Design and synthesis of novel ROR inverse agonists with a dibenzosilole scaffold as a hydrophobic core structure

Article abstract of DOI:10.1016/j.bmc.2015.05.004

Abstract Molecular structure calculations indicated that the dibenzosilole skeleton could be well superposed on phenanthridinone, which is a structural component of ligands of retinoic acid receptor-related orphan receptors (RORs). Therefore, we designed,

Full text of DOI:10.1016/j.bmc.2015.05.004

Accepted Manuscript
Design and synthesis of novel ROR inverse agonists with a dibenzosilole scaf-
fold as a hydrophobic core structure
Hirozumi Toyama, Masaharu Nakamura, Yuichi Hashimoto, Shinya Fujii
PII:
S0968-0896(15)00402-2
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.05.004
BMC 12298
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
15 April 2015
2 May 2015
5 May 2015
Please cite this article as: Toyama, H., Nakamura, M., Hashimoto, Y., Fujii, S., Design and synthesis of novel ROR
inverse agonists with a dibenzosilole scaffold as a hydrophobic core structure, Bioorganic & Medicinal
Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.05.004
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Design and synthesis of novel ROR inverse agonists with a dibenzosilole scaffold
as a hydrophobic core structure
Hirozumi Toyama, Masaharu Nakamura, Yuichi Hashimoto, Shinya Fujii*
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku,
113-0032 Tokyo, Japan
To whom correspondence should be addressed: E-mail: fujiis@iam.u-tokyo.ac.jp
Tel.: +81-3-5841-7848; fax: +81-3-5841-8495
Abstract
Molecular structure calculations indicated that the dibenzosilole skeleton could be well superposed
on phenanthridinone, which is a structural component of ligands of retinoic acid receptor-related
orphan receptors (RORs). Therefore, we designed, synthesized and biologically evaluated a series
of novel ROR ligands based on the dibenzosilole scaffold as a hydrophobic core structure.
Dibenzosilole derivatives bearing a hexafluoro-2-hydroxypropyl group on the benzene ring
exhibited significant ROR-inhibitory activity, comparable to that of the lead phenanthridinone
derivative 5. Our results indicate that the dibenzosilole skeleton would be a useful scaffold for
developing novel biologically active compounds, and that cis-amide structure can be replaced by an
alkylsilyl functionality.
Keywords: retinoic acid receptor-related orphan receptor, ROR, dibenzosilole, sila-substitution
1. Introduction
Various silicon-containing bioactive compounds have been developed and some of them, such as
1
-4
alkylsilyl derivatives 1 and 2, have been evaluated in clinical trials (Figure 1). The design
rationale has been that introduction of a silicon atom in place of a carbon atom (sila-substitution)
can alter the activity, selectivity and pharmacokinetics of bioactive compounds, owing to the
5
differences of covalent radius, hydrophobicity and electronegativity. We previously hypothesized
that a silyl group can function as a cis-olefin mimetic, and we designed silyl analogs of
combretastatin A-4 (CA-4), such as compound 3 (Figure 1), by replacement of the unstable
6
cis-olefin moiety with a silyl group. The resulting compounds were potent inhibitors of tubulin

polymerization and tumor cell proliferation. These results suggested that silyl groups can serve as
mimics of two-atom substructure such as cis-olefinic double bond.
Figure 1. Structures of silicon-containing compounds used in clinical trials (1, 2) and our silyl
analog of CA-4 (3).
Retinoic acid receptor-related orphan receptor (ROR) is a member of the nuclear receptor
7
superfamily of ligand-dependent factors that regulate DNA transcription; its three subtypes, α, β
and γ, are differentiated by alternative promoter usage and alternative splicing. ROR is classified as
an orphan receptor, since its endogenous ligands have not been fully identified, and it is thought to
8
be involved in immunity, cellular metabolism and circadian rhythm. ROR is constitutively active
in the absence of any activating ligand, and increased transcriptional activation of ROR (especially
9
RORα and RORγ) is thought to be involved in autoimmune diseases. Therefore, ROR inverse
agonists, which inhibit the constitutive activity of ROR, would be candidate drugs for treatment of
these diseases. Various ROR inverse agonists have been developed, among which sulfonamide
derivative T0901317, which was originally developed as an LXR agonist, is a representative ROR
1
0
inverse agonist with RORα/γ selectivity (Figure 2A).

