Acylideneoxoindoles: A new class of reversible inhibitors of human transglutaminase 2

Article abstract of DOI:10.1016/j.bmcl.2010.12.037

Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had K_i values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals.

Full text of DOI:10.1016/j.bmcl.2010.12.037

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2692–2696
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Acylideneoxoindoles: A new class of reversible inhibitors of human
transglutaminase 2
Cornelius Klöck a, Xi Jin a, Kihang Choi a, Chaitan Khosla a,b, , Peter B. Madrid c, Andrew Spencer d,
⇑
Brian C. Raimundo e, Paul Boardman e, Guido Lanza e, John H. Griffin e,
⇑
a Department of Chemistry, Stanford University, Stanford, CA 94305, USA
b Deparment of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
c Department of Medicinal Chemistry, SRI International, Menlo Park, CA 94025, USA
d Celiac Sprue Research Foundation, PO Box 61193, Palo Alto, CA 94306-1193, USA
e Numerate, Inc., 1150 Bayhill Drive, Ste 203, San Bruno, CA 94066, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of
diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxo-
indoles was identified as potent reversible inhibitors of human TG2. Structure–activity relationship anal-
ysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with
significant non-competitive character were also identified, suggesting that the compounds bind at one
or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had Ki val-
Received 16 October 2010
Revised 4 December 2010
Accepted 7 December 2010
Available online 16 December 2010
Keywords:
Transglutaminase 2
Oxoindole
ues below 1.0
lM in two different kinetic assays for human TG2, and may therefore be suitable for inves-
tigations into the role of TG2 in physiology and disease in animals.
Ó 2010 Elsevier Ltd. All rights reserved.
Celiac sprue
Structure–activity relationships
Allostery
Transglutaminase 2 (TG2), a ubiquitous member of the mam-
malian transglutaminase enzyme family, is found in intracellular
as well as extracellular environments of many organs. In the pres-
ence of Ca2+ and the absence of guanine nucleotides, TG2 adopts an
Isatin (indoline-2,3-dione) is an endogenous indole in mammals
with a range of biological activities.19,20 Our motivation to screen
this natural product as a candidate TG2 inhibitor was guided by
the hypothesis that the cyclic
a-keto amide structure of isatin
open, catalytically competent conformation, which activates
taminyl residues on proteins as acyl donors and cross-links these
to -amino groups of lysyl residues. As a result, proteolytically
resistant isopeptide bonds are formed between proteins. Hydroly-
sis of the -glutamylacyl-enzyme intermediate results in deamida-
c
-glu-
may mimic the -carboxamide group of TG2 substrates. a
c
-Keto
amides, including isatin analogs, are widely utilized as reversible
inhibitors of cysteine-dependent proteases.21 This led us to pro-
pose that isatin analogs may also be reversible inhibitors of the
cysteine transglutaminase TG2. In preliminary screening efforts,
isatin was found to be a weak, reversible inhibitor of human
TG2 (IC50 >0.25 mM), and certain five-substituted analogs with
electron-withdrawing functional groups were somewhat more
e
c
tion of the substrate.1,2 TG2 is implicated in the pathogenesis of
disorders including neurological diseases such as Huntington’s,
Alzheimer’s and Parkinson’s diseases, certain types of cancers
and renal diseases, cystic fibrosis and celiac sprue,3–8 and may
therefore be a suitable therapeutic target for one or more of these
conditions.9 Consequently, small molecule modulators of in vivo
TG2 activity are of pharmacological and medicinal interest.
