Organometallic analogues of tamoxifen: Effect of the amino side-chain replacement by a carbonyl ferrocenyl moiety in hydroxytamoxifen

Article abstract of DOI:10.1016/j.jorganchem.2006.11.016

Since the widely prescribed selective estrogen receptor modulator (SERM) tamoxifen encounters growing cases of resistance in long-term treatments, alternative drugs with different therapeutic scopes have to be developed. Many investigators have modified t

Full text of DOI:10.1016/j.jorganchem.2006.11.016

Journal of Organometallic Chemistry 692 (2007) 1219–1225
www.elsevier.com/locate/jorganchem
Communication
Organometallic analogues of tamoxifen: Effect of the amino side-chain
replacement by a carbonyl ferrocenyl moiety in hydroxytamoxifen
*
`
´
Anh Nguyen, Siden Top , Anne Vessieres, Pascal Pigeon, Michel Huche,
*
´
Elizabeth A. Hillard, Gerard Jaouen
Laboratoire de Chimie et Biochimie des Complexes Mole´culaires, UMR CNRS 7576, Ecole Nationale Supe´rieure de Chimie de Paris,
11 rue Pierre et Marie Curie, F-75231 Paris Cedex 05, France
Received 10 October 2006; received in revised form 6 November 2006; accepted 6 November 2006
Available online 16 November 2006
Abstract
Since the widely prescribed selective estrogen receptor modulator (SERM) tamoxifen encounters growing cases of resistance in long-
term treatments, alternative drugs with different therapeutic scopes have to be developed. Many investigators have modified the triphen-
ylethylene scaffold, but very few have changed its amino side chain, essential for the antiestrogenic activity. For the first time, a lipophilic
and stable organometallic entity, –OCH2CO-[(g5-C5H4)FeCp], has replaced this key functional side chain, while keeping a good affinity
for the estrogen receptor and an antiproliferative activity on cancer cells (MCF-7 and PC-3). Its mechanism of action is likely to be dif-
ferent from the antihormonal pathway followed by hydroxytamoxifen, and from the cytotoxicity observed for the ferrocifens.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: Bioorganometallic chemistry; Ferrocene; Breast cancer; Tamoxifen; SERM
1. Introduction
induces a stabilizing interaction with the Aspartate 351 res-
idue (Asp 351) of ERa [2]. This interaction prevents the
association of Helix 4 with Helix 12, impeding the recruit-
ment of specific co-effectors and co-activators.
Breast tumours are generally classified into two types:
those defined as hormone-dependent (2/3 of cases), in
which the estrogen receptor is present in tumour cells
(ER+), and those defined as hormone-independent (1/3
of cases), in which the estrogen receptor is not detected
(ERꢀ). In the case of ER+ tumours, the selective estrogen
receptor modulator (SERM) tamoxifen is widely used to
treat hormone-dependent breast cancer [1]. The antiestro-
genic effect of its active metabolite, hydroxytamoxifen
(Chart 1), is primarily attributed to its competitive binding
to Estrogen Receptor a (ERa) and to its amino side chain
–O(CH2)2N(CH3)2 [1a]. The X-ray structure of the LDB
(ligand binding domain) of ERa, crystallized with 4-
hydroxytamoxifen, has shown that this basic side chain
However, in addition to its inefficacy against ERꢀ
tumours, one-third of ER+ tumours do not respond satis-
factorily to administration of tamoxifen [1b]. Moreover,
long exposure to the same drug often leads to a resistance
phenomenon. For these reasons, many new molecules
structurally related to the popular hydroxytamoxifen have
been thoroughly screened, in order to obtain different ther-
apeutic effects [1,3,4]. Since modification of substituents on
the alkyl amine of the key side chain –O(CH2)2N(CH3)2
has demonstrated the importance of the nitrogen atom in
the antiestrogenic potency [1c,1d,3], only a few researchers
have attempted to replace this functional group. The sub-
stitution of the amino side chain by a carboxylic acid side
chain by Ruenitz et al. (compound 3 in Chart 1) was the
only important estrogen antagonist example found so far
[4]. In this case, the elongation of the chain length (to
n = 3) in 3 is crucial to observe a potent antiproliferative
*
Corresponding authors. Tel.: +33 144276699; fax: +33 143260061
´
(Siden Top); tel.: +33 143269555; fax: +33 143260061 (Gerard Jaouen).