A.
F3C
O
S
n-Bu
O
O
N
O
N
Si
Si
N
H
3
F C
HO
R
CF3
T0901317
R = Et (4)
3 2
R = C(CF )
OH (5)
6
B.
Figure 2. (A) Chemical structures of T0901317 and our phenanthridinone (4,5) and benzanilide (6)
derivatives (B) Binding model of the phenanthridinone derivative 5 at the RORγ LBD
1
1
2
We have also developed ROR inverse agonists such as phenanthridinone derivatives 4 and 5,
which were derived from T0901317, and silicon-containing benzanilide derivative 6 (Figure 2A).
1
In the present work, we further investigated the use of silyl functionalities for structural
development of bioactive compounds by designing and synthesizing novel ROR inverse agonists
based on the dibenzosilole skeleton, focusing on the replacement of the cis-amide structure of
phenanthridinone with an alkylsilyl moiety.
2
2
. Results and discussion
.1. Molecular design
The cocrystal X-ray structure of RORγ ligand-binding domain (LBD) and T0901317 was recently
1
3
reported. Based on this structure, we performed a computational docking study of the
phenanthridinone derivative 5 with RORγ LBD. The docking study suggested the amide structure
of compound 5 does not form a hydrogen bond to the RORγ LBD, and the ligand-binding site of
RORγ is quite hydrophobic (Figure 2B). Therefore, replacement of the amide moiety with a
hydrophobic substructure could be a promising strategy for structural development. As mentioned
above, we have recently reported that diphenylsilane structure can function as a cis-stilbene

6
surrogate. Therefore, the similar geometry of cis-amide and cis-olefin led us to hypothesize that
cis-amide bond in phenanthridinone derivatives could be replaced by a silyl functionality.
Figure 3A shows a superimposition of the calculated structures of phenanthridinone and
dimethyldibenzosilole, which has a dimethylsilyl group instead of the cis-amide moiety of
phenanthridinone. The overall structures, especially the two benzene rings of these compounds,
appear to be well superimposed.
A.
Top view
Side view
B.
1
2
R1 R2
R , R = Me, Et, n-Bu
3
Si
R = H, Et, C(CF ) OH
3
2
R3
Figure 3. (A) Superposition of phenanthridinone (cyan) and dimethyl dibenzosilole structures
(
magenta) calculated with MM2 program (B) Structural development of the dibenzosilole skeleton
Therefore, we focused on dibenzosilole derivatives as candidate ROR inverse agonists. Based on
11
our structure-activity relationship (SAR) study on phenanthridinone derivatives, we introduced an
ethyl group and a hexafluoro-2-hydroxypropyl group on the benzene ring of dibenzosilole, and
conducted an SAR study to examine the effect of substituents on the silicon atom (Figure 3B).

2.2. Synthesis
Scheme 1. Synthesis of dibenzosilole derivatives 14-17. Reagents and conditions: (a) SnCl
EtOH/H O, reflux, 5 h; (b) Ac O, Na CO , H O, 0°C to rt, 1 h, 42% (2 steps); (c) NBS, DMF, rt,
o/n, 74%; (d) HCl, EtOH, reflux, 6 h; (e) i) HCl/NaNO , H O, 0°C, 30 min; ii) KI, H O, rt, o/n,
4% (2 steps); (f) i) n-BuLi, THF, -78 °C, 30 min; ii) Si(n-Bu) Cl , -78°C to rt, o/n, 92%; (g)
n-BuLi, THF, -78°C, 30 min; acetaldehyde, THF, -78°C to rt, o/n; (h) H , Pd/C, MeOH, rt, o/n.
2 2
·2H O,
2
2
2
3
2
2
2
2
3
2
2
2
Dibenzosilole derivatives 14-17 were synthesized as shown in Scheme 1. Reduction of
,2'-dinitrobiphenyl (7) using SnCl ･2H O afforded 2,2'-diaminobiphenyl (8). Acetylation of
2
2
2
compound 8 with acetic anhydride gave amide 9, and then bromination with NBS gave
dibrominated compound 10. Deacetylation of 10 under acidic conditions afforded intermediate
diamine 11, which was iodinated by means of Sandmeyer reaction to give diodobiphenyl 12. The 2-
and 2’-positions of 12 were lithiated with n-butyllithium, and reaction between the lithiated form of
12 and dibutyldichlorosilane gave dibenzosilole 13. The lithiated form of 13 reacted with
acetaldehyde to give alcohol 14. The hydroxyl group of 14 was removed to afford 16 by

