Hydrogenative desulphurization of thienopyrrolizinones: An easy and selective access to (Z)-phenethylidenepyrrolizinones with in vitro cytotoxic activity

Article abstract of DOI:10.1016/j.ejmech.2009.12.021

Attempts in view to dearomatize some previously reported tripentones with potent antineoplastic activities led in thiophene series to an unexpected hydrogenative desulphurization reaction. The resulting (Z)-phenethylidenepyrrolizinones were tested in vitr

Full text of DOI:10.1016/j.ejmech.2009.12.021

European Journal of Medicinal Chemistry 45 (2010) 1146–1150
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Hydrogenative desulphurization of thienopyrrolizinones: An easy and selective
access to (Z)-phenethylidenepyrrolizinones with in vitro cytotoxic activity
a
a
a
a
´
Vittoria Perri , Christophe Rochais , Jana Sopkova-de Oliveira Santos , Remi Legay ,
Thierry Cresteil b, Patrick Dallemagne a , Sylvain Rault
,
a
*
a Centre d’Etudes et de Recherche sur le Me´dicament de Normandie, UPRES EA 4258, FR CNRS 3038 INC3M UFR des Sciences Pharmaceutiques, Universite´ de Caen Basse Normandie,
Bd Becquerel, 14032 Caen cedex France
b Institut de Chimie des Substances Naturelles, CNRS UPR 230, 1Avenue de la terrasse, 91198 Gif sur Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Attempts in view to dearomatize some previously reported tripentones with potent antineoplastic
activities led in thiophene series to an unexpected hydrogenative desulphurization reaction. The
resulting (Z)-phenethylidenepyrrolizinones were tested in vitro over human epidermoid carcinoma KB
cell line. The results of this biological evaluation indicated that the tricyclic core of our model can be
cleaved with a partial respect of the activity.
Received 15 April 2009
Received in revised form
3 December 2009
Accepted 10 December 2009
Available online 21 December 2009
Ó 2009 Published by Elsevier Masson SAS.
Keywords:
Pyrrolizinone
Tripentone
Hydrogenation
Desulphurization
Cytotoxicity
1. Introduction
2. Chemistry
We have previously reported the synthesis and the biological
evaluation of an original series of arylthienopyrrolizinones named
by us ‘‘tripentones’’ [1]. Some members of this new family
including compound MR22388 1, exhibit an in vitro cytotoxic
activity in the nanomolar range associated to an anti-tubulin
effect and to a cyclin-dependent kinase (CDK) inhibition (Fig. 1)
[2,3].
In order to better understand both the SAR and the cellular
mechanism of action in this series, we undertook recently some
pharmacomodulations of MR22388 aiming at diversifying the
nature of the aromatic ring by replacing its thiophene either by
a pyrrole or a pyrazole ring or at evaluating the enlargement of the
pyrrolizine moiety into a pyrrolopyrazinone system [4–7]. In order
to complete this study, we wish to describe herein our attempts to
partially dearomatize our thienopyrrolizinones in order to poten-
tially enhance their cytotoxicity, taking for model some tetrahydro-
5H-pyrrolo[2,1-a]isoindolones whose potent CDK1,2,4,6 inhibitory
activities were recently reported (Fig. 2) [8,9].
The previously reported chemical sequence leading to 3-(3-
hydroxy-4-methoxy)phenyl-8H-thieno[2,3-b]pyrrolizin-8-one 1 was
achieved in seven steps starting from (3-benzyloxy-4-methox-
y)phenyl-acetonitrile 2 (Scheme 1) [3].
Very few examples of dearomatization of pyrrolizinone into
pyrrolizidinone are described in literature. To the best of our
knowledge, only one article reported it in 1960 [10]. This reaction
took place in two steps. The first one consisted in rhodium-
on-alumina hydrogenation of both the pyrrole nucleus of 10 into
pyrrolidine and of its carbonyl group into a hydroxyl one. A second
step was needed to re-oxidize, according to the Oppenauer’s
conditions, the alcohol 11 into the expected pyrrolizinone 12
(Scheme 2).
