A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis

Article abstract of DOI:10.1039/c2md20249b

Thirteen compounds in a new class of fluorinated 5-pyrrolidinylsulfonyl isatin derivatives were synthesised that have potent and selective inhibitory activity against effector caspases-3 and -7. With in vivo animal PET imaging studies of cerebral ischemia being planned, N-benzylation with selected para-substituted benzylic halides allowed systematic variation of lipophilicity (logP 1.94-3.31) without decreasing inhibition potency (IC₅₀). From this series the p-methoxybenzyl analogue was selected for initial 'proof-of-concept' [¹⁸F]-fluoride radiolabelling which proceeded in good yield and purity with no need for a protection/deprotection strategy. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2md20249b

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A new class of fluorinated 5-pyrrolidinylsulfonyl isatin
caspase inhibitors for PET imaging of apoptosis†
Cite this: DOI: 10.1039/c2md20249b
Anwen M. Krause-Heuer,a Nicholas R. Howell,a Lidia Matesic,a Geetanjali Dhand,a
Emma L. Young,a Leena Burgess,a Cathy D. Jiang,a Nigel A. Lengkeek,a
Christopher J. R. Fookes,a Tien Q. Pham,a Franck Sobrio,b Ivan Gregurica
a
*
and Benjamin H. Fraser
Thirteen compounds in a new class of fluorinated 5-pyrrolidinylsulfonyl isatin derivatives were synthesised
that have potent and selective inhibitory activity against effector caspases-3 and -7. With in vivo animal PET
imaging studies of cerebral ischemia being planned, N-benzylation with selected para-substituted benzylic
halides allowed systematic variation of lipophilicity (logP 1.94–3.31) without decreasing inhibition potency
(IC50). From this series the p-methoxybenzyl analogue was selected for initial ‘proof-of-concept’ [18F]-
fluoride radiolabelling which proceeded in good yield and purity with no need for a protection/
deprotection strategy.
Received 23rd August 2012
Accepted 11th November 2012
DOI: 10.1039/c2md20249b
www.rsc.org/medchemcomm
Isatins have been shown to be potent and selective inhibitors
of caspase-3 and -7 with the 5-nitrosulfonylisatins (1) (Fig. 1)
Introduction
some of the rst non-peptidic inhibitors reported.8,9 Modica-
tions at the 5-position have shown that electron withdrawing
groups – such as the N,N-dialkylsulfonamide group (2) – are
Apoptosis is the process of programmed cell death and serves to
maintain homeostasis within an organism. During apoptosis, a
series of proteases are activated by a signal transduction cascade;
these proteases then initiate cell death. The cysteine-dependent
aspartyl protease (caspase) family are the major contributors to
these processes.1,2 There are 11 known human caspases which
are divided into three groups. The Group I caspases (1, 4, 5, 11
and 12) are involved in inammation. Group II caspases (2, 8, 9
and 10) are involved in apoptosis by initiating the Group III
caspases (3, 6 and 7) which are known as effector (executioner)
caspases.3 Group III caspases destroy key cellular substrates and
activate the processes that degrade cellular DNA.4
Disregulation of apoptosis is implicated in a number of
diseases including cancer and the neurological diseases amyo-
trophic lateral sclerosis,5 Huntington's,6 Alzheimer's and Par-
kinson's disease. Activation, however, of caspases has been
demonstrated in cerebral ischemia and inhibition of caspases
(either pre- or post-event) has been shown to reduce tissue
damage.7 Small molecules radiolabelled with PET radionuclides
which display potent inhibition and selectivity towards caspase-
3 and -7 therefore have signicant potential in both the diag-
nosis and treatment of ischemic events.
aLifeSciences Division, Australian Nuclear Science and Technology Organisation,
Locked Bag 2001, Kirrawee DC, NSW 2232, Australia. E-mail: benjamin.fraser@
ansto.gov.au; Fax: +61 2 9717 9262; Tel: +61 2 9717 3887
bCEA, I2BM, LDM-TEP, UMR 6302 ISTCT, GIP Cyceron, BP 5229, F-14074, Caen,
France
Fig. 1 Structures of various isatins which have been reported to demonstrate
in vitro caspase inhibition. The numbering system of the isatin core has been
shown for 1.