hydrogenation using Pd/C. Compounds 15 and 17 were isolated as by-products in the preparation
of compound 14 and 16, respectively (Scheme 1).
.
Scheme 2. Synthesis of dibenzosilole derivatives 24-26, 29. Reagents and conditions: (a)
CF
min; ii) KI, EtOH/H
78°C, 30 min; ii) SiR
3
COCF
3
･1.5H
2
O, p-TsOH, MS4A, toluene, 100 °C, 3 h, 61%; (b) i) HCl/NaNO
O, rt, o/n, 24%; (c) BnBr, NaH, DMF, reflux, o/n, 79%; (d) i) n-BuLi, THF,
Cl (R = Me, Et, n-Bu), THF, -78°C to rt, o/n, 24-68%; (e) H , Pd/C, MeOH,
, THF, -78°C to rt,
2 2
, H O, 0°C, 30
2
-
2
2
2
rt, o/n, 17-71%; (f) i) t-BuLi, THF, -78°C, 20 min → rt, 15 min; ii) Si(n-Bu)Cl
3
o/n; (g) MeMgBr, THF, -78°C to rt, 3 h, 32%; (h) H , Pd/C, AcOH, MeOH, rt, o/n, 90%
2
The dibenzosilole derivatives 24-26, and 29 were synthesized as shown in Scheme 2. Reaction of
diamine 8 with hexafluoroacetone gave alcohol 18, and then iodination of 18 by means of
Sandmeyer reaction gave diiodobiphenyl 19. The hydroxyl group of 19 was protected with a benzyl
group to give 20. The lithiated form of 20 was treated with dialkyldichlorosilanes to give the
corresponding dibenzosiloles 21, 22 and 23. Removal of the benzyl group of 21, 22 and 23 by
hydrogenation using Pd/C afforded the desired compounds 24, 25 and 26, respectively. Lithiation
of 20 with t-butyllithium and reaction with butyltrichlorosilane gave a chlorosilane intermediate 27,
and then reaction with methylmagnesium bromide gave compound 28. Finally, the benzyl group of

28 was removed by hydrogenation using Pd/C to give 29 (Scheme 2).
2.3. Biological evaluation
Table 1. Inhibition of ROR transcriptional activity by dibenzosiloles 14-17. Values are inhibition
ratio (percent of control) at the concentration of 10 µM.
compound
R
-
RORα
37
RORβ
29
RORγ
37
4
1
1
1
1
4
5
6
7
CH(OH)CH
3
17
< 5.0
< 5.0
H
22
7.0
13
< 5.0
< 5.0
< 5.0
13
18
Et
COCH
3
< 5.0
Inverse agonistic potency of the synthesized compounds was evaluated by assay of inhibitory
activity toward constitutive activity of ROR, using luciferase reporter gene assay. Table 1 shows the
ROR-transcriptional repression activity of compounds 14-17. Compound 14 bearing a
1-hydroxyethyl group exhibited 17% inhibition of RORα. The simple dibutyldibenzosilole 15
exhibited 22% inhibition of RORα. Compound 16 bearing an ethyl group showed 18% inhibition of
RORγ, and acetyl derivative 17 showed 13% inhibition of RORα. However, the potencies of these
compounds were fairly low in comparison with that of the lead phenanthridinone derivative 4
(
Table 1).

Table 2. Inhibition of ROR-transcriptional activity by dibenzosiloles 24-26 and 29.
1
2
compound
RORα IC50 (µM) RORβ IC50 (µM) RORγ IC50 (µM)
R
R
5
-
-
7.2
6.2
5.7
6.7
4.7
5.5
5.4
4.2
4.4
2
2
2
2
4
5
6
9
n-Bu n-Bu
a
a
Me
Et
Me
Et
9.4
(40%)
(28%)
7.0
a
(34%)
7.7
n-Bu Me
a
Inhibition ratio at the concentration of 10 µM.
Table 2 shows the ROR-transcriptional repression activity of compound 24-26 and 29 bearing a
hexafluoro-2-hydroxypropyl moiety on the benzene ring. In contrast to compounds 14-17, these
hexafluoro-2-hydroxypropyl derivatives exhibited significant ROR inverse agonist activity. In
particular, they showed potent RORγ-inhibitory activity comparable to that of the lead
phenanthridinone 5. Compound 24 and compound 29 also exhibited potent RORα/β-transcriptional
repression activity. This result suggests that the n-butyl substituent is preferable to a short alkyl
group, such as methyl or ethyl group, for RORα/β inverse agonist activity. As for RORγ,
Si,Si-diethyl derivative 26 exhibited the most potent inverse agonistic activity. Overall,
dibenzosilole structure appears to function as an effective alternative structure to phenanthridinone
for ROR ligands bearing a hexafluoro-2-hydroxypropyl functionality.
2.4. Docking simulation
We performed a docking study of dibenzosilole derivative 26 with the reported cocrystal X-ray
1
3
structure of the RORγ ligand-binding domain (LBD) and T0901317 (PDB ID: 4NB6), using the
1
4
AutoDock 4.2 program (Figure 4). As described above, the ligand-binding site of RORγ is quite
hydrophobic and the hydrophobic moiety of dibenzosilole derivative 26 occupied the hydrophobic