E-mail addresses: siden-top@enscp.fr (S. Top), gerard-jaouen@
enscp.fr (G. Jaouen).
0022-328X/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.11.016

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A. Nguyen et al. / Journal of Organometallic Chemistry 692 (2007) 1219–1225
OH
OH
OH
OH
α
α
α
α'
β
α'
β
α'
β
Fe
HO
O
O
n
O
O
3
n
N
OH
(Z)-4
N
O
O
Fe
1
2
Carboxylic analogues
of tamoxifen with n = 1, 3
Hydroxytamoxifen
Ferrocifens with n = 2, 3, 4, 5
Chart 1.
effect on hormone-dependent MCF-7 breast cancer cells.
Indeed the carbonyl of the carboxylic acid may also inter-
act with Asp 351, but it is not obvious that this interaction
is the key to the antiproliferative activity of compound 3.
We have previously shown that some ferrocenyl deriva-
tives of hydroxytamoxifen (ferrocifens, 2) (Chart 1),
obtained by substituting the b-phenyl ring of hydroxytam-
oxifen by a ferrocenyl unit, exhibit a strong antiproliferative
effect on both hormone-dependent (ERa+) and hormone-
independent breast cancer cells [5]. Thus, we demonstrated
for the first time that the cytotoxic activity of tamoxifen can
be potentiated by an organometallic substituent. We postu-
lated, as to mechanism, the generation of ferricinium ion
that may engender a Fenton-type reaction [6], or the
in situ generation of a quinone methide species, assisted
by the ferrocenyl group [7]. Other series of organometallic
derivatives were also prepared to probe the cytotoxicity of
the ferrocenyl group on breast cancer cells [8]. In order to
elucidate the activity of ferrocenyl derivatives and find
new compounds with different activity, we propose now
to study compound 4 which is characterized by the replace-
ment of the –O(CH2)2N(CH3)2 side chain by a stable and
lipophilic ferrocenyl group –OCH2CO-[(g5-C5H4)FeCp]
(Chart 1). Its activity may be very interesting because, in
contrast to ferrocifens and tamoxifen, 4 does not have the
antiestrogenic amino side chain, and the ferrocenyl group
cannot assist the production of quinone methide. In addi-
tion, this ferrocenyl chain is a neutral group in contrast to
the basic nature of the amino chain of tamoxifen and to
the acidic nature of the carboxylato chain of 3. We describe
now the synthesis of 4 and the results on its antiproliferative
activity against cancer cell lines MCF-7 and PC-3.
ation reaction. For this reason, all phenols that are not
involved in the alkylation reaction must be first protected.
Gauthier et al. have shown that the protection of the phe-
nol functionalities can be achieved by using a pivaloate
group as a protecting group [10]. Thus, 4-hydroxypropi-
ophenone and 4,40-dihydroxybenzophenone were first
transformed into their protected forms, 5 and 6 respec-
tively. McMurry coupling of 5 with 6, using TiCl4/Zn in
THF, gave alkene 8 as a mixture of Z and E isomers in
67% yield. Chloroacetylferrocene 7 was prepared by
alkylation of ferrocene with chloroacetyl chloride using a
Friedel–Crafts reaction. Addition of 7 to the monopotas-
sium salt of 8, obtained from the reaction with KH, pro-
duced 9 in 41% yield. Finally, refluxing of 9 with NaOH
in H2O/THF for 6 h gave 4 as a mixture of Z and E iso-
mers in 72% yield. The separation of the Z isomer from
the E isomer was only achieved with preparative HPLC.