Several classes of irreversible inhibitors of TG2 have been de-
scribed thus far ( Fig. 1).2,10–15 More recently, three classes of
reversible inhibitors have also been reported.16–18 Here, we present
a structure–activity relationship (SAR) analysis for a new class of
reversible inhibitors of human TG2, the acylideneoxoindoles.
active (IC50 = 65–450
5,7-difluoroisatin).
lM for 5-chloro, 5-bromo, 5-iodo, and
Using this information and data available for other classes of
TG2 inhibitors, we built a ligand-based statistical model with
which to identify new TG2 inhibitors. This model was used to
screen ChemNavigator’s iResearch library of commercially avail-
able compounds, and to prioritize compounds for acquisition and
testing. Among these were a series of symmetrical isatin dimers
(1–6), as well as three 3-acylidene-2-oxoindoles: indirubin (7),
isoindigotin (8), and methyl ketone (9) (Table 1).
Using a standard glutamate dehydrogenase (GDH)-coupled
deamidation assay with Cbz-Gln-Gly (ZQG) as the acyl donor sub-
strate,22 isatin dimers linked 6,60 (1), 5,50 (2, 3), and 1,10 (4, 5) were
⇑
Corresponding authors.
E-mail addresses: khosla@stanford.edu (C. Khosla), john@numerate.com
(J.H. Griffin).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.037

C. Klöck et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2692–2696
2693
F
NH
A
B
X
n
O
n = 1-4
H
N
O N
O
H
N
H
N
O
O
CO2H
N
X =
O
N
H
Br
N
H
N
H
O
N
H
S
O
O
N
O
O
N
O
E
F
O
S
C
D
N
N
O
O2N
N
H
F
N
N
N
N
H
O
N
O
O
O
O
NH2
G
H
HN
Ph
O
N
Ph
H
N
O
S
N
S
NH2
N
O
N2
Br
O
S
Ph
O
Figure 1. Selected TG2 inhibitors—irreversible dipeptide inhibitors (A),11 irreversible DHI-based inhibitors (B),10 irreversible DON-based substrate mimics (C),2 reversible
thienopyrimidinones (D),16 irreversible imidazolium salts (E),12,13 reversible azachalcones (F)17 and aryl-b-aminoethylketones (G and H).14,15
R2
The acylidene oxoindoles were prepared by a two-step conden-
sation–dehydration sequence from isatin or a substituted isatin
along with acetone or an aryl methyl ketone (Scheme 1). The first
step, performed under basic conditions, afforded b-hydroxy
ketones which were isolated and then dehydrated under acidic
conditions, or via the agency of methane sulfonyl chloride in pyri-
dine, to produce the acylidene oxoindole.23 All compounds were
obtained as a single stereoisomer, which was assigned as the
(E)-diastereomer based on the 1H NMR spectra, which displayed
downfield chemical shifts for the aromatic C-4 proton reso-
nances.24,25 N-Substituted compounds were prepared either via
condensation–dehydration starting from the corresponding
N-substituted isatin or via copper-mediated N-arylation of an
acylidene oxoindole.26
The inhibitory properties of the acylidene oxoindoles toward
TG2-catalyzed deamidation of ZQG were initially characterized
using the GDH-coupled assay (Table 2). We first examined a small
series of analogs of parent compound 9 bearing fluoro, chloro or
ether substituents at the 4-, 5-, 6- or 7-position of the oxoindole
system (compounds 10–14). Here, the 4-chloro analog 10
O
R1
O
N
R3
Figure 2. Acylidene oxoindoles.
found to display inhibition constants in the range of 18–40 lM,
approximately 10-fold more potent than the simple 5-haloisatins.
The linker can play a role in determining the activity of isatin
dimers: the m-xylyl and methylene-linked analogs 4 and 6 were
active whereas the p-xylyl linked analog 5, a constitutional isomer
of 4, was not. Among the 3-acylidene oxoindoles, indirubin (7) was
inactive, but isoindigotin (8) and the E-methyl ketone 9 proved to
be promising inhibitors.
To explore the potential of acylidene oxoindoles as TG2 inhibi-
tors, we undertook the synthesis of analogs of compound 9 bearing
substitution in three regions—on the aromatic oxoindole ring (R1),
at the methyl position of the ketone (R2), and on the amide nitro-
gen (R3) (Fig. 2).
exhibited the highest potency, with an IC50 value of 1.5 lM and a
Ki value of 0.7
lM.
