Development of silicon-containing bis-phenol derivatives as androgen receptor antagonists: Selectivity switching by C/Si exchange

Article abstract of DOI:10.1016/j.bmc.2013.01.060

We previously reported that bis-phenol derivatives, including LG190178 (3a), possess not only vitamin D receptor (VDR) agonistic activity, but also androgen receptor (AR) antagonistic activity. Here, we describe the design, synthesis and evaluation of silicon-containing bis-phenol derivatives, with the objective of obtaining increased selectivity toward VDR or AR. We found that replacement of the quaternary carbon in the bis-phenol skeleton with silicon increased AR-antagonistic activity and reduced VDR-agonistic activity, that is, the AR selectivity of the silicon-containing compounds was higher than that of corresponding carbon compounds. To our knowledge, this is the first report of nuclear receptor (NR) selectivity switching by sila-substitution (C/Si exchange). Among the compounds synthesized, AR-selective ligand (S,R)-3b exhibited more potent anti-androgenic activity (IC₅₀ = 0.072 μM) than hydroxyflutamide, a well-known androgen antagonist (IC₅₀ = 1.4 μM), in SC-3 cell proliferation assay. These results suggest that sila-substitution is a useful approach for structural development of selective AR ligands.

Full text of DOI:10.1016/j.bmc.2013.01.060

Bioorganic & Medicinal Chemistry 21 (2013) 1643–1651
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Development of silicon-containing bis-phenol derivatives
as androgen receptor antagonists: Selectivity switching
by C/Si exchange
b
a
Masaharu Nakamura a, , Makoto Makishima , Yuichi Hashimoto
⇑
a Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
b Department of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We previously reported that bis-phenol derivatives, including LG190178 (3a), possess not only vitamin D
receptor (VDR) agonistic activity, but also androgen receptor (AR) antagonistic activity. Here, we describe
the design, synthesis and evaluation of silicon-containing bis-phenol derivatives, with the objective of
obtaining increased selectivity toward VDR or AR. We found that replacement of the quaternary carbon
in the bis-phenol skeleton with silicon increased AR-antagonistic activity and reduced VDR-agonistic
activity, that is, the AR selectivity of the silicon-containing compounds was higher than that of corre-
sponding carbon compounds. To our knowledge, this is the first report of nuclear receptor (NR) selectivity
switching by sila-substitution (C/Si exchange). Among the compounds synthesized, AR-selective ligand
Received 9 January 2013
Revised 25 January 2013
Accepted 28 January 2013
Available online 6 February 2013
Keywords:
Silicon
Vitamin D receptor
Androgen receptor
Bis-phenol derivative
(S,R)-3b exhibited more potent anti-androgenic activity (IC50 = 0.072
well-known androgen antagonist (IC50 = 1.4 M), in SC-3 cell proliferation assay. These results suggest
that sila-substitution is a useful approach for structural development of selective AR ligands.
Ó 2013 Elsevier Ltd. All rights reserved.
lM) than hydroxyflutamide, a
l
1. Introduction
OH
H
H
The biologically active form of vitamin D3, 1a,25-dihydroxyvi-
H
H
tamin D3 (1,25-VD3) (1) (Fig. 1), is a secosteroid hormone that reg-
ulates calcium homeostasis, bone metabolism, proliferation and
differentiation of various types of cells, and is also involved in im-
mune modulation.1–5 Almost all of these activities of 1,25-VD3 are
considered to be mediated by binding to and activating nuclear
vitamin D receptor (VDR) as a specific transcription factor.3,4 Re-
cently, it has been reported that 1,25-VD3 has a potent differentia-
tion-inducing activity in leukemic cells6,7 and growth-inhibitory
activity towards various types of cancer cells, including those of
prostate, breast and colon.8–11 Thousands of vitamin D analogs
with a secosteroidal skeleton have been designed and synthesized
so far.12 1,25-VD3 (1) and other synthetic vitamin D analogs, such
as alfacalcidol (2) (Fig. 1), have been used clinically to regulate cal-
cium metabolism and for treatment of psoriasis and osteoporo-
sis.13 However, these drugs often induce side effects, such as
hypercalcemia.
HO
OH
HO
OH
1α, 25-dihydroxyvitamin D3 (1)
Alfacalcidol (2)
Figure 1. Chemical structures of 1
alfacalcidol (2).
a,25-dihydroxyvitamin D3 (1,25-VD3) (1) and
gene assays (EC50 = 40–600 nM), and show monocytic cell differen-
tiation-inducing activity toward human leukemia cell line HL-60
(EC50 = 30–800 nM), growth inhibition of human prostate tumor
cell line LNCaP (EC50 = 20–300 nM), regulation of VDR target gene
expression in vivo, and other activities.
Recently, we reported the design and synthesis of various
LG190178 analogs.16,17 Among them, nitrogen analogs of
LG190178, including (R,S)-DPP-1023 (6) (Fig. 3), showed higher
vitamin D3-agonistic activity than LG190178 (3a). During our
structural development studies, we found that these nonsecoster-
oidal vitamin D derivatives also possess androgen receptor (AR)
antagonistic activity.
Boehm et al. have reported a series of nonsecosteroidal vitamin
D
derivatives, including LG190178 (3a), LG190176 (4b) and
LG190155 (5c), with a bis-phenol skeleton (Fig. 2).14,15 These com-
pounds exhibit significant potency and activity in VDR reporter
It is clearly of interest to separate the activities of these com-
pounds. Furthermore, sila-substitution (C/Si exchange) of existing
⇑
Corresponding author. Tel.: +81 3 5841 7847; fax: +81 3 5841 8495.
E-mail address: nakamura-nk@iam.u-tokyo.ac.jp (M. Nakamura).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.01.060

1644
M. Nakamura et al. / Bioorg. Med. Chem. 21 (2013) 1643–1651
O
O
O
O
OH
O
O
O
O
O
OH
OH
O
LG190176 (4b)
LG190155 (5c)
LG190178 (3a)
Figure 2. Chemical structures of nonsecosteroidal vitamin D derivatives, LG190178 (3a), LG190176 (4a) and LG190155 (5a).
synthetic methods, as illustrated in Scheme 1. 4,40-(Diet-
hylsilanediyl)bis(2-methylphenol) (8) was prepared according to
the reported method.26 Briefly, 4-bromo-2-methylphenol (7) was
reacted with dichlorodiethylsilane in the presence of n-butyllith-
ium (n-BuLi) in tetrahydrofuran (THF). Compounds 5b and 9 were
prepared by reaction of 8 with 1-chloropinacolone. By the use of an
optically pure isoform of glycidol in reactions c and e in Scheme 1,
optically pure diol (S)-10 and (R)-10 could be obtained, respec-
tively. Reduction of diol (S)-10 or (R)-10 with sodium borohydride
(NaBH4) gave an epimeric mixture of triols (RS,S)-3b and (RS,R)-3b,
which were separated by chiral HPLC to give pure optical isomers
(R,S)-3b, (S,S)-3b, (R,R)-3b and (S,R)-3b. [In this paper, all struc-
tures are drawn so as to put the pivaloyl moiety or its reduced form
(if present) on the left side, and the vicinal diol moiety (if present)
on the right side. For pure optical isomers of 3b, the configurations
(S or R) of the left- and right-side chains are represented by the
first and second letters, respectively, in parentheses before the
compound number].
The absolute stereoconfigurations of these compounds were
determined by comparison of the HPLC retention times with those
of authentic optically pure triols (R,S)-3b0 and (R,R)-3b0, which were
separately prepared by asymmetric synthesis as illustrated in
Scheme 2. Specifically, (R)-2-methyl-CBS(Corey–Baski–Shibata)-
oxazaborolidine-catalyzed asymmetric borane reduction27 of 9 gave
optically active alcohol (R)-11 in 93% ee. The absolute stereoconfig-
uration of (R)-11 was determined by the modified Mosher’s method
(R)
(S)
N
H
O
OH
OH
OH
(R,S)-DPP-1023 (6)
Figure 3. Chemical structure of (R,S)-DPP-1023 (6).
drugs is an attractive approach to find new drug candidates with a
clear intellectual property position and has the potential to im-
prove various biological properties, including selectivity, potency,
pharmacokinetics, pharmacodynamics and cell penetration.18–21
Indeed, several organosilicon agents have advanced to clinical
studies.22–25 Therefore, we planned to substitute a silicon atom
for a carbon atom in the bis-phenol derivatives with the objective
of increasing the selectivity for VDR or AR.