† Electronic supplementary information (ESI) available: Synthetic methods,
experimental data, radiolabelling conditions and procedures, details of enzyme
assay. See DOI: 10.1039/c2md20249b
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critical for maintaining high levels of inhibition. Early examples affecting potency.21 Herein we report the details of the rst stage
from this class of inhibitors include 5-(2-methoxymethyl)-pyr- of this work.
rolidinylsulfonyl isatin (3) and 5-(2-phenoxymethyl)-pyrrolidi-
nylsulfonyl isatin (4) (Fig. 1).9,10 Interestingly the (S)-enantiomer
Synthesis
of 3 is 150 times more active that the (R)-enantiomer9 which is
rationalised by the pyrrolidine ring forming an interaction with
the caspase S2 pocket.8 Numerous 4-substituted-N-benzylated
derivatives (5–7) (Fig. 1) of 5-(2-phenoxymethyl)- and 5-(2-
methoxymethyl) pyrrolidinylsulfonyl isatins have also been
synthesised11,12 with N-benzyl derivatives being among the most
potent.9 The N-substituent (most oen benzylic) also serves as
the primary reported method for introducing a suitable radio-
The Boc-protection of commercially available pyrrolidine
methanol afforded 9, which was converted to the corresponding
p-toluenesulfonate ester 10 under standard conditions.13 The
subsequent uorination has previously been performed using
the Kryptox[2.2.2] (K222)/KF complex;13 however no detailed
experimental method or data was reported. In our hands this
method was very low yielding and therefore not pursued
further. Alternatively, the uorination was performed using
tetrabutylammonium uoride, giving 11 in 78% yield. Subse-
quent deprotection using TFA and immediate reaction with
5-chlorosulfonylisatin (12) afforded 13 (Scheme 1). N-Benzyla-
tions were performed using K2CO3 and the corresponding
benzyl halide, with purication achieved by ash chromatog-
raphy (petroleum ether/ethyl acetate). Full synthetic details can
be found in the ESI.†
18
11
isotope (125I,10 F,11–13 C 14) for single photon emission
computed tomography (SPECT) or positron emission tomog-
raphy (PET) studies. Amongst these analogues is the compound
WC-II-89 (5). This compound has been studied extensively as a
potential PET radiotracer including for imaging of caspase-3
activation in rats14 but recent biodistribution studies have
identied impared tracer clearance and increased tracer activity
in blood. The authors concluded that further optimisation of
this class of caspase inhibitor would be required for clinical
application.15 Triazoles have previously been incorporated into
isatin sulfonamides at both the R116and R2 positions,17,18 with
[18F]ICMT-11 (8) displaying the ability to image apoptosis in
vivo,18 and is currently under further investigation in pre-clin-
ical models and humans.19
In vitro caspase inhibition
There is some variation in the literature for the IC50 values of 5
(0.3 nM10and 9.7 nM14 against caspase-3). Similarly, in our
assay, there is some variation between the IC50 values measured
for 5, 6, and 7 compared with the literature values; however, in
all assays each compound has been found to be highly potent
against caspase-3 and -7, with IC50 values of <30 nM.10,14 This
variation at such a low concentration is not unexpected due to
the changes that occur between assays. In our assay, each
individual experiment was validated with the use of peptide
inhibitors.
In our assay, the 2-(uoromethyl)pyrrolidinyl substituent
appeared to impart similar activity to phenoxy and methoxy
substituents (Table 1, cf. 14 to 5 and 6 and 7 to 22) while
providing an alternate position for [18F]-radiolabelling. As such,
a series of substituted N-benzyl derivatives (14–25) were syn-
thesised in order to investigate structure–activity relationships
whilst also providing a range of logP values (experimentally
determined 2.28–3.31) to allow for possible differences in organ
uptake, metabolism and clearance to be exploited. For neuro-
imaging, tracers should ideally have a logP of 0.9–2.5.20,22 The
N-benzyl derivatives synthesised all displayed nanomolar cas-
pase-3 and -7 inhibition (Table 1); with 4-benzyl substituted
compounds (16, 17, 18, 21, 22, 25) generally more active against
caspase-3 and -7 than the native benzyl compound (15).
Given the signicant potential for PET imaging with [18F]-
labelled caspase inhibitors and the improvement needed in the
characteristics of radiotracers including WC-II-89 (5), we
designed and synthesised a new class of 2-(uoromethyl)pyr-
rolidinylsulfonyl isatins (14–26). All compounds were tested for
in vitro caspase inhibition against caspase-1, -3, -6, -7 and -8 and
initial proof-of-concept [18F]-radiolabelling of 22 has proved
successful. Although a single compound of this class has been
reported previously no characterisation data or radiolabelling
experiments were reported.13 We anticipated this new class of
compounds could have improved radiotracer characteristics
compared to WC-II-89 (5) for the following reasons; (1) meta-
bolic stability – uoro substituted groups in place of the phe-
noxymethyl group have already shown improved stability in
vivo;16 (2) decreased lipophilicity – the uoro for phenoxymethyl
substituent change should decrease lipophilicity (logP 3.78 to
ꢀ2.5), which may increase brain uptake and promote faster
clearance of unbound radiotracer;20 and (3) overall lipophilicity
– by radiolabelling on the pyrrolidinylsulfonyl ring, the 4-
substituted-N-benzyl group can be modied to tailor the overall
lipophilicity and perhaps increase cell permeability10 without
Scheme 1 Reagents: (a) Et3N, Boc2O, CH2Cl2; (b) TsCl, pyridine, CH2Cl2; (c) TBAF, THF; (d) 1. TFA, CH2Cl2; 2. 5-chlorosulfonylisatin (12), DIPEA, THF/CHCl3; and (e) benzyl
halide, K2CO3, DMF.