Only the (E) isomer gave crystals of sufficient quality to
perform an X-ray structural analysis which were grown
from hexane/ether solution. Fig. 1 shows the molecular
structure of (E)-4, and the crystal data and structure refine-
ment are summarized in Table 1. The crystallographic
characteristics found are similar to those of the classical
hydroxytamoxifen-like structures [11]. As in the case of
the ferrocifens [5b], the rate of isomerization of 4 depends
on the nature of solvent; neither isomer showed isomeriza-
tion after a week in DMSO.
2.2. Receptor interactions
The relative binding affinity (RBA) of 4 was determined
by competitive binding with radiolabeled [3H]estradiol on
both isoforms of the estrogen receptor (ERa and ERb),
as previously described [5b]. Estradiol, natural hormone,
is used as the reference, and therefore has a RBA of
100%. The results are summarized in Table 2.
2. Results and discussion
2.1. Synthesis
The (Z)-isomer of 4 well recognizes both the ERa and
ERb isoforms of the estrogen receptor (13.9% and 12.8%
respectively). The change in configuration of 4 from (Z) to
(E) results in a dramatic drop in the affinity with both recep-
tor isoforms (1.2% and 1.6%). This is in agreement with pre-
vious results on tamoxifen, ferrocifens and other
triarylethylenes: the estrogen receptor has a preference for
the (Z)-isomer over the (E)-isomer [4b,5b].
The synthetic pathway of 4 is shown in Scheme 1. We
have found that the McMurry coupling reaction is very
effective for the synthesis of alkene organometallic deriva-
tives [5][9]. This coupling reaction is also suitable for the
synthesis of 4. The reaction starts from the cross-coupling
between 4-hydroxypropiophenone and 4,40-dihydroxy-
benzophenone and is followed by a Williamson-type alkyl-

A. Nguyen et al. / Journal of Organometallic Chemistry 692 (2007) 1219–1225
1221
O
O
1) NaH, THF
5
6
2) ClCOC(CH3)3, 2h
100%
HO
Pv
O
O
O
1) NaH, THF
2) ClCOC(CH3)3, 2h
42%
HO
OH
Pv
O
OH
Pv = COC(CH3)3
O
ClCH2COCl
Cl
Fe
Fe
7
AlCl3, CH2Cl2
O
Pv
O
Pv
TiCl4/Zn
1) KH, THF
+
5
6
THF, 4h reflux
67%
2)
7
41%
Pv
O
O
Pv
O
OH
(Z+E)-8
(Z+E)-9
O
O
Fe
Fe
OH
O
α
α
NaOH
(Z+E)-9
+
H2O/THF (1:1)
6h reflux
'
α
'
α
β
β
72%
HO
O
HO
OH
(E)-4
O
(Z)-4
Fe
Scheme 1. Synthetic pathway to ferrocenyl derivatives (Z)-4 and (E)-4.
In order to better understand these binding affinities,
molecular modeling on (E)-4 and (Z)-4 in the antiestro-
genic form of the estrogen receptor was investigated. We
used the LBD structure (Protein Data Bank (PDB) code:
3ERT), published by Shiau [2], and MacSpartan Pro Soft-
ware [12]. 4-Hydroxytamoxifen (OH-Tam) was removed
and replaced successively by the two isomers (E) and (Z)-
4 (Fig. 2). An energy minimization routine was carried
out with all the heavy atoms immobilized, except for those
of the ligand and the His 524 side chain, using the Merck
molecular force field (MMFF). A conformational study
in the cavity was also carried out to determine the best
position for the organometallic moiety in relation to the
rest of the molecule and by taking into account that there
is possibly a hydrogen bonding interaction both between
Asp 351 and the iron atom, as Fe of the ferrocenyl side

1222
A. Nguyen et al. / Journal of Organometallic Chemistry 692 (2007) 1219–1225
chain bears a slight negative charge (Mulliken charge ꢁ
ꢀ0.2), or between Asp 351 and the carbonyl group adja-
cent to the ferrocenyl moiety. The affinity of the bioligand
for the cavity was also determined using MMFF molecular
mechanics, with calculations for the bioligand-cavity com-
bination, and for the cavity and the bioligand done sepa-
rately, each retaining the conformation previously
determined for the molecular complex. This gives a value
of the energy variation DE of the reaction: ligand + cav-
ity ! ligand-cavity complex. The cavity containing the
amino side chain is large enough to host the bulky carbon-
ylferrocenyl group. The energy variation DE found for (Z)-
4 is ꢀ106 kcal molꢀ1 if we consider a direct interaction
between Asp 351 and C@O, and ꢀ89 kcal molꢀ1 with a
direct interaction between Asp 351 and Fe. Either way,
those exothermic values favor association. The [(Z)-4]-cav-
ity complex is twice as stable as that of the [(E)-4]-cavity
according to molecular modeling study which yielded a
value for [(E)-4]-cavity of ꢀ58 kcal molꢀ1s (in case Asp
351 interacts with CO) and ꢀ45 kcal molꢀ1 (in case Asp
351 interacts with Fe). This is consistent with the observed
loss of affinity for the estrogen receptor of the (E)-isomer as
compared to its (Z) counterpart.