Here, we describe the design and synthesis of organosilicon
analogs of bis-phenol derivatives, and evaluation of their biological
activities by means of VDR and AR reporter gene assays, as well as
SC-3 cell growth inhibition assay (as a measure of androgen-antag-
onistic activity).
2. Chemistry
Based on our previous work,16 we first planned to introduce sil-
icon in place of the quaternary carbon in LG190178 (3a), which
exhibits significant activity in VDR reporter gene assays and in cell
growth inhibition assays against various types of cancer cells. Sili-
con-containing LG190178 analogs were prepared by usual organic
(NMR) using (+)- or (ꢀ)-
a-methoxy-a-(trifluoromethyl)phenylace-
tyl (MTPA) esters 12 and 13.28 By the use of optically pure isoforms
of glycidol, optically pure authentic triols (R,S)-3b0 and (R,R)-3b0
Br
Si
a
b
Si
Si
+
HO
O
O
O
OH
HO
OH
O
O
O
7
5b
9
8
Si
(R)
(S)
O
O
OH
OH
OH
c
d
(R, S)-3b
Si
Si
9
(S)
(S)
O
O
OH
O
O
OH
Si
O
OH
OH
OH
(S)
(S)
(RS, S)-3b
(S)-10
O
O
OH
OH
OH
OH
(S, S)-3b
Si
(R)
(R)
O
O
OH
OH
e
f
Si
Si
(R, R)-3b
9
(R)
(R)
O
O
OH
O
O
OH
Si
O
OH
OH
OH
(S)
(R)
(RS, R)-3b
(R)-10
O
O
OH
OH
OH
(S, R)-3b
Scheme 1. Synthesis of the silicon-containing LG190178 analog 3b. Reagents and conditions: (a) n-BuLi, THF, dichlorodiethylsilane, ꢀ78 °C then rt, 6 h, 39%; (b) 1-
chloropinacolone, sodium hydride (NaH), DMF, 0 °C then rt, 5.5 h, 22% (5b), 20% (9); (c) (S)-glycidol, NaH, DMF, 0 °C then 80 °C, 3.5 h, 46%; (d) NaBH4, MeOH, rt 1 h, 84%; (e)
(R)-glycidol, NaH, DMF, 0 °C then 80 °C, 3.5 h, 39%; (f) NaBH4, MeOH, rt 1 h, 81%.

M. Nakamura et al. / Bioorg. Med. Chem. 21 (2013) 1643–1651
1645
Si
(R)
O
O-(S)-MTPA
O-(S)-MTPA
a
Si
b
12
13
9
NMR
(The modified
Mosher's method)
(R)
O
OH
Si
OH
(R)-11
(R)
O
O-(R)-MTPA
O-(R)-MTPA
Si
c
(R)
(S)
O
O
OH
OH
OH
(R, S)-3b'
(R)-11
Si
d
(R)
(R)
O
O
OH
OH
OH
(R, R)-3b'
Scheme 2. Asymmetric synthesis of (R,S)-3b0 and (R,R)-3b0. Reagents and conditions: (a) (R)-2-methyl-CBS-oxazaborolidine cat., borane N-ethyl-N-isopropylaniline complex,
THF, 20 °C, 1 h, 92%, 93% ee; (b) (R) or (S)-MTPA-Cl, pyridine, CH2Cl2, rt, 20 h; (c) (R)-glycidol, K2CO3, acetone, 60 °C, 6 h, 31%, >99% ee; (d) (S)-glycidol, K2CO3, acetone, 60 °C,
6 h, 20%, >99% ee.
3. Results and discussion
a
Si
9
3.1. Reporter gene assay
O
O
O
O
4b
The selectivities of the synthesized compounds toward VDR
and/or AR were evaluated by using reporter gene assay systems.
We first compared the activity of LG-compounds and the corre-
Scheme 3. Synthesis of the silicon-containing LG190176 analog 4b. Reagents and
conditions: (a) epichlorohydrin, NaH, DMF, 0 °C then 120 °C, 3.5 h, 64%.
sponding silicon analogs (Table 1). 1
(1,25-VD3) (1) showed very potent VDR transcriptional activity
with an EC50 value of 0.003 M. In this paper, the VDR transcrip-
tional activity of synthesized compounds is given as PC50 value,
which is defined as the test chemical concentration estimated to
elicit 50% of the positive control (PC) transcription activity ob-
a,25-Dihydroxyvitamin D3
could be obtained, and their HPLC retention times were consistent
with those of (R,S)-3b and (R,R)-3b, respectively.
The silicon-containing LG190176 analog 4b was synthesized by
reaction of 9 with epichlorohydrin (Scheme 3). LG190178 (3a),
LG190176 (4a) and LG190155 (5a) were prepared according to
the reported method.14
Next, we planned to prepare the aza-analogs of (R)-10 and (S)-
10, that is (R)-17 and (S)-17, based on our earlier development
studies on nitrogen-containing vitamin D3 antagonists, DLAMs.29
Compounds (S)-17 and (R)-17 were prepared by the method illus-
trated in Scheme 4. Compound 14 was prepared by the triflation of
9. Buchwald–Hartwig’s amination30,31 reaction of 14 gave 15. After
debenzylation of 15, optically pure diol (R)-17 and (S)-17 could be
obtained by the use of optically pure isoforms of glycidol in reac-
tions d and e in Scheme 4, respectively.
l
tained with 10
VDR transcriptional activity with the PC50 value of 0.14
corresponding silicon compound, that is compound 3b, also
showed rather strong VDR-agonistic activity (PC50 = 0.92 M), but
it was less potent than the carba-analog 3a. The VDR-agonistic
activity of LG190178 (4a) was also strong (PC50 = 0.68 M), and
that of its sila-analog 4b was only moderate (PC50 = 4.8 M).
LG190155 (5a) showed moderate VDR-agonistic activity with the
PC50 value of 4.6 M, and replacement of the quaternary carbon
lM 1,25-VD3 (1). LG190178 (3a) showed potent
l
M. The
l
l
l
l
of LG190155 (5a) with a silicon atom, that is, compound 5b, re-
sulted in disappearance of the VDR-agonistic activity. Overall,
Si
Si
a
b
9
O
N
H
O
OTf
O
O
15
14
Si
d
e
(R)
N
H
O
O
OH
OH
O
O
OH
c
Si
(R)-17
O
NH2
Si
O
16
(S)
N
H
OH
(S)-17
Scheme 4. Synthesis of the aza-analogs (R)-17 and (S)-17. Reagents and conditions: (a) triflic anhydride, triethylamine, CH2Cl2, rt, 1 h, 88%; (b) palladium diacetate, BINAP,
Cs2CO3, benzylamine, toluene, 100 °C, 6 h, 72%; (c)Pd/C, H2, EtOH, 61%; (d) (S)-glycidol, ethanol, 75 °C, 11 h, 42%; (e) (R)-glycidol, ethanol, 75 °C, 11 h, 47%.

1646
M. Nakamura et al. / Bioorg. Med. Chem. 21 (2013) 1643–1651
Table 1
The results of VDR and AR reporter gene assays of LG-compounds
X
X
X
O
O
OH
O
O
O
O
O
OH
OH
O
O
O
5a (X = C : LG190155)
5b (X = Si)
3a (X = C : LG190178)
3b (X = Si)
4a (X = C : LG190176)
4b (X = Si)
M)a,c
AR IC50
(
lM) (inhibition% at 10
l
M)
VDR(PC50)/AR(IC50)
b,c
d
Compound
X =
VDR PC50
(l
LG190178 (3a)e
3be
C
Si
C
Si
C
Si
—
—
0.14
0.92
0.68
4.8
>>10 (16%)
6.8
>>10 (12%)
>10 (49%)
>10 (44%)
6.2
<0.014
0.14
<0.068
ca.0.48
<0.46
>4.8
LG190176 (4a)f
4bf
LG190155 (5a)
5b
Hydroxyflutamide
1,25-VD3 (1)
4.6
>30
Inactiveg
0.3
>10 (45%)
—
—
0.003 (EC50
)
a
b
c
d
e
f
VDR transcriptional activity.
AR transcription-inhibitory activity.
Data are the means of three experiments.
