Synthesis and growth inhibition activity of fluorinated derivatives of tamoxifen

Article abstract of DOI:10.1016/j.bmcl.2013.01.057

The design and synthesis of 11 fluorinated derivatives of tamoxifen are described. Growth inhibition values (GI₅₀) on human HT-29, M21, MCF7, and MDA-MB-231 tumor cells are also reported. In general, the GI₅₀ values are similar or sl

Full text of DOI:10.1016/j.bmcl.2013.01.057

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1712–1715
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and growth inhibition activity of fluorinated derivatives
of tamoxifen
Bianca Malo-Forest a, Grégory Landelle a, Jessye-Ann Roy a, Jacques Lacroix b, René C. Gaudreault b,c
,
Jean-François Paquin a,
⇑
a Canada Research Chair in Organic and Medicinal Chemistry, PROTEO, Département de Chimie, Université Laval, Québec, QC, Canada G1V 0A6
b Unité des Biotechnologies et de Bioingénierie, CRCHUQ, Hôpital Saint-François d’Assise, Québec, QC, Canada G1L 3L5
c Faculté de Médecine, Université Laval, Québec, QC, Canada G1V 0A6
a r t i c l e i n f o
a b s t r a c t
Article history:
The design and synthesis of 11 fluorinated derivatives of tamoxifen are described. Growth inhibition val-
ues (GI50) on human HT-29, M21, MCF7, and MDA-MB-231 tumor cells are also reported. In general, the
GI50 values are similar or slightly higher than tamoxifen with the most active compound on MCF7 cell
Received 21 November 2012
Revised 7 January 2013
Accepted 16 January 2013
Available online 26 January 2013
line having a GI50 = 3.6
ilarly. We hypothesize that this behavior is due to in vitro isomerization of the compounds.
Ó 2013 Elsevier Ltd. All rights reserved.
lM. Surprisingly, as opposed to tamoxifen, both geometrical isomers behave sim-
Keywords:
Tamoxifen
Fluorine
Antiestrogens
Growth inhibition
Synthesis
Tamoxifen (1, Fig. 1) is a selective estrogen receptor modulator
(SERM) that is used in the first-line of treatment for estrogen-
dependent breast cancer since the 1970s.1 Nonetheless, one draw-
back of tamoxifen is the increased occurrence of endometrial tu-
mors.2 On the other hand, introduction of fluorine atoms is now
a common strategy to fine-tune the physico-chemical properties
of a bioactive compound.3 This has led, for example, to the devel-
opment of panomifene (2, Fig. 1)4, which has proved to be superior
to tamoxifen, particularly in preventing the incidence of new can-
cers.5 Notably, in both cases the bioactivity depends on the alkene
geometry.
We recently developed a novel synthetic approach to tetrasub-
stituted monofluoroalkenes (4, Fig. 2).6–8 Starting from commer-
cially available 2,2,2-trifluoro-1-iodoethane (3), this 5-step
sequence enables the stereoselective synthesis of a wide range of
monofluoroalkenes 4 bearing various aryl substituents.
stereoselective synthesis of fluorinated derivatives of tamoxi-
fen11and growth inhibition activities for the compounds prepared.
The first synthetic route, shown in Scheme 1, starts with
4-iodophenol (5) where phenol alkylation using three different 2-
amino-1-chloroethane hydrochloride salts gave 6a–c in moderate
to good yield.12 Following Burton’s protocol13 using CF3CH2I (3),
the b,b-difluorostyrene derivatives 7a–c where generated in good
yields. Iodine/lithium exchange utilizing n-BuLi followed by reac-
tion with chlorotrimethylsilane furnished the a-trimethylsilyl-b,b-
difluorostyrene derivatives 8a–c in low yield for 8a (10%) and good
yields for 8b–c (53–70%).14 The key addition/elimination reaction
of PhLi proceeded to give the tetrasubstituted monofluoroalkenes
9a–c with a 70/30 Z/E selectivity, which is consistent with our
previous studies on related substrates.7 Purification by flash chro-
matography allowed the removal of most or even all the minor E iso-
mers. The transformation of the C–Si bond to a C–Br bond was
attempted using a previously employed bromination/desilicobro-
mination sequence,7,15 but unfortunately these conditions failed to
give the desired bromofluoroalkenes 10. After intensive screening
and optimization, new conditions using n-Bu4NBr3 in MeOH
under microwave heating where developed.16 Thus, when the
trimethylsilylalkenes 9 were subjected to the bromination/desilico-
bromination sequence, the bromofluoroalkenes 10 were isolated,
though in moderate yields, with good Z/E selectivity (up to >97/3).