Concerning the tripentone series for which no hydrogenation
attempts were hitherto undertaken, we ran several reactions using
H2 in the presence of various catalysts on charcoal like Pd, Rh or
PtO2, in a Paar apparatus under atmospheric pressure. However, all
our attempts achieved either starting from 1 or from its protected
O-benzyl derivative 9 failed to reduce the aromatic rings of the
tripentone system. The starting material was recovered intact in
each case except for the PtO2 hydrogenation where an O-deben-
zylation of 9 took place partially yielding 1.
* Corresponding author. Tel.: þ33 2 3156 5910; fax: þ33 2 3193 1188.
E-mail address: patrick.dallemagne@unicaen.fr (P. Dallemagne).
0223-5234/$ – see front matter Ó 2009 Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2009.12.021

V. Perri et al. / European Journal of Medicinal Chemistry 45 (2010) 1146–1150
1147
O
O
ONa
CN
OSO2C6H5
CN
ii
i
X
Y
S
Ar
CN
Ar
Ar
N
N
2
3
4
IC50 L1210 = 0.015 µM
IC50 tubulin = 2.9 µM
Ar
1
iii
tripentones
OH
O
CO2Me
NH2
O
CO2Me
N
N
iv
v
S
X = S, Y = CH
X = NH, Y = CH
X = O, Y= CH
X = NH, Y = N
S
S
MR22388
N
Ar
Ar
Ar
7
6
5
Fig. 1. Structure of tripentones and IC50 values for compound MR22388.
vi
The well-known potent catalyst-poisoning properties of the
thiophene ring were invoked to explain these failures [11]. Taking
that reactivity into account, we attempted the reduction of one of
the heterocyclic isosters of MR22386 we previously described, the
pyrrole tripentone 13 [6]. Under treatment with H2 in the presence
of catalytic amount of palladium–charcoal in MeOH under atmo-
spheric pressure, the latter furnished successfully in good yield the
corresponding partially dearomatized tripentone 14 (Scheme 3).
During this reaction, only the pyrrolizine ring of 13 was reduced
into a tetrahydro one, its N-benzyl pyrrole ring, as well as its
carbonyl group remained intact. However, in the same time the
O-benzyl protecting group of 13 was selectively cleaved to liberate
the free hydroxyl, while its N-benzyl group remained unreactive.
Since it was also well established that Raney Nickel was less
poisoned by thiophene in determinate solvent, 1 was then hydro-
genated in the presence of this catalyst, in MeOH, under atmo-
spheric pressure and at room temperature. In these conditions
a hydrogenative desulphurization occurred leading to the phene-
thylidenepyrrolizinone 15. The latter was obtained in 67% yield
selectively in its Z form (Scheme 4). Surprisingly, no hydrogenation
of the alkene moiety of 15 was observed under those conditions,
probably due to its conjugation with the phenyl ring.
N+
-
PO2Cl2
O
vii
viii
S
S
1
N
N
Ar
Ar
9
8
2-9 Ar = C6H3(m-OBn,p-OMe)
1 : Ar = C6H3(m-OH,p-OMe)
Scheme 1. Reagents: (i) HCO2Et, MeONa, MeOH; (ii) benzenesulfonyl chloride, DMF;
(iii) HSCH2CO2Me, MeONa, MeOH; (iv) 2,5-dimethoxyTHF, 4-chloropyridine hydro-
chloride, dioxane; (v) pyrrolidine; (vi) POCl3; (vii) 2.5 M NaOH; (viii) 33% HBr in AcOH.
concentrations in triplicate, using taxotere at 2.5 ꢁ10ꢀ10 M as
reference. The results are expressed in terms of inhibition
percentage at each concentrations and IC50 were measured for
percentage greater than 80% at 10ꢀ6 M (Table 1).