VDR(PC50)/AR(IC50) was defined as VDR transcriptional activity (PC50 value)/AR transcription-inhibitory activity (IC50 value).
Diastereomeric mixture.
Enantiomeric mixture.
No activity was observed in the concentration range examined.
g
therefore, C/Si exchange of compounds 3-5 reduced the VDR-ago-
nistic activity.
None of the compounds listed in Table 1 showed AR-agonistic
activity, as evaluated by AR reporter gene assay in the presence
of testosterone (0.3 nM). Hydroxyflutamide, which is a well-known
androgen antagonist, showed strong AR transcription-inhibitory
VDR reporter gene assay, (R,S)-3b showed the strongest activity
with the PC50 value of 0.81 M. Its antipode, that is, compound
(S,R)-3b, showed the weakest activity (PC50 >10 M). This ten-
dency was consistent with that of the VDR binding affinities of
LG190178 stereo-isomers.16 Deletion of the vicinal diol moiety
on the right side of (R,S)-3b (compound (R)-11) resulted in a de-
crease of VDR-agonistic activity. The AR-antagonistic activities of
l
l
activity with the IC50 value of 0.3
ties of carbon compounds 3a, 4a and 5a were all weak with IC50
values larger than 10 M. Interestingly, the corresponding silicon
lM. The AR-antagonistic activi-
these optical isomers were moderate (IC50 = 5.8–7.4
lM), and the
l
IC50 value of compound (R)-11 was higher than 10 M. As a result,
l
compounds, that is, compounds 3b, 4b and 5b, exhibited higher
AR-antagonistic activities than 3a, 4a and 5a, respectively. A com-
parison of the results of VDR and AR reporter gene assays revealed
that the introduction of the silicon atom into the bis-phenol skele-
ton enhanced AR-antagonistic activity and reduced VDR-agonistic
activity. In consequence, the AR selectivities (VDR/AR value) of
silicon-containing compounds 3b, 4b and 5b were higher than that
of the corresponding carbon compounds.
Since the silicon-containing LG190178 analog, that is com-
pound 3b, showed higher AR selectivity than LG190178 (3a), we
next evaluated optically pure isomers of 3b and (R)-11 in the same
manner as described above. The results are shown in Table 2. In the
(S,R)-3b exhibited the highest AR selectivity among the isomers of
3b, and its AR selectivity (VDR/AR value) was more than 100 times
greater than that of LG190178 (3a).
Next, the VDR-agonistic/AR-antagonistic activity ratios of com-
pounds (R)- and (S)-10 and aza-analogs (R)- and (S)-17 were evalu-
ated (Table 3). Compound (S)-17 showed moderate VDR
transcriptional activity with the PC50 value of 2.5
(R)-17 and compounds (R)- and (S)-10 also showed moderate
VDR-agonistic activity with PC50 values of 2.0–7.0 M. In the AR re-
portergeneassay, compound(R)-10 showed moderateAR transcrip-
tion-inhibitory activity with the IC50 value of 4.0 M. On the other
hand, the IC50 values of other compounds were higher than 10 M.
lM. Its antipode
l
l
l
Table 2
Results of VDR and AR reporter gene assays of optically pure isomers of 3b and compound (R)-11
X
X
chiral-1
*
chiral-2
*
(R)
O
O
OH
O
OH
OH
OH
OH
3b
(R)-11
a,c
b,c
d
Compound
X =
VDR PC50
(lM)
AR IC50
(l
M) (inhibition% at 10
lM)
VDR(PC50)/AR(IC50)
(R,S)-3be
(S,S)-3be
(R,R)-3be
(S,R)-3be
(R)-11
Si
Si
Si
Si
Si
0.81
2.2
2.1
>10
8.2
5.8
8.3
6.7
7.4
0.14
0.27
0.31
>1.4
—
>10 (47%)
a
b
c
VDR transcriptional activity.
AR transcription-inhibitory activity.
Data are the means of three experiments.
VDR(PC50)/AR(IC50) was defined as VDR transcriptional activity (PC50 value)/AR transcription-inhibitory activity (IC50 value).
The chiralities are indicated as (chiral-1, chiral-2).
d
e

M. Nakamura et al. / Bioorg. Med. Chem. 21 (2013) 1643–1651
1647
Table 3
Results of VDR and AR reporter gene assays of compounds (R)- and (S)-10 and aza-analogs (R)- and (S)-17
X
O
R
O
a,c
b,c
d
Compound
X =
R =
VDR PC50
(
lM)
AR IC50
(l
M) (inhibition % at 10
lM)
VDR(PC50)/AR(IC50)
(S)-17
(R)-17
(S)-10
(R)-10
Si
Si
Si
Si
2.5
7.0
2.0
3.7
>10 (44%)
>10 (38%)
>10 (44%)
4.0
—
—
—
0.93
a
b
c
VDR transcriptional activity.
AR transcription-inhibitory activity.
Data are the means of three experiments.
VDR(PC50)/AR(IC50) was defined as VDR transcriptional activity (PC50 value)/AR transcription-inhibitory activity (IC50 value).
d
the isomers of the silicon-containing LG190178 analog 3b, showed
strong anti-androgenic activity with an IC50 value of 0.072 M in
Table 4
l
Androgen-antagonistic activity
SC-cell proliferation-inhibitory assay. It is 20 times more potent
than the well-known androgen antagonist, hydroxyflutamide
(IC50 = 1.4 lM). Our results suggest that sila-substitution (C/Si ex-
change) is a useful approach for structural development of AR-
OH
O2
S
H
N
H
OH
F3C
NC
F3C
O2N
N
O
O
F
Bicalutamide
Hydroxyflutamide
selective ligands.
a
Compound
SC-3 IC50 (lM)
5. Experimental
5.1. Chemistry
(S,R)-3b
(R)-10
Hydroxyflutamide
Bicalutamide
0.072
0.113
1.4
3.0
a
5.1.1. General
Inhibitory activity on testosterone-induced cell growth of androgen-dependent
1H NMR spectra were recorded on a JEOL JNM-GX500 and JNM-
ECA-500 (500 MHz) spectrometer. Chemical shifts for 1H NMR are
reported in parts per million (ppm) downfield from tetramethylsil-
ane (d) and coupling constants are in hertz (Hz). The following
abbreviations are used for spin multiplicity: s = singlet, d = doublet,
t = triplet, q = quartet, quint = quintet, sept = septet, m = multiplet,
br = broad. Chemical shifts for 13C NMR are reported in ppm rela-
tive to the centerline of the triplet at 77.0 ppm for deuteriochloro-
cell line SC-3. Data are the means of three experiments.
3.2. Cell growth-inhibitory activity assay as a measure of
androgen-antagonistic activity
Androgen-antagonistic activities of representative AR-selective
ligands were evaluated in terms of inhibitory activity on testoster-
one-induced cell growth of androgen-dependent mouse mammary
carcinoma cell line SC-3.32,33 As shown in Table 4, (S,R)-3b, which
exhibited the highest AR selectivity among the stereo-isomers of
the silicon-introduced LG190178 analog 3b, showed strong anti-
form. Mass spectra were recorded on
a JEOL JMS-HX110
spectrometer. Melting points were determined on a MP-J3 melting
point apparatus (Yanaco, Japan). Routine thin layer chromatogra-
phy (TLC) and preparative TLC (PTLC) were performed on silica
gel 60 F254 plates (Merck, Germany). Flash column chromatogra-
phy was performed on Silica gel 60 (spherical, particle size 40–
androgen activity with the IC50 value of 0.072
more potent than the well-known androgen antagonist, hydroxy-
flutamide (IC50 = 1.4 M). Compound (R)-10 also showed strong
lM. It was 20 times
l
100 lm; Kanto).The purity of tested compounds was determined
activity with an IC50 value of 0.113 lM.
by ultra-high-performance liquid chromatography (UHPLC (Nexera
system, Shimadzu, Japan)) [YMC-UltraHT Hydrosphre C18 column
(75 ꢁ 3.0 mm I.D. S-3, 12 nm), 20–90% acetonitrile in H2O with
0.1% phosphoric acid for 8.5 min, 0.8 mL/min, 40 °C, UV detection:
254 nm]. All tested compounds showed >95% purity in UHPLC (see
Supplementary data).
