi-
due in the active site of the cathepsin L-like cysteine protease
cruzain from the protozoan Trypanosoma cruzi.14 Recent studies
by our group and others have demonstrated the effectiveness of
the thiosemicarbazone moiety (I & II) for inhibition of cathepsin
L ( Fig. 1).14f,15 In addition, a variety of other small molecules
including peptidic: thiocarbazate (III),16 aldehyde (IV),17 epoxide
(V),18 nitrile (VI),19 cyanopyrrolidine (VII)20 and non-peptidic:
azepanon (VIII)21 and cyanamides (IX)4 have been identified as
inhibitors of cathepsin L (Fig. 1).
Previous work10,14a,d,15a has explored the role of functionalized
benzophenone thiosemicarbazone analogs as inhibitors of cruzain
and rhodesain with potential application in the treatment of
Chagas’ disease, sleeping sickness, and malaria. In order to
* Corresponding author. Tel.: +1 254 710 4117; fax: +1 254 710 4272.
E-mail address: Kevin_Pinney@baylor.edu (K.G. Pinney).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.090

1416
G. D. Kishore Kumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1415–1419
S
N
NH2
NH
S
N
NH2
NH
O
O
H
N
BocHN
S
N
H
N
H
CF3
Br
O
Et
HN
Me
CF3
(III)
(II)
(I)
H
N
O
NH
H
N
NH
CN
O
H
CONH
H
CONH(CH2)4NH
CHO
NH2
SO2HN
O
CONH
O
HO2C
(V)
(IV)
Cl
(VI)
O
S
O
H
O
O
HN
H
N
HN
N
N
O
O
N
H
N
S
O
O
O
O
N
CN
N
CN
(VII)
(VIII)
(IX)
Figure 1. Representative peptidic and non-peptidic inhibitors of cathepsin L.
evaluate the efficacy of selected benzophenone thiosemicarba-
zone derivatives as reversible inhibitors of cathepsins L and B, a
series of analogs was prepared by chemical synthesis as detailed
in Scheme 1. Briefly, the appropriate acid chloride was converted
to its corresponding Weinreb amide and then reacted with a Grig-
nard reagent (formed from dibromobenzene) to yield the requi-
site ketone. A condensation reaction with thiosemicarbazide in
the presence of para-toluenesulfonic acid resulted in formation
of the desired thiosemicarbazone analogs.
Most of the unsymmetrical benzophenone analogs gave two
peaks (major and minor) in the HPLC trace consistent with either
(i) formation of E and Z isomers14d around the carbon–nitrogen
double bond or (ii) exchange of a bromine atom for hydrogen
during the Grignard addition. For example, analog 1 showed
two peaks in the HPLC trace suggesting the existence of E/Z iso-
mers. However, LC–MS confirmed that the minor peak in the
HPLC trace of analog 1 represents hydrogen replacing bromine.
It is important to note that with other compounds distinct peaks
in the HPLC trace correspond to both E and Z isomers as well as
hydrogen replacing a bromine atom (see Tables 1 and 2 and Sup-
plementary data).
In general, cysteine proteases are small monomeric proteins
with an average mass of approximately 30 kDa. Structurally, the
cathepsins consist of two domains (left and right) with a V-
shaped active site cleft located along the domain interface.22 This
site contains two active residues, a Cys-25 located on the left do-
main and a His-159 located on the right domain which together,
form a stable thiolate-imidazolium ion pair required for the en-
zyme’s activity.4 Molecular modeling of the most active analog
1 with cathepsin L showed that the conformation with the most
favorable relative interaction energy places the bromophenyl ring
deep in the S2 pocket with the thiosemicarbazone in close prox-
imity to the active site Cys-25 (Fig. 2). The thiosemicarbazone is
oriented at the active site by two hydrogen bonds between the
O
Cl
X'
a
Me
N
H
S
N
N
O
R
OMe
NH
O
Br
MgBr
X'
d
b
X'
X'
X
X
X
X
c
X = F, Br
X' = F, Cl, Br, CF3, Me
R = H, Ph, CH2Ph, Et
Scheme 1. Synthesis of benzophenone based thiosemicarbazone derivatives. Reagents and conditions: (a) HClꢀNH(OMe)Me, Et3N, CH2Cl2, rt, 3–4 h; (b) Mg, Et2O, reflux,
1–2 h; (c) Et2O, rt, 3–6 h; (d) NH2NHCSNHR, para-toluenesulfonic acid, MeOH, reflux, 6–12 h.