R2
O
O
O
R1
O
R2
R1
HO
R1
R1
a
b
c
O
O
O
O
N
H
R3X
N
O
N
N
R3
R3
R3
R2
N
N
O
O
d
Cl
Cl
O
O
N
Ph
N
H
Scheme 1. Synthesis of 3-acylidene-2-oxoindoles. Top: synthesis of N1-H or N1-substituted analogs via condensation–dehydration of N1-H or N1-substituted isatins.
Bottom: synthesis of N1-substituted analogs via N-arylation of N1-H compounds: Reagents and conditions: (a) R3X (alkyl bromide or iodide), K2CO3, DMF, 16–48 h; (b)
acetone, NHEt2, 60 °C, 16 h or aryl methyl ketone, NHEt2, EtOH, rt, 2–48 h; (c) HCl, AcOH, reflux, 0.5 h or HCl, AcOH, rt, 16 h; (d) PhB(OH)2, CuSO4ꢀ5H2O, pyridine, DCM, 16 h.

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C. Klöck et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2692–2696
Table 1
Table 2
Structures and TG2 inhibitory characteristics of isatin dimers and analogs
Structures and activities of 3-acylidene-2-oxoindole inhibitors modified in all regions
Compd
IC50
(
lM)
Ki (
lM)
Compd
R =
IC50
(lM)
Ki (l
M)
O
O
10
11
12
13
14
4-Cl
5-Cl
6-F
6-OCF3
7-Cl
1.5
4.3
11
3.6
4.7
0.7
0.9
5.4
O
4
7
1
30–40
25
—
O
O
O
O
O
O
R
5
6
N
N
O
O
O
H
H
N
H
O
O
2
3
3
20-Pyridyl
30-Pyridyl
40-Pyridyl
30-Pyr-50-Br
30-Pyr-40-OMe
Ph
1.1
0.9
1.2
1.4
1.4
2.8
R
15
16
17
18
19
20
N
H
O
N
H
O
1.3
3.3
O
Cl
O
30
15
N
N
H
N
H
H
p
21
22
m-Cl
p-Cl
0.7
0.8
m
o
23
24
25
26
27
o-OMe
m-OMe
p-OMe
m-NH2
p-NH2
0.9
1.0
1.1
1.4
1.1
N
O
N
4
5
40
11
—
R
O
O
O
O
Cl
Cl
O
O
O
N
H
N
N
>250
O
28
29
30
31
Me
iPr
iBu
Ph
4.0
1.4
1.0
0.8
4.0
O
N
O
O
O
O
N
6
7
18
10
O
N
N
R
O
O
32
33
Cyclohexyl
Ph
CH2Ph
(CH2)2Ph
CONMe2
CO2Et
2.1
1.5
N
0.41
34
35
36
37
38
39
1.5
1.3
5.5
1.8
1.1
1.2
O
O
NH
O
Cl
>100
—
O
(m-CO2Me)Ph
(p-CO2Me)Ph
N
H
N
R
H
N
40
41
H
4-Br
22
0.9
12
0.4
N
42
43
44
45
46
47
48
49
5-Cl
6.0
4.8
6.3
7.9
8
9
8
41
10
O
5-Br
5-Me
5-NO2
6-Cl
6-Br
7-Cl
3.0
O
O
4
7
R
N
5
6
H
O
2.1 (70%)a
1.5 (35%)a
7.3
5.3
N
H
O
11
7-Br
2.9
N
H
Their inhibitory characteristics against TG2 were measured in the GDH assay
([TG2] = 0.5 M).
l
For IC50 values, the substrate was used at its Km = 10 mM. The errors were typically
Enzyme inhibition was measured using the coupled GDH assay ([TG2] = 0.5 lM).
For IC50 values, the substrate was used at its Km = 10 mM. The errors were typically
less than 10%.
less than 10%.
a
If partial inhibition was observed, the maximum inhibition effect is shown in
parentheses.