4. Conclusion
We designed and synthesized silicon-containing bis-phenol
derivatives with the aim of increasing the selectivity of the com-
pounds for VDR or AR, since we had previously found that bis-phe-
nol derivatives showed androgen-antagonistic activity, and the
selectivity could be changed by modifying the structure.16,17 The
results of VDR and AR reporter gene assays revealed that substitu-
tion of the silicon atom for carbon in the bis-phenol skeleton gen-
erally enhanced AR activity and reduced VDR activity. In
consequence, the AR selectivity of the silicon-containing com-
pounds was higher than that of corresponding carbon compounds.
To our knowledge, this is the first report of nuclear receptor (NR)
selectivity switching by sila-substitution (C/Si exchange). Com-
pound (S,R)-3b, which exhibited the highest AR selectivity among
5.1.2. 3-(4-(3-(4-(2-Hydroxy-3,3-dimethylbutoxy)-3-methyl-
phenyl)pentan-3-yl)-2-methylphenoxy)propane-1,2-diol
LG190178 (3a)
LG190178 (3a) was prepared according to the reported meth-
od.14 1H NMR (500 MHz, CDCl3): d 6.96–6.94 (m, 2H), 6.91–6.89
(m, 2H), 6.70 (d, 2H, J = 8.5 Hz), 4.12–4.07 (m, 2H), 4.03 (d, 2H,
J = 4.9 Hz), 3.87–3.84 (m, 2H), 3.77 (dd, 1H, J = 5.5, 11.6 Hz), 3.70
(d, 1H, J = 8.5 Hz), 2.17 (s, 3H), 2.16 (s, 3H), 2.04 (q, 4H,
J = 7.3 Hz), 1.01 (s, 18H), 0.59 (t, 6H, J = 7.3 Hz). 13C NMR
(500 MHz, CDCl3):
d 154.32, 154.01, 141.41, 141.09, 130.66,

1648
M. Nakamura et al. / Bioorg. Med. Chem. 21 (2013) 1643–1651
130.63, 126.24, 126.12, 125.51, 125.38, 110.13, 110.10, 77.31,
70.47, 69.22, 63.90, 48.44, 33.56, 29.29, 26.05, 16.59, 16.52,
14.17, 8.42. MS (FAB+) m/z: 485 (M+).
acetate. The extract was successively washed with water and brine,
and then dried over MgSO4. The solvent was evaporated, and the
residue was purified by means of silica gel column chromatogra-
phy (hexane/ethyl acetate = 9/1) to give 5b (347 mg, 20.4%) and 9
(304 mg, 22.2%). 5b: white solid, mp: 99–100 °C,1H NMR
(500 MHz, CDCl3): d 7.26 (s, 2H), 7.22 (d, 2H, J = 7.9 Hz), 6.59 (d,
2H, J = 7.9 Hz), 4.87 (s, 4H), 2.28 (s, 6H), 1.26 (s, 18H), 1.01–0.97
(m, 10H). 13C NMR (500 MHz, CDCl3): d 209.67, 157.18, 137.51,
133.80, 128.00, 126.43, 110.41, 69.17, 43.20, 26.34, 16.40, 7.45,
4.18. MS (FAB+) m/z: 497(M+). Compound 9: White solid, mp:
117–119 °C, 1H NMR (500 MHz, CDCl3): d 7.26–7.22 (m, 2H), 7.19
(d, 1H, J = 7.9 Hz), 6.76 (d, 1H, J = 7.9 Hz), 6.59 (d, 1H, J = 7.9 Hz),
4.87 (s, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.26 (s, 9H), 1.01–0.95 (m,
10H). 13C NMR (500 MHz, CDCl3): d 209.84, 157.20, 154.82,
137.71, 137.52, 134.12, 133.77, 128.13, 127.52, 126.46, 123.09,
114.51, 110.42, 69.18, 43.20, 26.34, 16.40, 15.70, 7.46, 4.20. MS
(FAB+) m/z: 398 (M+).
5.1.3. 3,3-Dimethyl-1-(2-methyl-4-(3-(3-methyl-4-(oxiran-2-
ylmethoxy)phenyl)pentan-3-yl)phenoxy)butan-2-one:
LG190176 (4a)
LG190176 (4a) was prepared according to the reported meth-
od.14 1H NMR (500 MHz, CDCl3): d 6.93–6.88 (m, 4H), 6.67 (d, 1H,
J = 8.4 Hz), 6.49 (d, 1H, J = 8.4 Hz), 4.83 (s, 2H), 4.18 (dd, 1H,
J = 3.4, 9.4 Hz), 3.95 (dd, 1H, J = 5.4, 11.0 Hz), 3.37–3.34 (m, 1H),
2.90–2.89 (m, 1H), 2.78–2.77 (m, 1H), 2.23 (s, 3H), 2.19 (s, 3H),
2.00 (q, 4H, J = 7.3 Hz), 1.25 (s, 18H), 0.58 (t, 6H, J = 7.3 Hz). MS
(FAB+) m/z: 438 (M+).
5.1.4. 1,10-((Pentane-3,3-diylbis(2-methyl-4,1-
phenylene))bis(oxy))bis(3,3-dimethylbutan-2-one): LG190155
(5a)
LG190155 (5a) was prepared according to the reported meth-
od.14 white solid, mp: 106–108 °C, 1H NMR (500 MHz, CDCl3): d
7.27–7.25 (m, 2H), 6.89 (d, 2H, J = 8.5 Hz), 6.49 (d, 2H, J = 8.5 Hz),
4.83 (s, 2H), 2.23 (s, 6H), 2.00 (q, 4H, J = 7.3 Hz), 1.24 (s, 18H),
0.58 (t, 6H, J = 7.3 Hz). 13C NMR (500 MHz, CDCl3): d 210.01,
153.99, 141.44, 130.77, 126.09, 125.95, 110.18, 69.62, 48.46,
43.22, 29.31, 26.35, 16.62, 8.49. MS (FAB+) m/z: 480 (M+).
5.1.8. (S)-1-(4-((4-(2,3-Dihydroxypropoxy)-3-
methylphenyl)diethylsilyl)-2-methylphenoxy)-3,3-
dimethylbutan-2-one((S)-10)
To a solution of 9 (245 mg, 0.62 mmol) in dry N,N-dimethylform-
amide (3 mL) was added sodium hydride (27 mg of a 60% suspension
in mineral oil, 0.68 mmol) at 0 °C, and the mixture was stirred at the
same temperature for 0.5 h. To this was added (S)-glycidol
(0.044 mL, 0.68 mmol), and stirring was continued at 80 °C for 3 h.
The reaction was quenched with H2O, and the whole was extracted
with ethyl acetate. The extract was successively washed with water
and brine, and then dried over MgSO4. The solvent was evaporated,
and the residue was purified by means of silica gel column chroma-
tography (hexane/ethyl acetate = 4/1 to 1/1) to give (S)-10 (134 mg,
46.2%) as a colorless oil. 1H NMR (500 MHz, CDCl3): d 7.29–7.22 (m,
4H), 6.81 (d, 1H, J = 7.9 Hz), 6.59 (d, 1H, J = 7.9 Hz), 4.87 (s, 2H), 4.14–
4.10 (m, 1H), 4.05 (d, 2H, J = 4.9 Hz), 3.85 (dd, 1H, J = 3.7, 11.0 Hz),
3.76 (dd, 1H, J = 5.5, 11.0 Hz), 2.28 (s, 3H), 2.21 (s, 3H), 1.25 (s, 9H),
1.02–0.97 (m, 10H). 13C NMR (500 MHz, CDCl3): d 209.78, 157.30,
157.16, 137.47, 137.27, 134.02, 133.73, 127.97, 127.77, 126.42,
125.87, 110.49, 110.41, 70.43, 69.12, 68.85, 63.80, 43.20, 26.30,
16.37, 16.26, 7.42, 4.14. HRMS (FAB+) m/z: calcd for C27H40O5Si
472.2645, found 472.2654 (M+).