G. D. Kishore Kumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1415–1419
1417
Table 1
Inhibition of human cathepsins L and B by substituted 3-bromobenzophenone thiosemicarbazone derivatives 1–23
R1
R2
IC50 (nM) Cat Lb
IC50 (nM) Cat Bb
S
N
NH2
NH
Isomer ratio estimated
by HPLCa
H replaced by Br
(% determined by HPLC)
R2
A
B
R1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
H
2-F
2-Cl
2-Br
2-Me
3-F
NDc
ND
9
30.5
1610
2600
>10,000
250
131
46.5
224
79.6
327
>10,000
521
2160
83.8
610
59.4
415
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
5690
>10,000
>10,000
>10,000
>10,000
1590
>10,000
>10,000
>10,000
>10,000
>10,000
2.3
ND
1.5
1.7
1.2
6
NAd
ND
ND
ND
1:0.7
1:0.4
1:0.9
ND
ND
ND
1:1
1:0.1
1:0.4
1:0.5
1:0.8
ND
ND
ND
1:0.5
ND
NA
3-Cl
3-CF3
3-Me
4-F
4-Cl
4-Br
4-CF3
4-Me
2,3-F
2,6-F
3,5-F
3,5-Cl
3,5-CF3
3-Br,2-F
3-Br,4-F
3,4,5-F
2,3,4,5-F
2-F
8
1.3
8.3
2.4
2.2
1.5
ND
ND
1.1
1.4
2.2
10
7
96.0
233
114
118
63.2
>10,000
4
1.1
ND
a
b
c
E/Z isomer not assigned.
2% DMSO.
ND = not detected.
NA = not applicable.
d
Table 2
Inhibition of human cathepsins L and B by substituted 4-bromobenzophenone thiosemicarbazone derivatives 24–30
Isomer ratio estimated by HPLCa
H replaced by Br (% determined by HPLC)
IC50 (nM) Cat Lb
IC50 (nM) Cat Bb
S
N
NH2
NH
R
A
B
R
Br
24
25
26
27
28
29
30
2-F
2-Br
4-F
4-Cl
4-Br
4-CF3
4-Me
NDc
ND
1:0.8
ND
ND
1:0.6
1:0.6
1.2
ND
2.1
8
ND
6
2220
>10,000
3320
>10,000
>10,000
>10,000
4570
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
1.9
a
b
c
E/Z isomer not assigned.
2% DMSO.
ND = not detected.
NH and NH2 groups and the enzyme Asp-162 (Fig. 2). Details
regarding the molecular modeling studies can be found in the
Supplementary data.
All 36 thiosemicarbazone analogs were evaluated based on
their ability to inhibit both cathepsin L and cathepsin B in separate
assays (Tables 1–3). The most active inhibitors of cathepsin L all
contain a 3-bromo functionality in one of the aryl rings (Table 1).
Activity against cathepsin L decreases dramatically when the
A-ring bromide is located at the 4-position (Table 2), as observed
stituent at the 3-position. Additional fluorine substituents in the B-
ring tend to provide compounds that are potent inhibitors of
cathepsin L (analogs 14, 16 and 22), although certain substituent
patterns are less desirable in terms of cathepsin activity (analogs
15 and 21). Analog 23 (nor-3-bromo, 20-fluoro) is an important
control compound verifying that the strong inhibitory activity of
analog 1 (3-bromo, 20-fluoro) against cathepsin L is due to this
compound itself and not the inseparable by-product (H replacing
Br).
in a comparison of analog 1 (IC50 = 30.5 nM) with 24 (IC50
=
In an effort to extend the binding of the inhibitors from the S2
to the S10 pockets of the enzyme, three analogs were prepared,
which are functionalized with phenyl, benzyl, and ethyl at the
terminal nitrogen of the thiosemicarbazone moiety. Unfortu-
nately, these analogs were not effective inhibitors of cathepsin L
(Table 3).
2220 nM). Within the 3-bromo A-ring series, as the functional
group at position 2 in the B-ring is varied (F, Cl, Br, and Me) the
activity decreases substantially. A fluorine substituent at positions
2 or 4 in the B-ring leads to compounds that are more active inhib-
itors of cathepsin L compared to analogs containing a fluorine sub-

1418
G. D. Kishore Kumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1415–1419
Compared with analog 1, the activity against cathepsin L de-
creases when the A-ring aryl bromide is replaced with aryl fluoride
(Table 4).
With the exception of compounds 13 and 18, none of the
synthetic analogs showed appreciable activity against cathepsin
B, thus demonstrating the selectivity of this series of analogs
against cathepsin L. The best cathepsin L inhibitor in this new li-
brary, analog 1, was also an effective inhibitor of DU-145 cell
invasion and migration indicating that this compound may find
application as a therapeutic agent against cancer metastasis.