space. In addition, the hexafluoro-2-hydroxypropyl group of the dibenzosilole derivative 26 and the
main-chain carbonyl group of CYS299 formed a polar interaction. This result suggests that the
hexafluoro-2-hydroxypropyl group on the benzene ring can increase RORγ-transcriptional
repression activity, and is consistent with the observation that hexafluoro-2-hydroxypropyl
derivatives exhibited higher ROR-transcriptional repression activity than dibenzosilole derivatives
14-17 without the hexafluoro-2-hydroxypropyl group. On the other hand, hydroxyl group of
T0901317 did not form hydrogen bonding in the crystal structure. The significance of the suggested
polar interaction of 26 is under further investigation.
Figure 4. Binding model of the dibenzosilole derivative 26 at the RORγ LBD
3. Conclusion
Based on the hypothesis that a silyl group can function as a mimic of cis-amide, as well as olefinic
cis-double bond structure, we designed and synthesized novel ROR inverse agonists bearing a
dibenzosilole scaffold in place of the phenanthridinone skeleton. The synthesized dibenzosilole
derivatives bearing a hexafluoro-2-hydroxypropyl group exhibited similar ROR-transcriptional
repression activities to the parent phenanthridinone derivative. These results suggest that the
cis-amide moiety can be replaced by a silyl functionality, at least in the case of ROR ligands. Few
bioactive compounds containing a dibenzosilole skeleton have so far been reported, but our results
indicate that dibenzosilole could be a versatile scaffold for development of novel ligands of ROR
and other nuclear receptors.

4
. Experimental
.1 Chemistry
4
General
1
13
H-NMR and C-NMR spectra were recorded on a JEOL JNM-GX500 (500 MHz) spectrometer.
Chemical shifts are expressed in δ (ppm) values with tetramethylsilane (TMS) as an internal
reference. The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m
=
multiplet. Fast atom bombardment mass spectra (FAB-MS) and high-resolution mass spectra
HRMS) were recorded on a JEOL JMS-DX303 spectrometer with m-nitrobenzyl alcohol. Flash
column chromatography was performed on silica gel 60 Kanto Kagaku (40-100 µm).
(
2
,2'-Diaminobiphenyl (8)
A mixture of 7 (10.0 g, 40.8 mmol) and SnCl
O (70 mL) was refluxed for 4 h. Ethanol was evaporated and sat. Na
remaining solution until the pH reached 10. Excess SnCl was filtered off and the solution was
extracted several times with EtOAc. The organic layer was washed with brine and H O, dried over
anhydrous MgSO and evaporated. The residue was purified by silica gel column chromatography
2
･2H
2
O (55.2 g, 245 mmol) in ethanol (100 mL) and
CO aq. was added to the
H
2
2
3
2
2
4
1
(
3
n-hexane/EtOAc = 5:1) to give 8 as a yellow solid (5.30 g, 70%). H-NMR (500 MHz, CDCl ) δ
7.19 (td, 2H, J = 7.7, 1.5 Hz), 7.13 (dd, 2H, J = 7.4, 1.7 Hz), 6.85 (td, 2H, J = 7.4, 1.1 Hz), 6.80 (dd,
+
H, J = 8.0, 1.1 Hz), 3.31 (s, 4H). MS (FAB [M]) m/z 184, MS (FAB [M+H] ) m/z 185.
2
2
,2'-Bisacetamidobiphenyl (9)
A mixture of 7 (10.0 g, 40.8 mmol) and SnCl
O (70 mL) was refluxed for 6 h. Ethanol was evaporated and sat. Na
remaining solution until the pH reached 10. Excess SnCl was filtered off and the solution was
extracted several times with EtOAc. The organic layer was washed with brine and H O, dried over
anhydrous MgSO and evaporated to give 2,2'-diaminobiphenyl (8), which was added to Na CO
aq. (7.30 g in 26.2 mL of H O). The solution was cooled to 0 °C, then acetic anhydride (20 mL)
was added, and the mixture was stirred for 1 h. The precipitate was collected by filtration and
washed with H O. Recrystallization from ethanol afforded 9 as a pink-white powder (4.50 g, 42%).
2
･2H
2
O (55.2 g, 245 mmol) in ethanol (100 mL) and
H
2
2
CO aq. was added to the
3
2
2
4
2
3
2
2
1
H-NMR (500 MHz, CDCl
3
) δ 8.09 (d, 2H, J = 8.0 Hz), 7.46-7.43 (m, 2H), 7.27-7.20 (m, 2H), 6.93
(
s, 2H), 1.97 (s, 6H).
2,2'-Bisacetamido-5,5’-dibromobiphenyl (10)