5.1.5. 1-(4-(3-(4-Hydroxy-3-methylphenyl)pentan-3-yl)-2-
methylphenoxy)-3,3-dimethylbutan-2-one (6a)
Compound 6a was prepared according to the reported meth-
od.14 Pale yellow paste. 1H NMR (500 MHz, CDCl3): d 6.91–6.88
(m, 3H), 6.83 (d, 1H, J = 7.9 Hz), 6.63 (d, 1H, J = 7.9 Hz), 6.49 (d,
1H, J = 7.9 Hz), 4.83 (s, 2H), 2.22 (s, 6H), 2.00 (q, 4H, J = 6.7 Hz),
1.24 (s, 9H), 0.58 (t, 6H, J = 6.7 Hz). 13C NMR (500 MHz, CDCl3): d
210.36, 153.90, 151.39, 141.59, 140.84, 130.74, 130.54, 126.58,
126.02, 125.94, 122.54, 113.99, 110.15, 69.58, 48.39, 43.20, 29.29,
26.31, 16.58, 16.62, 8.40. MS (FAB+) m/z: 382 (M+).
5.1.6. 4,40-(Diethylsilanediyl)bis(2-methylphenol) (8)
To a solution of 4-bromo-o-cresol (7) (6.0 g, 32 mmol) in dry tet-
rahydrofuran (36 mL) was added n-butyl lithium in n-hexane
(2.69 M, 27.6 mL, 75.6 mmol) under an Ar atmosphere at ꢀ78 °C.
The mixture was stirred at the same temperature for 1 h, and then
added to a solution of dichlorodiethylsilane (1.6 mL, 10.6 mmol) in
dry tetrahydrofuran (1.6 mL) at ꢀ78 °C, and stirring was continued
at room temperature for 5.5 h. The reaction was quenched with
NH4Cl aq, and the whole was extracted with ethyl acetate. The ex-
tract was successively washed with water and brine, and then dried
over MgSO4. The solvent was evaporated, and the residue was puri-
fied by means of silica gel column chromatography (hexane/ethyl
acetate = 9/1 to 5/1) to give 8 (1.24 g, 39.1%) as a white solid. mp:
110–112 °C, 1H NMR (500 MHz, CD3OD): d 7.15 (s, 2H), 7.11 (d, 2H,
J = 7.9 Hz), 6.73 (d, 2H, J = 7.9 Hz), 2.16 (s, 6H), 0.96–0.94 (m, 10H).
13C NMR (500 MHz, CD3OD): d 157.51, 138.54, 134.85, 127.19,
124.92, 115.21, 16.22, 7.85, 5.32. MS (FAB+) m/z: 300 (M+).
5.1.9. (R)-1-(4-((4-(2,3-Dihydroxypropoxy)-3-methylphenyl)
diethylsilyl)-2-methylphenoxy)-3,3-dimethylbutan-2-one((R)-
10)
The title compound was prepared according to the procedure de-
scribed for (S)-10, starting from compound 9 and (R)-glycidol.
(132 mg, 39.1%), NMR spectra were the sameas thoseof (S)-10. HRMS
(FAB+) m/z: calcd for C27H40O5Si 472.2645, found 472.2671 (M+).
5.1.10. (2S)-3-(4-(Diethyl(4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl)silyl)-2-methylphenoxy)propane-1,2-diol
[diastereomeric mixture] ((RS,S)-3b)
To a solution of (S)-10 (103 mg, 0.22 mmol) in methanol (2 mL)
was added sodium borohydride (9.9 mg, 0.26 mmol) and methanol
(1 mL) at 0 °C. The mixture was stirred at room temperature for
1 h. The reaction was quenched with NH4Cl aq, and the whole
was extracted with ethyl acetate. The extract was successively
washed with water and brine, and then dried over MgSO4. The sol-
vent was evaporated, and the residue was purified by means of sil-
ica gel column chromatography (hexane/ethyl acetate = 2/1) to
give (RS,S)-3b (86.6 mg, 84.1%). 1H NMR (500 MHz, CDCl3): d 7.28
(d, 2H, J = 7.9 Hz), 7.25 (s, 2H), 6.81 (d, 2H, J = 7.9 Hz), 4.12 (dd,
1H, J = 3.1, 9.2 Hz), 4.06 (d, 2H, J = 4.9 Hz), 3.91–3.84 (m, 2H),
3.78 (dd, 1H, J = 5.5, 11.0 Hz), 3.72 (d, 1H, J = 8.5 Hz), 2.22 (s, 3H),
2.21 (s, 3H), 1.01 (s, 9H), 1.01–098 (m, 10H). 13C NMR (500 MHz,
CDCl3): d 157.63, 157.30, 137.33, 137.30, 134.06, 133.98, 127.94,
5.1.7. 1,10-(((Diethylsilanediyl)bis(2-methyl-4,1-phenylene))
bis(oxy))bis(3,3-dimethylbutan-2-one) (5b) and 1-(4-(diethyl
(4-hydroxy-3-methylphenyl)silyl)-2-methylphenoxy)-3,3-
dimethylbutan-2-one (9)
To a solution of 8 (1.03 g, 3.43 mmol) in dry N,N-dimethylform-
amide (8 mL) was added sodium hydride (137 mg of a 60% suspen-
sion in mineral oil, 3.43 mmol) and N,N-dimethylformamide (2 mL)
at 0 °C. The mixture was stirred at the same temperature for 0.5 h.
To this was added 1-chloropinacolone (0.45 mL, 3.43 mmol), and
stirring was continued at room temperature for 5 h. The reaction
was quenched with H2O, and the whole was extracted with ethyl

M. Nakamura et al. / Bioorg. Med. Chem. 21 (2013) 1643–1651
1649
127.54, 126.03, 125.91, 110.62, 110.53, 77.26, 70.43, 69.11, 68.96,
63.83, 33.61, 26.05, 16.39, 16.31, 7.46, 4.17. HRMS (FAB+) m/z:
calcd for C27H43O5Si 475.2880, found 475.2871 (M+H+).
1H), 4.00–3.97 (m, 1H), 3.38–3.35 (m, 1H), 2.90 (dd, 1H, J = 4.0,
5.0 Hz), 2.77 (dd, 1H, J = 3.0, 5.0 Hz), 2.28 (s, 3H), 2.23 (s, 3H),1.01–
0.97 (m, 19H). 13C NMR (500 MHz, CDCl3): d 209.83, 157.59,
157.27, 137.61, 137.41, 134.03, 133.87, 128.13, 12.73, 126.54,
126.35, 110.63, 110.50, 69.26, 68.46, 50.40, 44.79, 43.34, 26.45,
16.53, 16.37, 7.57, 4.27. HRMS (FAB+) m/z: calcd for C27H38O4Si
454.2539, found 454.2542 (M+).
5.1.11. (2R)-3-(4-(Diethyl(4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl)silyl)-2-methylphenoxy)propane-1,2-diol
[diastereomeric mixture] ((RS,R)-3b)
The title compound was prepared according to the procedure
described for (RS,S)-3b, starting from compound (R)-10 (78.7 mg,
81.0%). NMR spectra were the same as those of (RS,S)-3b.
HRMS(FAB+) m/z: calcd for C27H43O5Si 475.2880, found 475.2876
(M+H+).
5.1.16. 4-((4-(3,3-Dimethyl-2-oxobutoxy)-3-methylphenyl)
diethylsilyl)-2-methylphenyl trifluoromethanesulfonate (14)
To a solution of 9 (366 mg, 0.92 mmol) in dichloromethane
(3 mL) was added triethylamine (0.19 mL, 1.4 mmol) and trifluoro-
methanesulfonic anhydride (0.19 mL, 1.1 mmol) at 0 °C. The mix-
ture was stirred at room temperature for 1 h and then
evaporated, and the residue was purified by means of silica gel col-
umn chromatography (hexane/ethyl acetate = 9/1) to give a solid of
14 (427 mg, 87.5%) as a colorless oil. 1H NMR (500 MHz, CDCl3): d
7.38 (s, 1H), 7.35 (d, 1H, J = 7.9 Hz), 7.24–7.18 (m, 2H), 7.19 (s, 1H),
6.60 (d, 1H, J = 7.9 Hz), 4.89 (s, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 1.26 (s,
9H), 1.04–0.96 (m, 10H). 13C NMR (500 MHz, CDCl3): d 209.69,
157.54, 149.39, 138.63, 137.96, 137.41, 134.20, 133.77, 129.76,
126.81, 126.52, 120.37, 110.56, 69.07, 43.21, 26.36, 16.42, 16.34,
7.32, 3.91. MS (FAB+) m/z: 530 (M+).