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Table 1 The structure, logP and in vitro caspase inhibition (IC50) of the known (5–7) and novel (14–26, 30) caspase inhibitors synthesised
IC50b (nM)
Compound
R1
R2
logPa
3.78
Caspase-1
Caspase-3
Caspase-6
>10 000
Caspase-7
Caspase-8
>10 000
5
>10 000
6.1 ꢁ 1.1
5.9 ꢁ 1.8
6
7
2.08
2.20
>10 000
>10 000
8.3 ꢁ 1.4
>10 000
>10 000
4.6 ꢁ 1.2
6.1 ꢁ 2.3
>10 000
>10 000
17.6 ꢁ 5.6
14
15
16
17
18
2.33
2.61
3.11
2.96
2.50
>10 000
>10 000
>10 000
>10 000
>10 000
19.2 ꢁ 5.5
13.9 ꢁ 3.3
6.2 ꢁ 2.4
7.1 ꢁ 0.4
15.2 ꢁ 0.5
>10 000
>10 000
>10 000
>10 000
>10 000
41.4 ꢁ 15.4
20.4 ꢁ 8.1
15.9 ꢁ 5.6
14.2 ꢁ 4.5
14.0 ꢁ 3.6
>10 000
>10 000
>10 000
>10 000
>10 000
19
3.25
522 ꢁ 88
9.6 ꢁ 1.0
3878 ꢁ 1618
24.0 ꢁ 1.8
>10 000
20
21
3.21
3.31
1697 ꢁ 102
11.6 ꢁ 2.5
8.1 ꢁ 0.9
>10 000
21.8 ꢁ 4.7
5.4 ꢁ 0.5
>10 000
>10 000
>10 000
3790 ꢁ 595
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Table 1 (Contd. )
IC50b (nM)
Caspase-1
Compound
R1
R2
logPa
2.65
Caspase-3
Caspase-6
>10 000
Caspase-7
Caspase-8
>10 000
22
>10 000
13.7 ꢁ 1.6
9.6 ꢁ 2.8
23
2.28
672 ꢁ 24
3.1 ꢁ 0.5
5082 ꢁ 1431
19.8 ꢁ 3.3
>10 000
24
25
2.28
2.39
4695 ꢁ 646
12.8 ꢁ 1.3
6.3 ꢁ 0.6
>10 000
>10 000
16.5 ꢁ 1.1
11.2 ꢁ 1.1
>10 000
>10 000
>10 000
26
1.94
1878 ꢁ 557
4.4 ꢁ 1.2
>10 000
25.3 ꢁ 7.5
>10 000
30
1.19
>10 000
2209 ꢁ 171c
>10 000
3512 ꢁ 935
>10 000
a
logP was determined experimentally using HPLC method, see ESI.† b IC50 values are the mean ꢁ SD of at least three independent assays, except
when IC50 > 10 000 nM in which case n ¼ 2. c n ¼ 2. The IC50 values of peptide controls can be found in the ESI.†
However, the 2-substituted benzyl derivatives (cf. 19 to 21 and 23 interest as it can allow for more efficient interactions between
to 25), whilst displaying similar activity to the respective 4- the ligand and biological targets.24 This also presented another
substituted compound against caspase-3 and -7, also exhibited method for producing more polar analogues. Introduction of
some activity against caspase-1 and -6. This suggests that the the azabicycle substituent did decrease the lipophilicity of this
substituent position on the benzyl group may be important for compound (experimentally determined logP 1.19), however; the
interaction with the S1 enzyme pocket.