Chromatographic separation of the desired products from
n-Bu4NBr3 related residues partly explains the low isolated yields.
Given the interest in the development of tamoxifen analogues,9
and the fact that tamoxifen and its derivatives has been shown to
interact with other biological targets,10 we envisioned that the syn-
thetic sequence shown in Figure 2 could potentially be applied to
prepare fluorinated analogues of tamoxifen where the ethyl substi-
tuent would be replaced by a fluorine atom. Herein, we report the
⇑
Corresponding author. Tel.: +1 418 656 2131x11430; fax: +1 418 656 7916.
E-mail address: jean-francois.paquin@chm.ulaval.ca (J.-F. Paquin).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.057

B. Malo-Forest et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1712–1715
1713
Ph
OH
Ph
CF3
H
N
Me2N
Ph
Ph
O
HO
O
Br
a
F
F
Tamoxifen (1)
Panomifene (2)
Figure 1. Structures of tamoxifen (1) and panomifene (2).
X
X
15a
; X = H (Z/E = 76/24)
16
; X = H (Z/E = 71/29)
15b; X = CF3 (Z/E = 88/12)
17; X = CF3 (Z/E = 78/22)
[Si]
Br
(1) Ar2Li
2 steps
F
F
Ar1
Ar1
3
CF3CH2I ( )
Scheme 2. Synthetic route to 16–17. Reagents and conditions: (a) 4-OH-
C6H4B(OH)2, Pd(PPh3)4 cat., K2CO3, PhH/H2O/EtOH, 80 °C, 22–57%.
(2) [Si] → Br
F
Ar2
[Si] = TMS or TES
Ar3B(OH)2
Pd cat.
alcohol was alkylated by 2-bromoethoxy-tert-butyldimethylsi-
lane18 to afford 18 in 85% yield. Conversion of the latter into b,b-
difluorostyrene derivatives 19 was accomplished in 87% yield
using Burton’s protocol.13 Unfortunately, replacement of the iodine
atom for a TMS group, using the condition used previously,14
proceeded sluggishly furnishing 20 contaminated with its reduced
by-product (i.e., hydrogen instead of TMS). The mixture was then
subjected to the key addition/elimination reaction with PhLi,
giving the fluoroalkene 21 in 81% yield for the two steps. Here
again, while the selectivity of the PhLi addition was 70/30, removal
of most of the minor E isomer by flash chromatography was possi-
ble. Bromination/desilicobromination using the newly developed
condition proceeded with a concomitant inconsequential depro-
tection of the TBS protecting group resulting in the alcohol 22.
The alcohol was converted into a bromide using Appel’s condi-
tions19 to give 23 in 63% yield. Finally, nucleophilic substitution
of the bromide using various secondary amines followed by
Suzuki–Miyaura cross-coupling using various arylboronic acid
furnished the fluorinated tamoxifen derivatives 24–27. As a result
this synthetic sequence offers better overall yields, with the possi-
bility of using a single advanced synthetic intermediate (23) for the
synthesis, in two steps, of a number of tamoxifen derivatives.
Finally, to assess the effect of the geometry of the alkene on the
biological activity, compound (Z)-30 was prepared (Scheme 4).
Thus, 4-iodophenol (5) was coupled with bis(pinacolato)diboron
(B2Pin2)20 under palladium catalysis to provide 28. The phenol
was alkylated with 1-(2-chloroethyl)piperidine hydrochloride to
give 29 in 80% yield. Finally, Suzuki–Miyaura cross-coupling of
Ar3
F
Ar1
Ar2
4
Figure 2. Previously developed stereoselective synthetic approach to tetrasubsti-
tuted monofluoroalkenes.