Fig. 1. ORTEP diagram of compound (E)-4. Thermal ellipsoids shown at
50% probability. Minor part of the disordered (unsubstituted) Cp ring, the
diethyl ether solvent molecule, and hydrogen atoms omitted for clarity.
Table 1
Crystal data and structure refinement for compound (E)-4 Æ 0.5(C4H10O)
Empirical formula
Formula weight
Crystal System
Space group
C36H35FeO4.50
587.521
Triclinic
ꢀ
P1
Unit cell dimensions
˚
a (A)
10.6911(1)
13.5700(3)
13.7129(1)
68.664(1)
84.440(1)
68.520(1)
1722.87(4)
2
1.148
0.40 · 0.28 · 0.14
0.473
626
0.71073
2.3. Antiproliferative effects
˚
b (A)
˚
c (A)
The antiproliferative effects of (Z)-4 and (E)-4 were
studied on hormone-dependent MCF-7 cells, derived from
a breast cancer line containing the estrogen receptor
(ER+), and on hormone-independent PC-3 prostate cancer
cells, as described previously [6]. Both diastereoisomers
have similar antiproliferative activity, with an average
IC50 value of 10.4 lM on MCF-7 cells and 8.9 lM on
PC-3 cells. This is better than cis-platin (16.7 lM on
MCF-7) [13]. However, it is not as strong as that of the fer-
rocifens (n = 3: IC50 = 0.5 lM), or the ferrocenyl diphenol
10 (IC50 = 0.7 lM) (Chart 2) [5b,7]. The antiproliferative
activity of 4 may be due either to an antihormonal mecha-
nism, or to the cytotoxic character of the ferrocenyl group.
According to the antiproliferative test results, although
there is probably a ligand–receptor interaction occurring,
the bulky carbonylferrocenyl group might not be basic
enough to strongly interact with Asp 351, as observed with
the amino group of the hydroxytamoxifen [3a]. Since this
interaction is required to produce an efficient antihormonal
effect, it may explain the weaker antiproliferative activity of
4 than that of hydroxytamoxifen.