Our lead compound MR22388 (1) exhibited an IC50 of 5.7 nM
against KB cells, confirming its cytotoxicity already observed against
a large panel of cell lines [3]. During the courseof ourstudy, it hasbeen
proven that the replacement of the thiophene ring by various isosteres
had a great influence on the activity of this series [3,5,6]. The hydro-
genative desulphurization of 1 conduced for the first time to a novel
phenethylidenepyrrolizinone 15 with a good cytotoxicity over human
KB cells (IC50 ¼ 70 nM). According to the initial SAR highlighted for the
MR22388series,replacementofthem-OH, p-OMephenylgroupsof15
by other substituents dramatically decreases the activity. This moiety
appears thus closely implied again in the biological activity of 15 in
a similar manner as established for some antimitotic drugs including,
for example, combretastatin A4, anthracenone (23) and naph-
thothiophenone (24), whose analogy with 15 must be pointed out
(Fig. 4) [12–15]. This result gives us some important information in
order to explore new developments of our series.
Structure of 15 was assigned on the basis of 2D NMR spectra,
completed by NOE experiments. Specifically, irradiation of protons
H2 led to an NOE with the cis methyl group, without effect on H200
and H600 protons of the trans phenyl ring. These observations were
consistent with a Z relative configuration for 15 (Fig. 3).
This unexpected reaction led us to exemplify it starting from
other thienopyrrolizinones 16–18, we previously described [2,3]. In
all cases, a Raney Nickel desulphurization took place leading to
19–22 (Scheme 4). The p-MeO and p-Cl phenethylidene derivatives
19, 20 were again selectively formed in their Z relative configura-
tion. The 3-methyltripentone 18 conduced in the same conditions
to a mixture of the isopropylidene 21 and isopropylpyrrolizinone
22. The absence of any aromatic ring conjugated with the alkene of
21 implied a higher reactivity of this one to hydrogenation.
3. Biology
4. Conclusion
Compounds synthesized in this work were tested for their in
vitro cytotoxicity against KB cells at 10ꢀ5 and 10ꢀ6 M
Even if these results do not improve the antineoplastic activity
inherent to some tripentones, they allowed us to work out an
original method of desulphurisation in thiophene series leading to
O
O
H
O
S
OH
O
N
i
ii
N
H
N
Ar
tetrahydropyrroloisoindolones
N
Ar
tetrahydrothienopyrrolizinones
N
10
11
12
Fig. 2. Structure of expected tetrahydropyrrolizinones and reference tetrahydro-
Scheme 2. Dearomatization of pyrrolizinone 10 into pyrrolizidinone 12. Reagents:
pyrrolo-isoindolones.
(i) H2 (42 psi), Rh/alumina, AcOH; (ii) Al[OC(CH3)3]3, toluene, cyclohexanone.

1148
V. Perri et al. / European Journal of Medicinal Chemistry 45 (2010) 1146–1150
O
H
2
O
H
H
O
i
N
H3C
N
N
N
N
2''
6''
Ar
Ar
HO
14
O
13
13: Ar = C6H3(m-OBn,p-OMe)
14: Ar = C6H3(m-OH,p-OMe)
Fig. 3. NOE correlations for 15.
Scheme 3. Synthesis of compound 14. Reagents: (i) H2 atmP, Pd/C, MeOH.
Pd/C for 90 min. The solution was filtered from catalyst through
filter paper, then through a small pad of Celite and dried over
MgSO4. Filtration and evaporation afforded 80 mg of 14 as an
orange solid. Yield: 73%. MP: 120 ꢂC. IR (cmꢀ1): 3272, 2936, 2901,
2835, 1651, 1563, 1418, 1257, 700. HRMS (m/z): 374.16448 (calc:
novel phenethylidenepyrrolizinones. This work furthermore opens
novel possibilities to diversify the tripentone structure towards
new biologically active series that partially conserve the cytotox-
icity. These compounds must be considered as new hits whose
pharmacomodulation is currently under investigation.