Finally, Suzuki–Miyaura reaction using either phenylboronic or 4-
hydroxyphenylboronic acids under standard conditions7 gave the
fluorinated tamoxifen derivatives 11–14.
To complete our study on the effect of the aminoethyl side-
chain, two derivatives lacking this substituent were prepared
(Scheme 2). In both cases, they were synthesized from previously
reported compounds 15a–b7 through a Suzuki–Miyaura cross-cou-
pling with 4-hydroxyphenylboronic acid. Thus compounds 16 and
17 were obtained in 22–57% yields as Z enriched isomeric mixture
(71/29–78/22).17
While the first synthetic route (cf. Scheme 1) allowed the prep-
aration of four fluorinated derivatives of tamoxifen, the overall
yields were low due to a number of synthetic issues (e.g., 7 ? 8)
or isolation problems (e.g., compounds 10). Based on these obser-
vations, we hypothesized that part of the problems were related to
the early introduction of the dialkylamino group. We therefore de-
signed a second route where it would be introduced later in the se-
quence (Scheme 3). Starting again with 4-iodophenol (5), the
I
TMS
F
I
I
F
F
a
b
c
R
R
F
R
HO
O
O
O
5
6a
7a
8a
; R = NMe2
; R = NMe2
; R = NMe2
6b; R = N(CH2)4
7b; R = N(CH2)4
8b; R = N(CH2)4
6c
; R = N(CH2)5
7c
8c
; R = N(CH2)5
; R = N(CH2)5
d
Ar
Br
TMS
F
f
F
e
F
R
Ph
R
Ph
R
Ph
O
O
O
11
; R = NMe2, Ar = Ph
10a
9a
; R = NMe2
; R = NMe2
12; R = N(CH2)4, Ar = Ph
13
10b; R = N(CH2)4
9b; R = N(CH2)4
10c
; R = N(CH2)5
9c
; R = N(CH2)5
; R = N(CH2)5, Ar = Ph
14; R = N(CH2)5, Ar = 4-(OH)-C6H4
Scheme 1. First synthetic route to fluorinated tamoxifen derivatives 11–14. Reagents and conditions: (a) RCH2CH2ClÁHCl, K2CO3, TBAI, DMF, 50 °C, 68–95%; (b) CF3CH2I, LDA,
ZnCl2, THF, rt then 6a–c, Pd(PPh4)3 (10 mol %), 20–65 °C, 54–88%; (c) n-BuLi, TMSCl, THF, À78 °C to rt, 10–70%; (d) PhLi, THF, À78 °C to rt, 20–74% (Z/E = 95/5 to >97/3); (e) (i)
n-Bu4NBr3, MeOH, 80 °C (MW), (ii) CH3ONa, CH3OH, 0 °C to rt 25–39% (Z/E = 88/12 to >97/3); (f) ArB(OH)2, Pd(PPh3)4 cat., K2CO3, PhH/H2O/EtOH, 80 °C, 22–61%.

1714
B. Malo-Forest et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1712–1715
TMS
F
I
F
F
I
F
a
b
c
5
TBSO
TBSO
TBSO
F
O
O
O
18
19
20
d
Ar
TMS
Ph
Br
f
F
F
g, h
e
R
Ph
TBSO
R
Ph
O
O
O
24
22
; R = OH
21
; R = NMe2, Ar = 4-(OH)-C6H4
23; R = Br
25; R = N(CH2)4, Ar = 4-(OH)-C6H4
26
27
; R = N(CH2)5, Ar = 4-(CH2OH)-C6H4
; R = N(CH2)5, Ar = 4-(CHO)-C6H4
Scheme 3. Second synthetic route to fluorinated derivatives of tamoxifen 24–27. Reagents and conditions: (a) TBSOCH2CH2Br, K2CO3, TBAI, DMF, 0–50 °C, 85%; (b) CF3CH2I,
LDA, ZnCl2, THF, rt then 18, Pd(PPh4)3 (5 mol %), 20–65 °C, 87%; (c) n-BuLi, TMSCl, THF, À78 °C to rt; (d) PhLi, THF, À78 °C to rt, 81% from 19 (Z/E = 97/3); (e) (i) n-Bu4NBr3,
MeOH, 80 °C (MW), (ii) CH3ONa, CH3OH, 0 °C to rt, 84% (Z/E = 85/15); (f) CBr4, PPh3, CH2Cl2, 0 °C to rt, 63%; (g) amine, TBAI cat., MeOH, 65 °C, 81–82%; (h) ArB(OH)2, Pd(PPh3)4
cat., K2CO3, PhH/H2O/EtOH, 80 °C, 20–49%.