5.1.12. (S)-3-(4-(Diethyl(4-((R)-2-hydroxy-3,3-dimethylbutoxy)-
3-methylphenyl)silyl)-2-methylphenoxy)propane-1,2-diol
((R,S)-3b) and (S)-3-(4-(diethyl(4-((S)-2-hydroxy-3,3-dimethyl-
butoxy)-3-methylphenyl)silyl)-2-methylphenoxy)propane-1,2-
diol ((S,S)-3b)
The diastereomeric mixture (RS,S)-3b was separated by chiral
HPLC [Chiralpak IA (4.6 ꢁ 250 mm, IPA/hexane = 15/85), 1.0 mL/
min, 20 °C]. (R,S)-3b: NMR spectra were the same as those of
(RS,S)-3b. HRMS (FAB+): calcd for C27H43O5Si 475.2880, found
475.2883 (M+H+). HPLC: Chiralpak IA (4.6 ꢁ 250 mm, IPA/hex-
ane = 15/85), 0.5 mL/min, 20 °C, retention time = 18.4 min,
>99%ee. (S,S)-3b: NMR spectra were the same as those of (RS,S)-
3b. HRMS (FAB+): calcd for C27H43O5Si 475.2880, found 475.2876
(M+H+). HPLC: Chiralpak IA (4.6 ꢁ 250 mm, IPA/hexane = 15/85),
0.5 mL/min, 20 °C, retention time = 35.8 min, >99%ee.
5.1.17. 1-(4-((4-(Benzylamino)-3-methylphenyl)diethylsilyl)-2-
methylphenoxy)-3,3-dimethylbutan-2-one (15)
To a mixture of cesium carbonate (468 mg, 1.44 mmol), palladium
diacetate (13.9 mg, 0.06 mmol) and (2,20-bis(diphenylphosphino)-
1,10-binaphthyl) (57.6 mg, 0.09 mmol) was added a mixture of 14
(327 mg, 0.62 mmol), benzylamine (0.135 mL, 1.23 mmol) and tolu-
ene (2 mL) under an Ar atmosphere at room temperature. The reac-
tion mixture was stirred at the same temperature for 0.5 h and at
100 °C for 6 h, and then filtered through a Celite pad. The filtrate
was evaporated and the residue was purified by means of silica gel
column chromatography (hexane/ethyl acetate = 20/1) to give 15
(216 mg, 71.8%) as a colorless oil. 1H NMR (500 MHz, CDCl3): d
7.40–7.34 (m, 4H), 7.30–7.22 (m, 4H), 7.19 (s, 1H), 6.62 (d, 1H,
J = 7.9 Hz), 6.59 (d, 1H, J = 8.5 Hz), 4.86 (s, 2H), 4.37 (s, 2H), 2.28 (s,
3H), 2.14 (s, 3H), 1.26 (s, 9H), 0.99–0.97 (m, 10H). 13C NMR
(500 MHz, CDCl3): d 209.67, 157.07, 146.86, 139.41, 137.57, 136.55,
164.36, 133.57, 136.55, 134.36, 133.80, 128.66, 127.61, 127.30,
126.33, 122.58, 121.18, 110.39, 109.43, 69.24, 48.16, 43.20, 16.35,
17.57, 16.40, 7.55, 4.31. MS (FAB+) m/z: 487 (M+).
5.1.13. (R)-3-(4-(Diethyl(4-((R)-2-hydroxy-3,3-dimethylbutoxy)-
3-methylphenyl)silyl)-2-methylphenoxy)propane-1,2-diol
((R,R)-3b) and (R)-3-(4-(diethyl(4-((S)-2-hydroxy-3,3-dimethyl-
butoxy)-3-methylphenyl)silyl)-2-methylphenoxy)propane-1,2-
diol((S,R)-3b)
The diastereomeric mixture (RS,R)-3b was separated by chiral
HPLC [Chiralpak IA (4.6 ꢁ 250 mm, IPA/hexane = 1/4), 1.0 mL/min,
20 °C]. (R,R)-3b: NMR spectra were the same as those of (RS,R)-
3b. HRMS (FAB+): calcd for C27H43O5Si 475.2880, found 475.2883
(M+H+). HPLC: Chiralpak IA (4.6 ꢁ 250 mm, IPA/hexane = 15/85),
0.5 mL/min, 20 °C, retention time = 17.8 min, >99%ee. (S,R)-3b:
NMR spectra were the same as those of (RS,R)-3b. HRMS (FAB+):
calcd for C27H43O5Si 475.2880, found 475.2880 (M+H+). HPLC:
Chiralpak IA (4.6 ꢁ 250 mm, IPA/hexane = 15/85), 0.5 mL/min,
20 °C, retention time = 38.0 min, >99%ee.
5.1.18. 1-(4-((4-Amino-3-methylphenyl)diethylsilyl)-2-methyl-
phenoxy)-3,3-dimethylbutan-2-one (16)
5.1.14. 3-(4-(Diethyl(4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl)silyl)-2-methylphenoxy)propane-1,2-diol
[diastereomeric mixture] (3b)
A diastereomeric mixture 3b was prepared by mixing equal
amounts of pure optical isomers (R,S)-3b, (S,S)-3b, (R,R)-3b and
(S,R)-3b.
To a solution of 15 (195 mg, 0.40 mmol) in ethanol (3 mL) was
added Pd/C (5%, 10 mg) at room temperature. The mixturewas stirred
at the same temperature for 12 h and then filtered through a Celite
pad. The filtrate was evaporated and the residue was purified by
means of silica gel column chromatography (hexane/ethyl ace-
tate = 9/1) to give crude 16 (96.4 mg, 60.8%) as a colorless oil. 1H
NMR (500 MHz, CDCl3): d 7.27–7.11 (m, 2H), 7.15(s, 2H), 6.66 (d,
2H, J = 7.9 Hz), 6.59 (d, 2H, J = 7.9 Hz), 4.86 (s, 2H), 2.28 (s, 3H), 2.14
(s, 3H), 1.25 (s, 9H), 0.96–0.94 (m, 10H). MS (FAB+) m/z: 397 (M+).
5.1.15. 1-(4-(Diethyl(3-methyl-4-(oxiran-2-ylmethoxy)phenyl)
silyl)-2-methylphenoxy)-3,3-dimethylbutan-2-one (4b)
To a solution of 9 (149 mg, 0.37 mmol) in dry N,N-dimethylform-
amide (2 mL) was added sodium hydride (15 mg of a 60% suspension
in mineral oil, 0.40 mmol) at 0 °C, and the mixture was stirred at the
same temperature for 0.5 h. To this was added epichlorohydrin
(0.029 mL, 0.40 mmol), and stirring was continued at 120 °C for
3 h. The reaction was quenched with H2O, and the whole was ex-
tracted with ethyl acetate. The extract was successively washed
with water and brine, and then dried over MgSO4. The solvent was
evaporated, and the residue was purified silica gel column chroma-
tography (hexane/ethyl acetate = 9/1) to give 4b (108 mg, 63.6%) as
a colorless oil. 1H NMR (500 MHz, CDCl3): d 7.27–7.21 (m, 4H), 6.79
(d, 2H, J = 8.0 Hz), 6.59 (d, 2H, J = 8.0 Hz), 4.87(s, 2H), 4.24–4.21 (m,
5.1.19. (S)-1-(4-((4-((2,3-Dihydroxypropyl)amino)-3-methyl-
phenyl)diethylsilyl)-2-methylphenoxy)-3,3-dimethylbutan-2-
one((S)-17)
To a solution of crude 16 (38.1 mg, 0.10 mmol) in ethanol
(0.4 mL) was added (R)-glycidol (0.044 mL, 0.68 mmol) at room
temperature. The mixture was stirred at 75 °C for 11 h and at room
temperature for 11 h, and then evaporated. The residue was puri-
fied by PTLC (hexane/ethyl acetate = 1/1) to give (S)-17 (19.2 mg,
42.0%) as a colorless oil. 1H NMR (500 MHz, CDCl3): d 7.26–7.23
(m, 2H), 7.16 (s, 1H), 6.64 (d, 1H, J = 7.9 Hz), 6.59 (d, 1H,

1650
M. Nakamura et al. / Bioorg. Med. Chem. 21 (2013) 1643–1651
J = 7.9 Hz), 4.87 (s, 2H), 4.02–4.00 (m, 1H), 3.80 (dd, 1H, J = 3.4,
11.3 Hz), 3.66 (dd, 1H, J = 5.3, 11.3 Hz), 3.35 (dd, 1H, J = 4.0,
13.1 Hz), 3.26– m, 1H), 2.28 (s, 3H), 2.14 (s, 3H), 1.25 (s, 9H),
0.99–0.97 (m, 10H). 13C NMR (500 MHz, CDCl3): d 209.67, 157.07,
146.73, 137.55, 136.74, 134.30, 133.78, 128.55, 126.35, 123.25,
121.94, 110.40, 109.59, 70.21, 69.21, 64.89, 46.29, 43.19, 26.34,
17.53, 16.40, 7.52, 4.27. HRMS (FAB+) m/z: calcd for C27H43NO4Si
472.2883, found 475.2892 (M+H+).