a (ꢁ)
b (ꢁ)
c (ꢁ)
3
˚
Volume (A )
Z
Calculated density (g/cm3)
Crystal size (mm)
Absorption coefficient (mmꢀ1
F(000)
)
˚
Wavelength (A)
Orientation reflections, number, range
(h)
h Range for data collection
Reflections collected
Independent reflections
Data/restraints/parameters
Refinement method
4301, 1.60–29.86
1.60–24.00
8530
5365 [Rint = 0.0286]
5365/30/396
Full-matrix least-squares on
F2
Final R indices [I > 2r(I)]
R Indices (all data)
Goodness-of-fit on F2
R1 = 0.0640, wR2 = 0.1640
R1 = 0.0895, wR2 = 0.1803
0.939
0.76 and ꢀ0.32
3
˚
Largest peak and hole (e/A )
On the other hand, the cytotoxic character of the ferr-
ocenyl group could also be responsible for the antiprolifer-
ative activity of 4. This hypothesis is supported by the
observed antiproliferative effect of 4 on prostate PC-3 can-
cer cells, which lack ERa. This mechanism, illustrated by
the ferrocenyl diphenol 10 and the ferrocifens, may be
based on the generation of a cytotoxic quinone methide,
assisted by the ferrocene moiety [7]. However, the electron
carrier p-system ‘‘ferrocene-double bond-phenol’’ required
for this mechanism is missing in 4. Therefore, the
Table 2
Relative binding affinity of (Z)-4 and (E)-4 with the estrogen receptors (in
DMSO, at 0 ꢁC, for 3 h30) measured as described in Ref. [8]
Compound
RBA (%)
ERa
ERb
17b Estradiol
Hydroxytamoxifen (Z+E)
(Z)-4
(E)-4
100
38.5
13.9
1.2
100
18.5
12.8
1.6

A. Nguyen et al. / Journal of Organometallic Chemistry 692 (2007) 1219–1225
1223
Fig. 2. Representations of (a) (E)-4 and (b) (Z)-4 docked in ERa, assuming a direct interaction between the carbonyl group of 4 with Asp 351.
OH
on the ER negative prostate PC-3 cancer cells. Moreover, it
has been shown that ferrocenyl derivatives can be used as
stable precursors of rhenium and technetium derivatives in
the double ligand-transfer reaction [15]. We found that 4
can indeed be transformed into technetium and rhenium
Fe
analogues. Thus, 4 may be very useful in the synthesis of
new radiopharmaceuticals. This study is now under way.
OH
10
4. Experimental
Chart 2. Ferrocenyl diphenol 10.
4.1. (Z + E) 9
antiproliferative effect observed must follow another mech-
In a Schlenk tube, under inert atmosphere, KH dispersed
anism, which might involve ferricinium ion and hydroxyl
radicals via the Fenton process [14,6].
at 25–35% in oil (0.03 mL, 1.2 mmol, 1.2 equiv.) was added
in 10 mL of anhydrous THF. After stirring for 5 min, a red
solution
1-(p-hydroxyphenyl)-1,2-di(p-trimethylacetoxy-
3. Conclusions
phenyl)but-1-ene (8) (500 mg, 1 mmol, 1 equiv.) in 10 mL
of anhydrous THF was added. The mixture was stirred
under reflux for 25 min. The (1,2-chlorooxoethyl)ferrocene
(7) (348 mg, 1.3 mmol, 1.3 equiv.) in 10 mL of anhydrous
THF was finally added. The solution was heated under
reflux for 24 h. The reaction mixture was hydrolyzed and
extracted with dichloromethane, the organic phase was
washed with water, dried over MgSO4, filtered, and the sol-
vent removed under reduced pressure. By flash chromatog-
raphy, an orange solid 9 (300 mg, 41% yield) was obtained.
In summary, for the first time, an organometallic moiety
has replaced the amino side chain of hydroxytamoxifen. The
substitution did not greatly disrupt the interaction of the
ligand with the estrogen receptor a, as shown in the molec-
ular modeling studies; and the relative binding affinity tests
with the receptor confirm the good affinity of these com-
pounds. Compound 4 exhibits an anti-proliferative activity
on the hormone-dependent MCF-7 breast cancer cells, and

1224
A. Nguyen et al. / Journal of Organometallic Chemistry 692 (2007) 1219–1225
4.2. (Z)-4 and (E)-4
squares refinement and difference Fourier maps in the
SHELXL-97 [21] program. Non-hydrogen atoms were refined
with anisotropic displacement parameters. The hydrogen
atoms were included in the structure factor calculations
at idealized positions. The diethylether solvent molecule
was disordered over the inversion centre, and thus the
occupancy was fixed at 0.5. The unsubstituted cyclopenta-
dienyl ring was disordered over two rotational positions.
These were modeled as rigid pentagons with a major part
occupancy of 80%.