The antiproliferative activity of the fluorinated tamoxifen deriv-
atives and tamoxifen was evaluated on four human tumor cell
lines, namely, HT-29 colon carcinoma cells, M21 skin melanoma,
MCF7 estrogen-dependent breast adenocarcinoma, and MDA-MB-
231 estrogen-independent breast adenocarcinoma. Cell growth
inhibition was assessed according to the NCI/NIH Developmental
Therapeutics Program.21 The results are summarized in Table 1
BPin
BPin
a
b
5
N
HO
O
28
29
c
and expressed as the concentration, in
cell growth by 50% (GI50).
lM, of drug inhibiting the
N
O
Comparison of the nature of the amino group on the side-chain
revealed that compound 13 bearing a piperidine moiety is the
more active of the series on all cell lines especially on M21 and
MCF7. Removing completely the side-chain (i.e., compounds 16–
17) resulted in significant loss in activity. Interestingly, compound
F
Ph
16 maintained a significant growth inhibition of 21.3
lM (as com-
Ph
30
pared to 11.2 M for tamoxifen) on MCF7 cell line indicating that
l
with appropriate substituents on the other aromatic rings, the
aminoethoxy side-chain may not be necessary.10,22 4-Hydroxytam-
oxifen is one of the main metabolites of tamoxifen and is more ac-
tive than the parent compound.10,23 In our case, the 4-hydroxy
version of 11 and 12, compounds 24 and 25, respectively, proved
to be slightly more active. The effect is however notable for the
MCF7 cell line where compound 25 is 7-times more potent than
compound 12. Also, from all the fluorinated derivatives of tamox-
ifen generated in this study, compound 24 was the most active
Scheme 4. Synthesis of (Z)-30. Reagents and conditions: (a) B2Pin2, Pd(dppf)Cl2 cat.,
KOAc, DMSO, 80 °C, 35%; (b) (i) K2CO3, DMF, 0 °C, (ii) (CH2)5NCH2CH2ClÁHCl, TBAI
cat., DMF, 50 °C, 80%; (c) (Z)-1-bromo-2-fluoro-1,2-diphenylethene, Pd(PPh3)4 cat.,
K2CO3, PhH/H2O/EtOH, 80 °C, 72%.
Table 1
Growth inhibition activity of compounds (11–14, 16–17, 24–27, 30) on four different
human cancer cell lines
against the MCF7 cell line with a GI50 = 3.6 lM. Conversely, com-
a
Compd
GI50
(
lM)
pound 14 resulting from the addition of a hydroxyl group on 13
was less potent especially on M21 and MDA-MB-231 cell lines.
Replacing the hydroxyl group of compound 14 for a hydroxy-
methyl group (26) or a formyl group (27) resulted in more active
compounds. Interestingly, this order of inhibition differs from the
one found with tamoxifen derivatives where 4-formyltamoxifen
was found to inhibit growth of MCF-7 cells whereas 4-hydroxy-
methyl was found to stimulate growth by acting as an agonist.22,24
Finally, the effect of the geometry of the alkene on the activity was
evaluated as this factor has been shown to be crucial in tamoxifen
activity since (Z)-tamoxifen (also referred to as trans-tamoxifen)
behaves as an antagonist whereas the E isomer (cis-tamoxifen) per-
forms as an agonist.24 Surprisingly, compound 30, the geometrical
isomer of compound 13, gave GI50 values on all the cell lines tested
nearly identical to 13. Given the fact that the ethyl chain on tamox-
ifen has been to shown to have little importance in the affinity for
the estrogen receptor.10 it seems unlikely that the replacement of
the ethyl group for a fluorine atom would transform an agonist into
HT-29
M21
MCF7
MDA-MB-231
Tamoxifen
9.5
10.5
40.3
8.7
11.0
13.5
44.0
5.8
15.9
53.0
89.6
4.4
6.8
5.9
4.2
5.6
11.2
10.4
41.7
6.5
18.8
22.2
>100
14.4
25.8
46.9
104.8
7.3
10.6
12.6
10.6
12.5
11
12
13
14
16
17
24
25
26
27
30
8.9
8.4
32.8
59.8
8.7
8.9
6.9
21.3
71.7
3.6
5.6
7.4
5.9
7.3
5.6
8.8
a
Values are means of three experiments and the deviation from the mean is <10%
of the mean value.