374.16302). 1H NMR (CDCl3)
d: 7.32 (m, 5H, Harom), 7.05 (s, 1H, H2),
0
0
7.04 (d, 1H, J ¼ 1.9 Hz, H2 ), 6.98 (dd, 1H, J ¼ 1.9 Hz, J ¼ 8.3 Hz, H6 ),
0
6.83 (d, 1H, J ¼ 8.3 Hz, H5 ), 5.20 (d, 1H, J ¼ 14.5 Hz, NCHPh), 5.07 (d,
5. Experimental protocols
1H, J ¼ 14.5 Hz, NCHPh), 4.33 (m, 1H, H7a), 3.89 (s, 3H, OCH3), 3.31
(m, 1H, H7), 2.94 (m, 1H, H7), 2.17 (m, 1H, H5), 1.90 (m, 3H, 2H6 and
5.1. General
Melting points were determined on a Kofler melting point
apparatus and are uncorrected. IR spectra were recorded on
a Genesis series FTIR spectrometer using KBr pellets. The 1H
(400 MHz) and 13C (100 MHz) NMR spectra were obtained on a Jeol
Lambda 400 spectrometer using DMSO-d6 or CDCl3 as solvent and
Table 1
Percentage of inhibition of KB cells growing at various concentrations and IC50 for
taxotere and compounds 1, 15, 19, 20, 22.
Cmpd
Taxotere 2.5 ꢁ 10ꢀ10 M
10ꢀ5 M (%)
–
10ꢀ6 M (%)
–
IC50 ꢃ SD (nM)
0.4
TMS as internal standard. The chemical shifts (d) are reported in
ppm, and the coupling constants are in hertz. NOE experiments
were recorded on a Bruker AC 400 spectrometer and the samples
were degassed by bubbling nitrogen through the solution. Electron
impact mass spectra (EIMS) were obtained using a Jeol JMS GCMate
spectrometer. Reactions were monitored by thin-layer chroma-
tography (TLC) using 0.2 mm Polygram Sil silica gel G/UV 254
precoated plates with visualization by irradiation with a short-
wavelength UV light. Silica gel flash chromatography was per-
formed using 63–200 mM Kieselgel Merck 60 silica gel.
86
84
86
92
5.7 ꢃ 1.15
OH
O
O
1
S
N
Ar
50 ꢃ 10
16
O
5.2. Chemistry
5.2.1. 1-Benzyl-3-(3-hydroxy-4-methoxyphenyl)-5,6,7,7a-
tetrahydropyrrolo[2,3-b]pyrrolizin-8(1H)-one (14)
A solution of 150 mg (0.33 mmol) of 13 in methanol (50 mL) was
hydrogenated at room temperature and atmospheric pressure over
95
91
70 ꢃ 5.2
OH
O
15
O
O
O
i
O
S
N
N
N
N
78
1
0
–
–
R
R
19
R
O
22
1,16-18
(Z)-15, (Z)-19, (Z)-20, 21
0
1,15
16,19
17,20
18,21,22
20
Cl
CH3
R =
HO
O
O
O
Cl
0
0
–
N
22
Scheme 4. Synthesis of compounds 15, 19–22. Reagents: (i) H2 atmP, Raney Ni, MeOH.

V. Perri et al. / European Journal of Medicinal Chemistry 45 (2010) 1146–1150
1149
5.2.4. (3Z)-3-[1-(4-Chlorophenyl)ethylidene]-2,3-dihydro-1H-
pyrrolizin-1-one (20)
Using the same procedure described for 15 and starting from
a solution of 100 mg (34.9 mmol) of 17 in MeOH (30 mL), 30 mg
of 20 was obtained as a brown solid. Yield: 33%. MP: 158 ꢂC. IR
(cmꢀ1): 1708, 1360, 1276, 1076, 737. HRMS (m/z): 257.06131
O
O
O
O
O
S
(calc: 257.06073). 1H NMR (CDCl3)
d
: 7.37 (d, 2H, J ¼ 8.8 Hz, H300
O
O
O
and H500), 7.15 (d, 2H, J ¼ 8.8 Hz, H200 and H600), 6.63 (d, 1H,
J ¼ 3.9 Hz, H5), 6.19 (dd, 1H, J ¼ 2.7 Hz, J ¼ 3.9 Hz, H6), 6.00 (d, 1H,
J ¼ 2.7 Hz, H7), 3.57 (s, 2H, 2H2), 2.01 (s, 3H, CH3). 13C NMR
OH
23
OH
OH
combretastatin A-4
24
(CDCl3) d
: 186.53 (C1), 159.23 (C400), 134.51 (C7a), 134.52 (C100),
129.16 (C300 and C500), 126.33 (C3), 122.13 (C7), 118.28 (C10), 116.66
(C6), 114.69 (C200 and C600), 107.92 (C5), 55.28 (OCH3), 43.42 (C2),
22.5 (CH3).