A mixture of 9 (1.14 g, 4.24 mmol), N-bromosuccinimide (1.66 g, 9.33 mmol) and
N,N-dimethylformamide (12 mL) was stirred overnight at room temperature, and then poured into
excess H
2
O. The precipitate was collected by filtration and washed with H
2
O. Recrystallization
) δ
1
from ethanol afforded 10 as a yellow-white powder (1.34 g, 74%). H-NMR (500 MHz, CDCl
3
7.94 (d, 2H, J = 8.6 Hz), 7.57 (dd, 2H, J = 8.6, 2.3 Hz), 7.36 (d, 2H, J = 2.3 Hz), 1.99 (s, 6H).
5,5'-Dibromo-2,2'-diiodobiphenyl (12)
2
To a solution of 10 (495 mg, 1.16 mmol) in ethanol (9.9 mL) and H O (9.9 mL) was added dropwise
conc. HCl aq. (4.9 mL). The mixture was refluxed for 6 h, then ethanol was removed by evaporation,
and sat. Na CO aq. was added to the remaining solution until the pH reached 10. The precipitate
was collected by filtration to give 5,5'-dibromobiphenyl-2,2'-diamine (11), which was added to a
mixture of sodium nitrite (0.176 g, 2.55 mmol in 4.0 mL of H O) and conc. HCl aq. (1.2 mL) at 0 °C.
The reaction mixture was stirred for a further 20 min, then added to a vigorously stirred solution of
KI (4.24 g, 25.5 mmol) in 9.8 mL of H O at room temperature. Stirring was continued overnight. Sat.
Na CO aq. was added until the pH reached 7, and the solution was extracted several times with
EtOAc. The organic layer was washed with H O, dried over anhydrous MgSO , and evaporated. The
2
3
2
2
2
3
2
4
residue was purified by silica gel column chromatography using hexane to give 12 as an off-white
1
solid (225 mg, 34%). H-NMR (500 MHz, CDCl
3
) δ 7.78 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 2.9
Hz), 7.24 (dd, 2H, J = 8.3, 2.6 Hz). MS (FAB) not found.
2,8-Dibromo-5,5-dibutyl-5H-dibenzosilole (13)
To a solution of 12 (233 mg, 0.410 mmol) in THF (3.0 mL) at -78 °C was added dropwise n-BuLi in
hexane (1.60 M, 619 µL, 0.990 mmol) under an Ar atmosphere. The resulting mixture was stirred for
a further 30 min at the same temperature. Dibutyldichlorosilane (133 µL, 0.620 mmol) was added,
and the mixture was allowed to warm to room temperature. Stirring was continued overnight. The
reaction was then quenched with H
2
O, and the whole was extracted with EtOAc. The organic layer
and evaporated. The residue was
was washed with brine and H O, dried over anhydrous MgSO
2
4
purified by silica gel column chromatography using hexane to yield 13 as a pale yellow oil (172 mg,
1
2%). H-NMR (500 MHz, CDCl
9
3
) δ 7.90 (d, 2H, J = 1.7 Hz), 7.46 (d, 2H, J = 7.4 Hz), 7.42 (dd, 2H,
J = 7.7, 1.4 Hz), 1.39-1.24 (m, 8H), 0.91 (tt, 6H, J = 12.0, 3.3 Hz), 0.81 (dd, 2H, J = 9.2, 4.6 Hz).
1
3
0
.60 (t, 2H, J = 8.0 Hz). C-NMR (125 MHz, CDCl
3
) δ 149.2, 136.8, 134.6, 130.71, 125.3, 124.5,
26.4, 26.3, 26.1, 25.0, 15.9, 13.9, 13.7, 11.9. MS (FAB [M]) m/z 452.