5.1.24. (S)-(R)-1-(4-(Diethyl(3-methyl-4-(((S)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoyl)oxy)phenyl)silyl)-2-methyl-
phenoxy)-3,3-dimethylbutan-2-yl-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate (12)
To a solution of (R)-11 (9.5 mg, 0.024 mmol) in dichlorometh-
ane (0.2 mL) were added (R)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoyl chloride (0.0098 mL, 0.072 mmol) and pyridine
(0.2 mL) at room temperature. The mixture was stirred at same
temperature for 20 h and then evaporated, and the residue was
purified by PTLC (hexane/ethyl acetate = 9/1) to give 12 (1.7 mg)
as a colorless oil. 1H NMR (500 MHz, CDCl3): d 7.69–7.66 (m, 2H),
7.54 (d, 2H, J = 8.0 Hz), 7.47–7.44 (m, 3H), 7.33–7.31 (m, 3H),
7.28–7.21 (m, 4H), 7.04 (d, 1H, J = 8.5 Hz), 6.72 (d, 1H, J = 8.0 Hz),
5.34 (dd, 1H, J = 3.0, 7.5 Hz), 4.12 (dd, 1H, J = 3.0, 10. Hz), 4.05
(dd, 1H, J = 7.5, 10.5 Hz), 2.11 (s, 3H), 2.10 (s, 3H),1.03 (s, 9H),
1.03–0.96 (m, 10H). MS (FAB+) m/z: 833 (M+H+).
5.1.20. (R)-1-(4-((4-((2,3-Dihydroxypropyl)amino)-3-methyl-
phenyl)diethylsilyl)-2-methylphenoxy)-3,3-dimethylbutan-2-
one((R)-17)
The title compound was prepared according to the procedure
described for (S)-17, starting from compound 16 and (S)-glycidol
(21.5 mg, 47.0%). NMR spectra were the same as those of (S)-17.
HRMS(FAB+) m/z: calcd for
C27H43NO4Si 472.2883, found
475.2888 (M+H+).
5.1.25. (R)-(R)-1-(4-(diethyl(3-methyl-4-(((R)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoyl)oxy)phenyl)silyl)-2-methyl-
phenoxy)-3,3-dimethylbutan-2-yl-3,3,3-trifluoro-2-methoxy-2-
Phenylpropanoate (13)
The title compound was prepared according to the procedure
described for 12, starting from compound (R)-11 (9.5 mg) and
(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (y.
2.6 mg). 1H NMR (500 MHz, CDCl3): d 7.70–7.67 (m, 2H), 7.54 (d,
2H, J = 8.0 Hz), 7.45–7.44 (m, 3H), 7.34–7.32 (m, 2H), 7.26–7.21
(m, 3H), 7.12–7.09 (m, 3H), 7.05 (d, 1H, J = 8.5 Hz), 6.76 (d, 1H,
J = 8.0 Hz), 5.40 (dd, 1H, J = 2.0, 8.0 Hz), 4.22 (dd, 1H, J = 2.0, 10.
Hz), 4.15 (dd, 1H, J = 8.0, 10.0 Hz), 2.11 (s, 3H), 2.06 (s, 3H), 1.00
(s, 9H), 1.07–0.96 (m, 10H). MS (FAB+) m/z: 833 (M+H+)
5.1.21. (R)-4-(Diethyl(4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl)silyl)-2-methylphenol((R)-11)
To a solution of 9 (104 mg, 0.26 mmol) in dry tetrahydrofuran
(1.5 mL) was added a mixture of (R)-2-methyl-CBS-oxazaboroli-
dine (1 M solution in toluene, 0.026 mL), borane N-ethyl-N-isopro-
pylaniline complex (2 M solution in tetrahydrofuran, 0.156 mL)
and dry tetrahydrofuran (1.5 mL) at 20 °C under an Ar atmosphere,
and the mixture was stirred at the same temperature for 1 h. The
reaction was quenched with NH4Cl aq, and the whole was evapo-
rated. The residue was purified by means of silica gel column chro-
matography (hexane/ethyl acetate = 20/1 to 4/1) to give (R)-11
(95.8 mg, 92.0%) as a colorless oil. 1H NMR (500 MHz, CDCl3): d
7.30–7.19 (m, 4H), 6.83 (d, 2H, J = 8.0 Hz), 6.76 (d, 2H, J = 8.0 Hz),
4.14 (dd, 1H, J = 3.0, 9.5 Hz), 3.92 (dd, 1H, J = 9.5, 8.5 Hz), 3.74
(dd, 1H, J = 3.0, 8.5 Hz), 2.24 (s, 3H), 2.23 (s, 3H),1.03 (s, 9H),
1.01–0.97 (m, 10H). 13C NMR (500 MHz, CDCl3): d 157.67, 154.95,
137.82, 137.43, 134.20, 134.11, 127.80, 127.56, 126.11, 123.32,
114.61, 110.69, 77.45, 69.15, 33.73, 26.17, 16.52, 15.86, 7.59,
5.2. Reporter gene assays34,35
Human embryonic kidney (HEK 293) cells were cultured in Dul-
becco’s modified Eagle’s medium (DMEM) containing 5% fetal bo-
vine serum (FBS) and antibiotic-antimycotic (Nacalai) at 37 °C in
a humidified atmosphere of 5% CO2 in air. Transfections were per-
formed by the calcium phosphate coprecipitation method. Test
compounds were added at 22 h after transfection. Cells were har-
vested approximately 16–20 h after the treatment, and luciferase
and b-galactosidase activities were assayed using a luminometer
and a microplate reader (ARVO-SX, Perkin Elmer, USA). In the
DVR-reporter assay, DNA cotransfection experiments were done
with 50 ng of reporter plasmid (TK-MH100x4-Luc), 10 ng of
pCMX-s-galacosidase, and 15 ng of each receptor expression plas-
mid (CMX-GAL4 N-hVDR) per well in a 96-well plate. In the AR-re-
porter assay, DNA cotransfection experiments were done with
33 ng of reporter plasmid (ARE-tlc-Luc), 10 ng pCMX-s-galactosi-
dase and 33 ng of each receptor expression plasmid (pSG5-hAR)
per well in a 96-well plate. Luciferase data were normalized to
an internal b-galactosidase control, and reported values are means
of triplicate assays.
4.32. HRMS (FAB+): calcd for
C24H37O3Si 401.2515, found
401.2503 (M+H+). HPLC: Chiralpak IA (4.6 x 250 mm, IPA/hex-
ane = 15/85), 0.5 mL/min, 20 °C, retention time = 13.1 min, 93%ee.
((S)-4-(Diethyl(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methyl-
phenyl)silyl)-2-methylphenol: retention time = 33.9 min).
5.1.22. (R)-3-(4-(Diethyl(4-((R)-2-hydroxy-3,3-dimethylbutoxy)-
3-methylphenyl)silyl)-2-methylphenoxy)propane-1,2-diol
((R,R)-3b0)
To a mixture of (R)-11 (19.2 mg, 0.05 mmol), K2CO3 (9.9 mg,
0.07 mmol) and acetone (0.2 mL) was added (R)-glycidol
(0.046 ml, 0.07 mmol) at room temperature. The mixture was stir-
red at 60 °C for 6 h and at room temperature for 16 h, and then
evaporated. The residue was purified by PTLC (hexane/ethyl ace-
tate = 1/1) to give (R,R)-3b0 (7.1 mg, 31.3%) as a colorless oil.
NMR spectra were the same as those of (RS,S)-3b. HRMS (FAB+):
calcd for C27H43O5Si 475.2880, found 475.2890 (M+H+). HPLC:
Chiralpak IA (4.6 ꢁ 250 mm, IPA/hexane = 15/85), 0.5 mL/min,
20 °C, retention time was the same as that of (R,R)-3b. >99%ee.