Using compound 10 as a new lead, we next examined the
effects of replacing the methyl group on the ketone moiety with
aromatic groups (compounds 15–27). We observed that phenyl,
substituted phenyl, pyridinyl, and substituted pyridinyl groups
were well-tolerated at this position, affording compounds with
IC50 values very similar to that of compound 10. Negligible
differences in TG2 inhibitory potency were observed among
regioisomeric pyridin-2-yl, -3-yl or -4-yl analogs (15–17), 40- or
50-substituted pyridin-3-yl analogs (18, 19), phenyl analog 20, or
phenyl analogs substituted at the 20-, 30- or 40-positions with
chloro, methoxy or amino groups (21–27).
The 4-chloro-pyridin-30-yl analog 16 was used as a scaffold to
examine the effects of substitution at the oxoindole nitrogen (com-
pounds 28–39). While methyl and dimethyl acetamido substitu-
ents led to 4- and 6-fold losses in potency for compounds 28 and
36, respectively, a range of other substituents afforded analogs that
were essentially equipotent to 16. These substituents included pri-
mary and secondary alkyl (29, 30, 32), phenyl (31), 2-phenylethyl
(34), 3-phenylpropyl (35) benzyl (33, 38, 39), and ethyl acetyl
(37) groups.
We also used compound 16 as a starting point from which to
examine more systematically the effects of substitution on the

C. Klöck et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2692–2696
2695
Table 4
0.6
0.4
0.2
Analysis of inhibition constants of selected 3-acylidene-2-oxoindolesin the GDH assay
([TG2] = 0.5 M) and the fluorescent assay ([TG2] = 15 nM),
mixed inhibition model
l
a
is the ratio Ki0/Ki in a
8 µM cpd 46
2 µM cpd 46
0 µM cpd 46
Compd
GDH-coupled assay
Fluorescent assay
Ki (
lM)
a
Ki (
lM)
a
10
11
12
16
20
28
33
40
41
43
46
0.7
>100
>100
>100
>100
>100
>100
1.8
>100
>100
>100
0.86
0.9
5.4
1.3
3.3
4.0
0.41
12
0.4
3.0
5.3
1.0
3.6
0.25
0.68
2.6
4.4
-0.4
-0.2
0.2
0.4
The larger
a
, the more competitive is the inhibition; when
a
= 1, the inhibition is
simple non-competitive and when
competitive.
a < 1, the inhibition is increasingly un-
-0.2
c(ZQG)-1 [mM]-1
Figure 3. Lineweaver–Burk analysis of the 6-chloro substituted compound 46,
confirming its non-competitive inhibitory character. Reversibility was assigned
based on the observation that preincubation of TG2 with inhibitors in the presence
of 4 mM Ca+2 for 40 min did not appreciably alter the outcome of inhibition
experiments (data not shown).
mented, which follows the TG2-catalyzed release of 7-hydroxy-
coumarin from an ester substrate and allows the use of enzyme
concentrations below 100 nM.27 Table 3 presents the IC50 values
obtained for 43 acylideneoxoindole inhibitors with this method
and with the GDH-coupled assay, where it may be seen that the
fluorometric assay indeed allowed us to determine lower IC50
oxoindole benzene ring (compounds 40–49). Removal of the 4-
chloro substituent led to a >20-fold loss in potency for compound
40, but replacing chlorine with bromine at the 4-position afforded
the sub-micromolar inhibitor 41. Analogs bearing chloro, bromo,
methyl or nitro groups at the 5-position (42–45), or with chloro
or bromo groups in the 7-position (48, 49), displayed IC50 values
values (range 0.090–20
lM) than did the GDH-coupled assay
(range 0.8–22 M). The fluorometric assay also uncovered partial
l
inhibition activity with a larger subset of compounds, including
compounds 19, 22, 27, 47, and 48. Furthermore, using a mixed
inhibition model for analyzing the observed inhibition kinetic
behavior, non-competitive binding character could be detected
for a number of compounds that did not exhibit partial inhibition
towards TG2, including compounds 33, 41, and 43 (Table 4).