5,5-Dibutyl-2-(1-hyroxyethyl)dibenzosilole (14)
To a solution of 13 (19.6 mg, 43.3 mmol) in THF (0.30 mL) at -78 °C was added dropwise n-BuLi
in hexane (1.60 M, 64.9 µL, 0.104 mmol) under an Ar atmosphere. The resulting mixture was
stirred for a further 30 min at the same temperature. Acetaldehyde (12.0 µL, 0.156 mmol) was
added, and the mixture was allowed to warm to room temperature. Stirring was continued overnight.
The reaction was quenched with H
2
O and the whole was extracted with EtOAc. The organic layer
and evaporated. The residue was
was washed with brine and H O, dried over anhydrous MgSO
2
4
purified by silica gel column chromatography (n-hexane/EtOAc = 5:1) to give 14 as a colorless oil
1
5.4 mg, 37%). H-NMR (500 MHz, CDCl
(
3
) δ 7.86 (d, 2H, J = 8.6 Hz), 7.60 (t, 2H, J = 7.4 Hz),
7.43 (td, 1H, J = 7.7, 1.3 Hz), 7.27 (dd, 2H, J = 10.0, 3.7 Hz), 4.97 (q, 1H, J = 6.3 Hz), 1.57 (d, 3H,
1
3
J = 6.3 Hz), 1.37-1.25 (m, 8H), 0.93 (dd, 4H, J = 9.2, 6.9 Hz), 0.82 (t, 6H, J = 7.2 Hz). C-NMR
125 MHz, CDCl ) δ 148.9, 148.2, 147.8, 138.3, 137.1, 133.5, 133.3, 130.1, 127.3, 124.5, 120.9,
17.9, 70.9, 29.8, 26.5, 26.2, 25.2, 13.7, 12.1. HRMS (FAB) calcd for C22 30NaOSi 361.1964;
(
3
1
H
+
found: m/z 361.1949 (M+Na) .
5,5'-Dibutyl-5H-dibenzosilole (15)
This product was obtained in the reaction yielding the compound 14 when using reagents
1
containing impurities (54.0 mg, 98%, colorless oil). H-NMR (500 MHz, CDCl
3
) δ 7.82 (d, 2H, J =
8.0 Hz), 7.61 (d, 2H, J = 6.9 Hz), 7.42 (td, 2H, J = 7.7, 1.1 Hz), 7.26 (d, 2H, J = 14.3 Hz),
1
.37-1.25 (m, 10H), 0.94 (dd, 4H, J = 8.9, 7.2 Hz), 0.82 (t, 6H, J = 7.2 Hz). C-NMR (125 MHz,
3
1
CDCl
3
) δ 148.4, 137.9, 133.3, 130.0, 127.2, 120.9, 29.8, 26.5, 26.2, 13.7, 12.1, 1.1. MS (FAB, [M])
m/z 294.
5
,5-Dibutyl-2-ethyl-5H-dibenzosilole (16)
A mixture of 14 (17.6 mg, 52.0 µmol) and 10% Pd/C (1.8 mg) in MeOH (3.5 mL) was stirred at
room temperature. The reaction vessel was evacuated and back-filled with H , and the mixture was
2
stirred vigorously overnight, then filtered over a pad of Celite (hexane and EtOAc eluent). The
filtrate was extracted with hexane, and the organic solution was washed with brine, dried over
MgSO
4
and concentrated. The residue was purified by silica gel column chromatography using
1
hexane to give 16 (1.8 mg, 11%) as a colorless oil. H-NMR (500 MHz, CDCl
3
) δ 7.83 (d, 1H, J =
8.0 Hz), 7.67 (s, 1H), 7.60 (d, 1H, J = 6.9 Hz), 7.53 (d, 1H, J = 7.4 Hz), 7.41 (td, 1H, J = 7.7, 1.3
Hz), 7.24 (t, 1H, J = 3.7 Hz), 7.12 (t, 1H, J = 4.0 Hz), 2.72 (q, 2H, J = 7.6 Hz), 1.30 (m, 8H),
1
3
0
3
.93-0.87 (m, 4H), 0.82 (m, 9H). C-NMR (125 MHz, CDCl ) δ 146.3, 138.4, 134.7, 133.3, 130.0,

127.1, 127.0, 120.8, 120.6, 32.0, 29.8, 29.5, 29.3, 26.6, 26.2, 25.0, 22.8, 15.9, 15.6, 14.2, 13.9, 13.7,
12.2. MS (FAB [M]) m/z 322.
2-Acetyl-5,5-dibutyl-5H-dibenzosilole (17)
This product was obtained as a by-product (0.4 mg, 4%, colorless oil) in the reaction yielding 16.
1
H-NMR (500MHz, CDCl
3
) δ 8.37 (s, 1H), 7.94 (d, 1H, J = 7.4 Hz), 7.83 (dd, 1H, J = 7.4, 1.7 Hz),
7.71 (d, 1H, J = 7.4 Hz), 7.63 (d, 1H, J = 6.9 Hz), 7.47 (td, 1H, J = 7.6, 1.3 Hz), 7.31 (t, 1H, J = 6.9
1
3
Hz), 2.67 (s, 3H), 1.35-1.24 (m, 8H), 0.96 (t, 4H, J = 8.0 Hz), 0.81 (t, 6H, J = 6.9 Hz). C-NMR
125 MHz, CDCl ) δ 198.8, 149.1, 147.5, 144.6, 138.7, 137.8, 133.4, 133.4, 130.4, 127.8, 127.1,
21.3, 119.9, 29.8, 27.0, 26.4, 26.1, 13.7, 11.9. HRMS (FAB) calcd for C22 28NaOSi 359.1807;
(
3
1
H
+
found: m/z 359.1822 (M+Na) .
2-(2',6-Diaminobiphenyl-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (18)
To a solution of hexafluoroacetone･1.5H
(3.80 g, 20.6 mmol), p-TsOH･H O (470 mg, 2.50 mmol), and MS 4A (small amount), and the
mixture was stirred at 100 °C for 3 h, then allowed to cool to room temperature. The reaction was
2
O (4.70 mL, 41.2 mmol) in toluene (137 mL) was added
8
2
quenched with H
extracted several times with EtOAc. The organic layer was washed with brine and H
anhydrous MgSO and evaporated. The residue was purified by silica gel column chromatography
2
O, then sat. Na
2
CO
3
aq. was added until the pH reached 7, and the mixture was
2
O, dried over
4
1
(
3
n-hexane/EtOAc = 3:1) to give 18 as a yellow oil (4.40 g, 61%). H-NMR (500 MHz, CDCl ) δ
7.46 (s, 2H), 7.23 (td, 1H, J = 7.7, 1.6 Hz), 7.15 (dd, 1H, J = 7.6, 1.6 Hz), 6.92 (m 2H), 6.79 (d, 1H,
+
J = 9.2 Hz), 4.00 (s, 4H). MS (FAB [M]) m/z 350, MS (FAB [M+H] ) m/z 351.
2-(2',6-Diiodobiphenyl-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (19)
A solution of 18 (4.40 g, 12.6 mmol in 40 mL of EtOH) at 0 °C was added to a mixture of sodium
nitrite (3.81 g, 55.3 mmol in 43 mL of H
continued for a further 30 min, and then the mixture was added to a vigorously stirred solution of
KI (45.9 g, 276 mmol in 102 mL of H O) at room temperature. Stirring was continued overnight,
and then sat. Na CO aq. was added until the pH reached 7. The solution was extracted several
times with EtOAc. The organic layer was washed with H O, dried over anhydrous MgSO , and
2
O) and conc. HCl aq. (26 mL) at 0 °C. Stirring was
2
2
3
2
4
evaporated. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 3:1)
1
to give 19 as a yellow oil (1.70 g, 24%). H-NMR (500 MHz, CDCl
3
) δ 8.04 (dd, 1H, J = 8.6, 2.3
Hz), 7.96 (dd, 1H, J = 8.0, 1.1 Hz), 7.54 (d, 1H, J = 2.3 Hz), 7.47-7.41 (m, 2H), 7.23 (dd, 1H, J =