29 with (Z)-1-bromo-2-fluoro-1,2-diphenylethene7 gave 30 in
good yield.

B. Malo-Forest et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1712–1715
1715
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an antagonist. A probable explanation for the observed change in
the biological response could be the in vitro isomerization of the
double bond, which has already been observed with molecules
such as combretastatin A-4. While tamoxifen has been shown
not to isomerize, 4-hydrotamoxifen, a more electron-rich analogue
of tamoxifen, has been shown to isomerize, a transformation either
promoted by cytochromes P45025,26 or through acid catalysis.17 In
our case, the replacement of an ethyl group by a fluorine atom
would increase the electron density at the alkene moiety thus ren-
dering it more reactive. In addition, the fluorine atom would better
stabilize any intermediate (radical or cationic) that may form
6. Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F. Chem. Soc. Rev.
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Champagne, P. A.; Paquin, J.-F. Org. Lett. 2009, 11, 5406; (b) Pigeon, X.;
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Savard, M.-O.; Angers, L.; Paquin, J.-F. Org. Lett. 2011, 13, 1568; (e) Bergeron, M.;
Johnson, T.; Paquin, J.-F. Angew. Chem., Int. Ed. 2011, 50, 11112.
9. For selected recent examples, see (a) Lashley, M. R.; Niedzinski, E. J.; Rogers, J.
M.; Denison, M. S.; Nantz, M. H. Bioorg. Med. Chem. 2002, 10, 4075; (b) Shiina, I.;
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11. Compound 11 (Scheme 1) has been described previously as a 1:1 E/Z mixture in
a study on Clomiphene analogs, see Baumann, R. J.; Bush, T. L.; Cross-Doersen,
D. E.; Cashman, E. A.; Wright, P. S.; Zwolshen, J. H.; Davis, G. F.; Matthews, D. P.;
Bender, D. M.; Bitonti, A. J. Biochem. Pharmacol. 1998, 55, 841.
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16. Malo-Forest, B.; Roy, J.-A.; Paquin, J.-F. J. Fluorine Chem. 2012, 145, 77.
17. A slight erosion of the stereochemistry was observed, probably due to a partial
isomerisation of the 4-hydroxyphenyl derivatives, which was previously
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9489. and references therein.
during isomerization since fluorine is known to stabilize
a-fluoro-
carbon radicals27 or -fluorocarbocation.28 In any case, the isomer-
a
ization may also explain the lack of apparent structure–activity
relationship for some of the compounds prepared.
In summary, we have described the stereoselective synthesis of
11 fluorinated derivatives of tamoxifen and have reported growth
inhibition activity for these compounds. In general, the GI50 values
are similar or slightly better than tamoxifen with the most active
compound on MCF7 cell line having a GI50 = 3.6 lM. Surprisingly,
as opposed to tamoxifen, both geometrical isomers, behave
similarly. We hypothesize that this behavior is due to in vitro
isomerization of the compounds. Experiments to explore this pos-
sible isomerization of the fluorinated analogues of tamoxifen are
underway and will be reported in due course.
Acknowledgments
This work was supported by the Canada Research Chair Pro-
gram, the Natural Sciences and Engineering Research Council of
Canada, the Canada Foundation for Innovation, the Fonds de
recherche sur la nature et les technologies (FQRNT), FQRNT Centre
in Green Chemistry and Catalysis, FQRNT Research Network on
Protein Function, Structure and Engineering (PROTEO) and the Uni-
versité Laval.
18. Borbas, K. E.; Mroz, P.; Hamblin, M. R.; Lindsey, J. S. Bioconjugate Chem. 2006,
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