5.3. Androgen-antagonistic activity
Androgen-antagonistic activity of the compounds was evalu-
ated by measurement of inhibition of androgen-induced SC-3
(Shionogi Carcinoma-3) cell growth, as described previously.32,33
Briefly, SC-3 cells were cultured in Minimum Essential Medium, Al-
pha Modification (MEM-Alpha) supplemented with 2% FBS and
10 nM testosterone in the presence or absence of a test compound
for three days at 37 °C under 5% CO2. The number of cells with tes-
tosterone alone was defined as 100%. The concentration of test
compounds that inhibited by 50% the increase of the cell number
induced by 10 nM testosterone was quantified (IC50) (Table 4).
Androgen-agonistic activity can be evaluated in the same cell line,
5.1.23. (S)-3-(4-(Diethyl(4-((R)-2-hydroxy-3,3-dimethylbutoxy)-
3-methylphenyl)silyl)-2-methylphenoxy)propane-1,2-diol
((R,S)-3b0)
The title compound was prepared according to the procedure
described for ((R,R)-3b0), starting from compound (R)-11 and (S)-
glycidol (4.5 mg, 19.9%). NMR spectra were the same as those of
(RS,S)-3b. HRMS (FAB+): calcd for C27H43O5Si 475.2880, found
475.2902 (M+H+). HPLC: Chiralpak IA (4.6 ꢁ 250 mm, IPA/hex-
ane = 15/85), 0.5 mL/min, 20 °C, retention time was the same as
that of (R,S)-3b. >99%ee.

M. Nakamura et al. / Bioorg. Med. Chem. 21 (2013) 1643–1651
1651
13. Kaneko, C.; Yamada, S.; Sugimoto, A.; Eguchi, Y.; Ishikawa, M.; Suda, T.; Suzuki,
M.; Kakuta, S.; Sasaki, S. Steroids 1974, 23, 75.
14. Boehm, M. F.; Fitzgerald, P.; Zou, A.; Elgort, M. G.; Eric, D.; Mere, L.; Mais, D. E.;
Bissonnette, R. P.; Heyman, R. A.; Nadzan, A. M.; Reicman, M.; Allegretto, E. A.
Chem. Biol. 1999, 6, 265.
15. Fernández-Gacio, A.; Fernández-Marcos, C.; Swamy, N.; Ray, R. Bioorg. Med.
Chem. Lett. 2003, 13, 213.
16. Hosoda, S.; Tanatani, A.; Wakabayashi, K.; Makishima, M.; Imai, K.; Miyachi, H.;
Nagasawa, K.; Hashimoto, Y. Bioorg. Med. Chem. 2006, 14, 5489.
17. Maruyama, K.; Noguchi-Yachide, T.; Sugita, K.; Hashimoto, Y.; Ishikawa, M.
Bioorg. Med. Chem. Lett. 2010, 20, 6661.
18. Lippert, W. P.; Burschka, C.; Gotz, K.; Kaupp, M.; Ivanova, D.; Gaudon, C.; Sato,
Y.; Antony, P.; Rochel, N.; Moras, D.; Gronemeyer, H.; Tacke, R. ChemMedChem
2009, 4, 1143.
19. Tacke, R.; Muller, V.; Butter, M. W.; Lippeert, W. P.; Bertermann, R.; Daib, J. O.;
Khanwalkar, H.; Furst, A.; Gaudon, C.; Gronemeyer, H. ChemMedChem 2009, 4,
1797.
20. Bauer, J. B.; Lippert, W. P.; Dorrich, S.; Tebbe, D.; Burschka, C.; Christie, V. B.;
Tams, D. M.; Henderson, A. P.; Murray, B. A.; Marder, T. B.; Przyborski, S. A.;
Tacke, R. ChemMedChem 2011, 6, 1509.
but none of the prepared compounds showed androgen-agonistic
activity (growth promotion of SC-3 cells).
Acknowledgments
The work described in this paper was partially supported by a
Grant-in-aid for Scientific Research from The Ministry of Educa-
tion, Culture, Sports, Sciences and Technology, Japan, and a Grant
from the Japan Society for the Promotion of Science.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2013.01.060.
21. Fujii, S.; Miyajima, Y.; Masuno, H.; Kagechika, H. J. Med. Chem. 2013, 56, 160.
22. Showell, G. A.; Mills, J. S. Drug Discovery Today 2003, 8, 551.
23. Mills, J. S.; Showell, G. A. Expert Opin. Investig. Drugs 2004, 13, 1149.
24. Franz, A. K.; Wilson, S. O. J. Med. Chem. 2013, 56, 388.
25. Meanwell, N. J. Med. Chem. 2011, 54, 2529.
26. Hosoda, S.; Aoyama, H.; Goto, Y.; Salim, M. T. A.; Okamoto, M.; Hashimoto, M.;
Baba, M.; Hashimoto, Y. Bioorg. Med. Chem. Lett. 2009, 19, 3157.
27. Demizu, Y.; Nakatsu, A.; Sato, Y.; Honzawa, S.; Yamashita, A.; Sugiura, T.;
Kittaka, A.; Kato, S.; Okuda, H.; Kurihara, M. Lett. Org. Chem. 2011, 8, 43.
28. Kusumi, T.; Ooi, T.; Ohkubo, Y.; Yabuuchi, T. Bull. Chem. Soc. Jpn 2006, 79, 965.
29. Hashimoto, Y.; Miyachi, H. Bioorg. Med. Chem. 2005, 13, 5080.
30. Ahman, J.; Buckwald, S. L. Tetrahedron Lett. 1997, 38, 6363.
31. Peng, T.; Yang, D. Org. Lett. 2010, 12, 496.
32. Hiraoka, D.; Nakamura, N.; Nishizawa, Y.; Uchida, N.; Noguchi, S.; Matsumoto,
K.; Sato, B. Cancer Res. 1987, 47, 6560.
33. Kasayama, S.; Saito, H.; Kouhara, H.; Sumitani, S.; Sato, B. J. Cell. Physiol. 1993,
154, 254.
34. Makishima, M.; Lu, T. T.; Xie, W.; Whitfield, G. K.; Domoto, H.; Evans, R. M.;
Haussler, M. R.; Mangelsdorf, D. J. Science 2002, 296, 1313.
35. Makishima, M.; Okamoto, A. Y.; Repa, J. J.; Tu, H.; Learned, R. M.; Luk, A.; Hull,
M. V.; Lustig, K. D.; Mangelsdorf, D. J.; Shan, B. Science 1999, 284, 1362.
References and notes
1. Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr. Rev. 1995, 16, 200.
2. Norman, A. W.; Roth, J.; Orci, L. Endocr. Rev. 1982, 3, 331.
3. Mangelsdorf, D. J.; Thummel, C.; Beato, M.; Herrlich, P.; Schütz, G.; Umesono,
K.; Blumberg, B.; Kastner, P.; Mark, M.; Chambon, P.; Evans, R. M. Cell 1995, 83,
835.
4. Bjorklund, S.; Almouzni, G.; Davidson, I.; Nightingale, K. P.; Weiss, K. Cell 1999,
96, 759.
5. Baeke, F.; Takiishi, T.; Korf, H.; Gysemans, C.; Mathieu, C. Curr. Opin. Pharmacol.
2010, 10, 482.
6. Abe, E.; Miyaura, C.; Sakagami, H.; Takeda, M.; Konno, K.; Yamazaki, T.; Yoshiki,
S.; Suda, T. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 4990.
7. Bar-shavit, Z.; Teitelbaum, S. L.; Reitsma, P.; Hall, A. N. N.; Pegg, L. E.; Trial, J.;
Kahn, A. J. Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 5907.
8. Johnson, C. S.; Muindi, J. R.; Hershberger, P. A.; Trump, D. L. Anticancer Res.
2006, 26, 2543.
9. Guzey, M.; Kitada, S.; Reed, J. C. Mol. Cancer Ther. 2002, 1, 667.
10. James, S. Y.; Mackay, A. G.; Colston, K. W. J. Steroid Biochem. Mol. Biol. 1996, 58,
395.
11. Colston, K.; Colston, M. J.; Feldman, D. Endocrinology 1981, 108, 1083.
12. Guyton, K. Z.; Kensler, T. W.; Posner, G. H. Nutr. Rev. 2003, 61, 227.