O
N
5.2.5. 3-Isopropylidene-2,3-dihydro-1H-pyrrolizin-1-one (21) and
3-isopropyl-2,3-dihydro-1H-pyrrolizin-1-one (22)
Using the same procedure described for 15 and starting from
a solution of 100 mg (52.8 mmol) of 18 in MeOH (30 mL), 35 mg of
21 and 30 mg of 22 were obtained as a yellow solid and a brown oil
respectively.
O
OH
(Z)-15
21: Yield: 41%. MP: 96 ꢂC. IR (cmꢀ1): 1683, 1356, 1302, 1106,
Fig. 4. Structure of combretastatin A-4 and compounds 23, 24; analogy with
compound 15.
1030, 748. HRMS (m/z): 161.08397 (calc: 161.08405). 1H NMR
(CDCl3)
d
: 7.43 (d, 1H, J ¼ 2.9 Hz, H7), 6.78 (d, 1H, J ¼ 3.9 Hz, H5),
6.56 (dd, 1H, J ¼ 2.9 Hz, J ¼ 3.9 Hz, H6), 3.50 (s, 2H, 2H2), 2.06 (s, 3H,
H5). 13C NMR (CDCl3)
d: 188.29 (C8), 164.00 (C3a), 145.86, 145.08,
CH3), 1.85 (s, 3H, CH3). 13C NMR (CDCl3) : 186.53 (C1), 159.23 (C400),
d
136.69, 132.90, 128.86, 128.18, 128.12, 126.35, 122.66, 117.70, 112.29,
111.67, 110.97, 78.89 (C7a), 56.03 (OCH3), 51.56 (CH2), 50.89 (C5),
27.77 (C7), 27.03 (C6).
134.51 (C7a), 134.52 (C100), 129.16 (C300 and C500), 126.33 (C3), 122.13
(C7), 118.28 (C10), 116.66 (C6), 114.69 (C200 and C600), 107.92 (C5),
55.28 (OCH3), 43.42 (C2), 22.5 (CH3).
22: Yield: 35%. IR (cmꢀ1): 1687, 1526, 1366, 1304, 1071, 741.
5.2.2. (3Z)-3-[1-(3-Hydroxy-4-methoxyphenyl)ethylidene]-2,3-
dihydro-1H-pyrrolizin-1-one (15)
HRMS (m/z): 163.09995 (calc: 163.09972). 1H NMR (CDCl3)
d:
7.04 (d, 1H, J ¼ 2.9 Hz, H7), 6.69 (d, 1H, J ¼ 3.9 Hz, H5), 6.51 (dd,
1H, J ¼ 2.9 Hz, J ¼ 3.9 Hz, H6), 4.49 (dt, 1H, J ¼ 7.8 Hz, J ¼ 3.5 Hz,
J ¼ 3.5 Hz, H3), 3.03 (dd, 1H, J ¼ 18.1 Hz, J ¼ 7.8 Hz, H2a), 2.75
(dd, 1H, J ¼ 18.1 Hz, J ¼ 3.5 Hz, H2b), 2.25 (m, 1H, CH), 0.97 (d,
3H, J ¼ 6.8 Hz, CH3), 0.74 (d, 3H, J ¼ 6.8 Hz, CH3). 13C NMR
A solution of 200 mg (0.67 mmol) of 1 in methanol (100 mL) was
hydrogenated at room temperature and atmospheric pressure over
Ni-Raney for 2 h. The solution was filtered from catalyst through
filter paper, then through a small pad of Celite and dried over
MgSO4. The solvent was removed under reduced pressure and the
residue was purified by column chromatography on silica gel
(EtOAc/cyclohexane 1:3) to give 120 mg of 15 as a white solid.