IC50 value was >2000 nM against caspase-3 and >10 000 nM
The replacement of the N-benzyl derivative with a benzyl- against caspase-7. The lack of caspase inhibition is likely to be
protected tetrazole was also performed, due to the success of due to the conformationally restricted portion of the molecule
similar triazole containing compounds such as 8.17,19 Tetrazoles being a poorer t to the enzyme active site. As such, this series
are isosteres of carboxylic acids, with increased lipophilicity and was not pursued further.
metabolic stability.23 The introduction of the benzyl-protected
tetrazole produced the most polar analogue in the pyrrolidinyl
Radiochemistry
series (26) (experimentally determined logP value of 1.94), which
may more readily cross the blood–brain barrier, whilst also Synthesis of the [18F]-radiolabelling precursor (p-toluenesulfo-
being highly potent against caspase-3 (IC50 4.4 nM) (Table 1).
nate ester 33) was achieved as shown in Scheme 3. The reaction
We also investigated the substitution of the pyrrolidine ring of Boc-deprotected 10 (Scheme 1) with 12 was initially attempted
for a bicyclic conformationally restricted diamine (CRDA) (30) as a more direct synthetic route; however, this reaction
(Scheme 2). The conformational restriction of CRDAs is of was unsuccessful. Instead, L-prolinol was reacted with
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Table 2 Optimisation of radiolabelling conditions for [18F]22a
Precursor
Entry (mg)
Vol.
Temp. Time
HPLC RCYc
Solvent (mL) (ꢃC)
(min) yieldb (d.c.)
1
2
3
4
5
6
7
8
5
5
5
2
2
2
5
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
1
1
1
1
1
0.3
1
80
100
100
100
100
100
120
100
5
5
20
5
20
20
20
20
2
5
29
3
10
35
8
2
7
14
2
7
15
5
DMF
1
0
0
a
b
Precursor 33, 1 eq. K2CO3, 2 eq. Kryptox[2.2.2]. Radiochemical
yield, as calculated by collected HPLC yield as percentage of injected
c
activity. Isolated radiochemical yield, decay corrected (d.c.) to start
of synthesis (SOS).
unreacted starting material remaining; despite attempts at
optimising time, temperature and molar ratios of reagents.
Purication of 32 was achieved using ash chromatography (C-
18 reverse phase chromotography using H2O/MeCN eluent) with
subsequent N-benzylation with 4-methoxybenzyl chloride
affording the radiolabelling precursor (33).
Scheme 2 Reagents: (a) DIPEA, CHCl3; (b) K2CO3, DMF; and (c) TFA, CH2Cl2.
Radiolabelling of precursor 33 was performed by nucleo-
philic substitution in the presence of (K222)/[18F] KF complex,
followed by treatment with HCl to close the isatin ring. Longer
reaction times corresponded with increased radiochemical
yields. Although the use of 5 mg of precursor in 1 mL of MeCN
(Table 2, entry 3) resulted in a radiochemical yield of 14%, to
conserve precursor and improve the HPLC separation of [18F]22,
the mass of 33 and solvent volume were decreased to yield a
reaction mixture of comparable concentration (Table 2, entry 6).
These parameters were determined to be the optimal radio-
labelling conditions for [18F]22. In all cases a signicant
proportion (up to 50%) of the activity remained on the reaction
vial, which contributed to the disparity between HPLC and
isolated radiochemical yields (Table 2).
Scheme 3 Reagents: (a) pyrrolidine methanol, DIPEA, THF/CHCl3; (b) TsCl,
pyridine; (c) 4-methoxybenzyl chloride, K2CO3, DMF; and (d) (1) [18Fꢂ], K2CO3,
Kryptofix[2.2.2], MeCN, (2) HCl (1 mL, 4 M), 70 ꢃC, 10 min.
5-chlorosulfonylisatin (12) which produced a dark green reaction
mixture, which was puried using ash chromatography (C-18
reverse phase chromotography using H2O/MeCN eluent). The
product fractions (collected at 20% MeCN) were a yellow/green
colour, with later non-product fractions deep blue/purple.
Although the hygroscopic lyophilised product (31) was green in
colour, it was >99% pure as determined by HPLC, with the colour
believed to be due to the presence of a very small proportion of
the highly coloured blue impurity. The subsequent conversion to
Fig. 2 Absorbance at 254 nm (top) and corresponding radio-HPLC (bottom) of
the p-toluenesulfonate ester 32 was low yielding (ꢀ25%) with collected [18F]22 co-injected with non-radioactive [19F]-standard 22.
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Aer treatment with HCl, the crude reaction mixture was
then puried using HPLC to yield [18F]22 in 15 ꢁ 0.2% RCY (n ¼
3, decay corrected to SOS), in 98% radiochemical purity (Fig. 2).
Previously it has been reported that isatin derivatives require a
protecting group on the C3 carbonyl prior to radiosynthesis due
to the carbonyl being a trap for [18F]-uoride, leading to the
unsuccessful substitution of mesylate and tosylate groups by
[18F]-uoride.25 However, the radiosynthesis of [18F]22 was
achieved without a C3-protecting group and the successful
synthesis was conrmed by co-injection with the [19F]-standard
22 (Fig. 2).
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¨
¨
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¨
¨
¨
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¨
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