+
.6, 1.6 Hz), 7.12 (td, 1H, J = 7.7, 1.6 Hz), 3.76 (s, 1H). MS (FAB [M]) m/z 572, (FAB [M-I] ) m/z
7
446.
5-(2-Benzyloxy-1,1,1,3,3,3-hexafluoropropan-2-yl)-2,2'-diiodobiphenyl (20)
To a solution of 19 (1.75 g, 3.06 mmol) in N,N-dimethylformamide (3.15 mL) was added sodium
hydride (73.3 mg, 3.06 mmol). The resulting mixture was stirred for 30 min at room temperature.
Benzyl bromide (0.364 mL, 3.06 mmol) was added and the mixture was allowed to warm to 105 °C.
Stirring was continued overnight, then the reaction was quenched with H
extracted with EtOAc. The organic layer was washed with brine and H O, dried over anhydrous
MgSO and evaporated. The residue was purified by silica gel column chromatography using hexane
2
O, and the mixture was
2
4
1
to give 20 as a colorless paste (1.75 g, 79%). H-NMR (500 MHz, DMSO-d6) δ 8.29 (dd, 1H, J =
8.4, 3.3 Hz), 8.02 (dd, 1H, J = 7.9, 1.0 Hz), 7.56 (td, 1H, J = 7.4, 1.1 Hz), 7.44-7.38 (m, 6H), 7.34
(
dd, 1H, J = 7.6, 1.6 Hz), 7.30 (d, 1H, J = 2.0 Hz). 7.23 (td, 1H, J = 7.7, 1.6 Hz), 4.76-4.69 (m, 2H).
1
3
C-NMR (125 MHz, CDCl
3
) δ 149.8, 148.1, 139.7, 139.2, 136.0, 129.9, 129.0, 128.7, 128.6, 128.4,
+
28.3, 127.6, 127.4, 102.7, 99.3, 68.5. MS (FAB [M]) m/z 662, (FAB [M-I] ) m/z 535.
1
2-(2-Benzyloxy-1,1,1,3,3,3-hexafluoropropan-2-yl)-5,5-dibutyl-5H-dibenzosilole (21)
To a solution of 20 (146 mg, 0.220 mmol) in THF (2.0 mL) at -78 °C was added dropwise n-BuLi in
hexane (1.60 M, 330 µL, 0.530 mmol) under an Ar atmosphere. The resulting mixture was stirred for
a further 30 min at the same temperature. Dibutyldichlorosilane (71.1 µL, 0.330 mmol) was added
and the mixture was allowed to warm to room temperature. Stirring was continued overnight. The
reaction was then quenched with H
reached 7. Extraction with EtOAc afforded an organic layer, which was washed with brine and H
dried over anhydrous MgSO and evaporated. The residue was purified by silica gel column
chromatography using hexane to give 21 as a colorless oil (81.9 mg, 68%). H-NMR (500 MHz,
2
O, and sat. Na
2
CO
3
aq. was added to the mixture until the pH
2
O,
4
1
CDCl
3
) δ 8.02 (s, 1H), 7.69 (d, 1H, J = 7.7 Hz), 7.64 (dd, 2H, J = 12.5, 7.3 Hz), 7.50 (d, 1H, J = 7.7
Hz), 7.45-7.35 (m, 6H), 7.29 (td, 1H, J = 7.2, 0.9 Hz), 4.71 (s, 2H), 1.33 (m, 8H). 0.96 (m, 4H), 0.84
1
6H, t, J = 7.2 Hz). C-NMR (125 MHz, CDCl
3
(
3
) δ 149.2, 136.8, 134.6, 130.7, 125.3, 124.5, 26.4,
26.3, 26.1, 25.0, 15.9, 13.9, 13.7, 11.9. MS (FAB [M]) m/z 452.
2-(2-Benzyloxy-1,1,1,3,3,3-hexafluoropropan-2-yl)-5,5-dimethyl-5H-dibenzosilole (22)
To a solution of 20 (145 mg, 0.220 mmol) in THF (2.0 mL) at -78 °C was added dropwise n-BuLi in
hexane (1.60 M, 328 µL, 0.520 mmol) under an Ar atmosphere. The resulting mixture was stirred for