Acylidene oxoindoles have been widely utilized as synthetic
intermediates, for example, in the synthesis of stereochemically
rich and diverse spirocycles,28–32 natural products33 and chemical
libraries.34 Acylidene oxoindoles have also shown biological activ-
ity, for example, as kinase inhibitors,35,36 phosphatase inhibitors,37
promoters of vasodilatation,38 antifungal agents,39 and activators
of TRP1 ion channels.40 As described in this communication, we
have identified in 3-acylidene-2-oxoindoles a new class of revers-
ible inhibitors of human TG2. Through synthesis and biochemical
in the range of 2.9–7.9 lM, some 3- to 9-fold less potent than com-
pound 16. The 6-chloro and 6-bromo analogs 46 and 47 were
nearly as potent as compound 16. Interestingly, these compounds
were only partial inhibitors of TG2, achieving maximal inhibition
of only 70% and 35%, respectively. This behavior suggests a non-
competitive, allosteric mode of action, a hypothesis that was con-
firmed for compound 46 via Lineweaver–Burk analysis (Fig. 3).
The GDH-coupled assay for TG2 activity became problematic as
the potencies of acylidene oxoindole inhibitors increased. The
typical enzyme concentration used in this assay is 0.5 lM, which
precludes measurement of Ki values below this concentration.
Therefore, a more sensitive direct fluorometric assay was imple-
Table 3
Comparison of IC50 concentrations as determined by the widely used coupled GDH assay and the coumarin-based fluorescence assay with a better dynamic range for
submicromolar values
Compd
GDH
Fluoresc.
Compd
GDH
Fluoresc.
IC50 M)
Compd
GDH
Fluoresc.
IC50 (lM)
IC50
(
l
M)
IC50
(l
M)
IC50
(
l
M)
(
l
IC50
(
lM)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
11
19
—
3.7
20
2.6
3.9
0.89
1.7
1.0
23
24
25
26
27
28
29
30
31
32
33
34
35
36
0.9
1.0
1.1
1.4
1.1
4.0
1.4
1.0
0.8
2.1
1.5
1.5
1.3
5.5
0.74
1.1
1.3
37
38
39
40
41
42
43
44
45
46
47
48
49
1.8
1.1
1.2
22
0.9
6.0
4.8
6.3
7.9
2.5
5.6
0.66
8.5
1.0
1.2
0.56
4.5
1.7
1.5
4.3
11
1.8
3.6
4.7
1.1
0.9
1.2
1.4
1.4
2.8
0.7
0.8
3.0 (65%)a
11
1.5
4.1
0.57
6.7
0.36
2.9
1.0
0.97
2.1 (70%)a
1.5 (35%)a
7.3
20
0.95 (50%)a
0.36 (65%)a
1.6 (70%)a
3.2
20
2.8
2.9
0.09 (60%)a
9.2
For IC50 values in the GDH-coupled assay, the substrate was used at its Km = 10 mM with 500 nM TG2. In the fluorescent assay, IC50 values were measured at 10 lM substrate
concentration (=2 * Km) with 15 nM TG2. The errors were typically less than 10%.
a
If partial inhibition was observed, the maximum inhibition effect is shown in parentheses.

2696
C. Klöck et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2692–2696
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characterization of analogs substituted on the oxoindole benzene
ring, at the exocyclic ketone group and on the oxoindole nitrogen,
we have demonstrated that (1) TG2 inhibitory potency is increased
by substitution of chlorine or bromine at position C-4, and (2) a
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are allosteric inhibitors of TG2 with a non-competitive inhibition
mechanism. The most active compounds in this series inhibit
TG2 at submicromolar concentrations, and may therefore be suit-
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.12.037.
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