Yield: 67%. MP: 170 ꢂC. IR (cmꢀ1): 3295, 3143, 3002, 2937, 1688,
1537, 1509, 1360, 1296, 1258, 1145, 1029, 819, 748, 662. HRMS (m/z):
(CDCl3) d: 188.67 (C1), 132.52 (C7a), 121.27 (C7), 115.80 (C5),
106.17 (C6), 58.65 (C3), 40.72 (C2), 31.63 (CH), 17.31 (CH3), 14.72
(CH3).
5.3. Cell culture and proliferation assay
269.10484 (calc: 269.10518). 1H NMR (CDCl3)
d: 6.92 (d, 1H,
J ¼ 8.3 Hz, H500), 6.83 (d, 1H, J ¼ 2.0 Hz, H200), 6.75 (dd, 1H, J ¼ 2.0 Hz,
J ¼ 8.3 Hz, H600), 6.69 (d, 1H, J ¼ 3.9 Hz, H5), 6.25 (dd, 1H, J ¼ 2.7 Hz,
J ¼ 3.9 Hz, H6), 6.16 (d, 1H, J ¼ 2.7 Hz, H7), 5.70 (s, 1H, OH), 3.95 (s,
The human epidermoid carcinoma KB cell lines were obtained
from ECACC (Salisbury, UK) and grown in D-MEM medium sup-
plemented with 10% fetal calf serum (Invitrogen), in the presence
of penicilline, streptomycine and fungizone in 75 cm3 flask under
5% CO2. Cells were plated in 96-well tissue culture microplates at
3H, OCH3), 3.63 (s, 2H, 2H2), 2.05 (s, 3H, CH3). 13C NMR (CDCl3)
d:
186.50 (C1), 146.34 (C300), 146.27 (C400), 134.51 (C7a), 133.47 (C100),
126.26 (C3), 122.28 (C7), 119.61 (C600), 118.21 (C10), 116.68 (C6),
114.21 (C200), 111.27 (C500), 107.95 (C5), 56.00 (OCH3), 43.44 (C2),
22.41 (CH3).
a density of 650 cells/well in 200
later with compounds dissolved in DMSO with compound
concentrations ranged 0.5 nM to 10 M using a Biomek 3000
ml medium and treated 24 h
m
automate (Beckman). Controls received the same volume of
DMSO (1% final volume). After 72 h exposure MTS reagent
(Promega) was added and incubated for 3 h at 37 ꢂC: the absor-
bance was monitored at 490 nm and results expressed as the
inhibition of cell proliferation calculated as the ratio [(OD490
treated/OD490 control) ꢁ 100]. For IC50 determinations (50%
inhibition of cell proliferation) experiments were performed in
separate duplicate.
5.2.3. (3Z)-3-[1-(4-Methoxyphenyl)ethylidene]-2,3-dihydro-1H-
pyrrolizin-1-one (19)
Using the same procedure described for 15 and starting from
a solution of 100 mg (35.5 mmol) of 16 in MeOH (30 mL), 35 mg of
19 was obtained as a brown solid. Yield: 39%. MP: 118 ꢂC. IR (cmꢀ1):
1682, 1507, 1360, 1308, 1241, 1035, 839, 816, 759. HRMS (m/z):
253.11018 (calc: 253.11027). 1H NMR (CDCl3)
d: 7.19 (d, 2H,
J ¼ 8.8 Hz, H300 and H500), 6.98 (d, 2H, J ¼ 8.8 Hz, H200 and H600), 6.69
(d, 1H, J ¼ 3.9 Hz, H5), 6.24 (dd, 1H, J ¼ 2.7 Hz, J ¼ 3.9 Hz, H6), 6.09
(d, 1H, J ¼ 2.7 Hz, H7), 3.87 (s, 3H, OCH3), 3.64 (s, 2H, 2H2), 2.07 (s,
References
3H, CH3). 13C NMR (CDCl3) : 186.53 (C1), 159.23 (C400), 134.51 (C7a),
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