Compound 9 (220 mg, 0.3 mmol) was dissolved in 5 mL
of THF. NaOH (220 mg, excess) in 5 mL of water was
added. The mixture was allowed to stir under reflux for
6 h. The reaction mixture was hydrolyzed and extracted
with dichloromethane, the organic phase was washed with
water, dried over MgSO4, filtered, and the solvent removed
under reduced pressure. By flash chromatography, an
orange-red solid 4 (120 mg, 72% yield) was isolated as a
mixture of Z and E isomers. MS (EI): m/z = 558 [M]+,
121 [CpFe]+. The two isomers were separated by prepara-
tive HPLC (Kromasil C18, MeCN:H2O 70:30). (Z)-Isomer.
1H NMR (400 MHz, DMSO-d6): d 0.83 (t, 3H, J = 7.2 Hz,
CH3CH2), 2.35 (q, 2H, J = 7.2 Hz, CH3CH2), 4.23 (s, 5H,
Cp), 4.61 (t, 2H, Hb of C5H4), 4.88 (t, Ha of C5H4), 5.04 (s,
2H, O–CH2–CO), 6.40 and 6.59 (d, d, 2H, 2H, J = 8.4 Hz,
a0-C6H4), 6.54 and 6.87 (d, d, 2H, 2H, J = 8.2 Hz, b-C6H4),
6.95 and 7.06 (d, d, 2H, 2H, J = 8.4 Hz, a-C6H4), 9.14 and
9.20 (s, s, 1H, 1H, OH). 13C NMR (75.4 MHz, DMSO-d6):
d 13.5 (CH3CH2), 28.5 (CH3CH2), 68.8 (C5H4), 69.7 (Cp),
70.0 (O–CH2–CO), 72.3 (C5H4), 75.9 (Cip, C5H4), 113.6,
114.8, 114.9, 130.1, 130.3, 131.3 (CH of 3C6H4), 132.3,
134.2, 136.3, 136.7, 139.9 (3Cq of C6H4 and C@C), 155.4,
155.7, 155.9 (3Cq of C6H4), 198.4 (CO). IR (KBr):
1663 cmꢀ1 (CO). Anal. Calc. for C34H30O4Fe: C, 72.54; H,
5. Supplementary material
CCDC 626320 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retriev-
ing.html, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
Acknowledgments
`
We thank the Ministere de la Recherche and the Centre
National de la Recherche Scientifique for financial support,
A. Cordaville, M.-A. Plamont and Dr. X. Wang for
technical assistance, M.-N. Rager for 2D-NMR experi-
ments, and Dr. J. Marrot for collecting the crystallographic
data.
1
5.88. Found: C, 72.71; H, 5.58%. (E)-Isomer. H NMR
(400 MHz, DMSO-d6): d 0.81 (t, 3H, J = 7.2 Hz, CH3CH2),
2.33 (q, 2H, J = 7.2 Hz, CH3CH2), 4.28 (s, 5H, Cp), 4.65 (t,
2H, Hb of C5H4), 4.94 (t, Ha of C5H4), 5.19 (s, 2H, O–CH2–
CO), 6.40 and 6.59 (d, d, 2H, 2H, J = 8.4 Hz, a0-C6H4), 6.54
and 6.87 (d, d, 2H, 2H, J = 8.2 Hz, b-C6H4), 6.95 and 7.06
(d, d, 2H, 2H, J = 8.4 Hz, a-C6H4), 9.14 and 9.20 (s, s,
1H, 1H, OH). 13C NMR (75.4 MHz, DMSO-d6): d 13.5
(CH3CH2), 28.3 (CH3CH2), 68.8 (C5H4), 69.8 (Cp), 70.2
(O–CH2–CO), 72.3 (C5H4), 75.9 (Cip, C5H4), 114.4, 114.4,
114.7, 130.0, 130.3, 131.3 (CH of 3C6H4), 132.5, 133.9,
136.6, 140.0 (3Cq of C6H4 and C@C), 155.0, 155.2, 156.6
(3Cq of C6H4), 198.5 (CO). IR (KBr) : 1665 cmꢀ1 (CO).
Anal. Calc. for C34H30O4Fe: C, 72.54; H, 5.88. Found: C,
72.48; H, 5.53%.
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