Since chronic dosing would likely be required of such an anti-
metastatic treatment, it is important that such compounds dem-
onstrate low cytotoxicity. Three of the analogs were tested
against selected human cancer lines and found to exhibit low
cytotoxicity (Table 5).23
In summary, a small library of 36 functionalized thiosemicarba-
zone analogs was prepared by chemical synthesis and each com-
pound was evaluated for its inhibitory activity against cathepsins
L and B. The activity of six of these analogs (1, 7, 9, 14, 16, and
22) against cathepsin L is especially noteworthy, and suggests that
Figure 2. Analog 1 modeled at active site of cathepsin L [enzyme: oxygen (red),
carbon (green), nitrogen (blue), hydrogen (white); analog 1: carbon (cyan), nitrogen
(purple), sulfur (yellow), hydrogen (lavender)].
Table 3
Inhibition of human cathepsins L and B by N-substituted 3,30-dibromobenzophenone thiosemicarbazone derivatives 31–33
H
Isomer ratio estimated by HPLCa
IC50 (nM) Cat Lb
IC50 (nM) Cat Bb
H replaced by Br
(% determined by HPLC)
R
S
N
N
R
NH
A
B
Br
Br
31
32
33
Ph
CH2Ph
CH2CH3
NA
NA
NA
NA
NA
NA
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
NA = Not applicable.
a
E/Z isomer not assigned.
2% DMSO.
b
Table 4
Inhibition of human cathepsins L and B by difluoro-substituted benzophenone thiosemicarbazone derivatives 34–36
R1
R2
Isomer ratio estimated by HPLCa
H replaced by Br (% determined by HPLC)
IC50 (nM) Cat Lb
IC50 (nM) Cat Bb
S
N
NH2
NH
R1
R2
A
B
34
35
36
2-F
3-F
4-F
40-F
30-F
40-F
NA
NA
NA
NA
NA
NA
2460
4870
>10,000
>10,000
>10,000
>10,000
NA = not applicable.
a
E/Z isomer not assigned.
2% DMSO.
b
Table 5
Cytotoxicity, invasion and migration for analogs 1, 5, and 6
S
N
NH2
NH
X
Cytotoxicity GI50
DU-145
(lM)
% Invasion
DU-145a
% Migration
DU-145a
NCI-H460
SK-OV-3
A
B
X
Br
1
5
6
2-F
3-F
3-Cl
23.5
26.3
23.3
13.8
29.9
15.6
ND
17.7
20.7
61.5 3.5
70.5 7.8
86.0 1.4
40.5 3.5
43.2 1.13
41.9 1.6
ND = not determined.
a
Relative to normalized control.

G. D. Kishore Kumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1415–1419
1419
13. Joyce, J. A.; Baruch, A.; Chehade, K.; Meyer-Morse, N.; Giraudo, E.; Tsai, F. Y.
Cancer Cell 2004, 5, 443.
these analogs are excellent candidates for future in vivo preclinical
studies.
14. (a) Portions of this work have been reported in the following dissertation: Siles,
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containing combrastatins and novel cysteine protease inhibitors for the
treatment of chagas. Ph.D. Dissertation, Baylor University, Waco, TX, 2006.;
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(ASBMB), Experimental Biology Meeting, San Francisco, USA, 2006 (poster
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15. (a) Portions of this work have been reported in the following dissertation:
Arispe, W. M. Inhibitors of human cathepsin L and cruzain as therapeutic
agents. Ph.D. Dissertation, Baylor University, Waco, TX, 2008.; (b) Kishore, G. D.
K.; Lindsay, J. M.; Song, J.; Matthew, M.; Elizabeth, C.; Akash, D.; Grace, Y.;
Conner, E.; Arispe, W. M.; Chavarria, G. E.; Charlton-Sevcik, A. K.; Strecker, T. E.;
Chen, S.-E.; Trawick, M. L.; Pinney, K. G. 41st National Organic Symposium,
Boulder, Colorado, USA, 2009 (poster presentation).; (c) Mallari, J. P.; Shelat, A.;
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Acknowledgments
The authors are grateful to Oxigene Inc. (Waltham, MA, grants
to M.L.T. and K.G.P.), The Welch Foundation (Grant AA-1278 to
K.G.P.), and the Department of Chemistry and Biochemistry at Bay-
lor University for generous financial support of this research, and
the National Science Foundation for funding both the Varian
500 MHz NMR spectrometer (Award CHE-0420802) and the Bruker
X8 APEX diffractometer (Grant CHE-0321214). The authors thank
Dr. Alejandro Ramirez (Mass Spectrometry Core Facility, Baylor
University) for HRMS analysis, and Dr. James Karban and Dr. Mi-
chelle Nemec (Director) for use of the shared Molecular Biosci-
ences Center.
Supplementary data
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Supplementary data (detailed experimental syntheses, 1H NMR,
19F NMR, HRMS, HPLC, full spectral characterization of analog 1,
and details regarding biological assays) associated with this article
can be found, in the online version, at doi:10.1016/j.bmcl.2009.
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