a further 30 min at the same temperature. Dimethyldichlorosilane (39.2 µL, 0.330 mmol) was added
and the mixture was allowed to warm to room temperature. Stirring was continued overnight. The
reaction was then quenched with H
reached 7. Extraction with EtOAc afforded an organic layer, which was washed with brine and H
dried over anhydrous MgSO and evaporated. The residue was purified by silica gel column
chromatography using hexane to give 22 as a colorless oil (41.5 mg, 41%). H-NMR (500 MHz,
CDCl ) δ 8.02 (s, 1H), 7.71 (d, 1H, J = 7.4 Hz), 7.64 (d, 2H, J = 6.9 Hz), 7.44-7.37 (m, 7H), 7.31 (dd,
2
O, and sat. Na
2
CO
3
aq. was added to the mixture until the pH
2
O,
4
1
3
1
3
1
3
H, J = 11.2, 4.3 Hz), 4.70 (s, 2H), 0.45 (s, 6H). C-NMR (125 MHz, CDCl ) δ 148.6, 141.8, 136.5,
133.1, 133.0, 130.5,130.0, 128.8, 128.3, 128.1, 127.5, 126.85, 121.1, 120.4, 68.3, -3.3. MS (FAB
-
M]) m/z 466, (FAB [M-Me] ) m/z 451.
[
2-(2-Benzyloxy-1,1,1,3,3,3-hexafluoropropan-2-yl)-5,5-diethyl-5H-dibenzosilole (23)
To a solution of 20 (55.0 mg, 0.0831 mmol) in THF (0.740 mL) at -78 °C was added dropwise
n-BuLi in hexane (1.60 M, 124 µL, 0.199 mmol) under an Ar atmosphere. The resulting mixture was
stirred for 30 min at the same temperature. Diethyldichlorosilane (18.6 µL, 0.125 mmol) was added
and the mixture was allowed to warm to room temperature. Stirring was continued overnight. The
reaction was then quenched with H
reached 7. Extraction with EtOAc afforded an organic layer, which was washed with brine and H
dried over anhydrous MgSO and evaporated. The residue was purified by silica gel column
chromatography using hexane to give 23 as a colorless oil (9.9 mg, 24%). H-NMR (500 MHz,
2
O, and sat. Na
2
CO
3
aq. was added to the mixture until pH
2
O,
4
1
CDCl
3
) δ 8.02 (s, 1H), 7.70 (d, 1H, J = 7.4 Hz), 7.64 (dd, 2H, J = 10.9, 7.4 Hz), 7.50 (d, 1H, J = 8.0
Hz), 7.44-7.36 (m, 6H), 7.29 (t, 1H, J = 7.2 Hz), 4.70 (s, 2H), 1.03 (dt, 6H, J = 9.4, 3.6 Hz), 0.96 (tt,
1
3
4
H, J = 10.3, 2.8 Hz). C-NMR (125 MHz, CDCl
3
) δ 149.2, 147.5, 140.4, 137.5, 136.5, 133.6,
133.5, 130.4, 129.9, 128.8, 128.3, 127.9, 127.5, 126.6, 123.8, 121.1, 120.3, 68.3, 7.6, 3.7. MS (FAB
[
M]) not found.
2-(5,5-Dibutyl-5H-dibenzosilol-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (24)
A mixture of 21 (76.8 mg, 0.140 mmol) and 10% Pd/C (15.4 mg) in MeOH (9.3 mL) was stirred at
2
room temperature. The reaction vessel was evacuated and back-filled with H . The mixture was
stirred vigorously overnight, and then filtered over a pad of Celite (hexane and EtOAc eluent). The
filtrate was extracted with hexane, and the organic solution was washed with brine, dried over
MgSO
4
and concentrated. The residue was purified by silica gel column chromatography
1
n-hexane/EtOAc = 10:1) to give 24 as a colorless oil (45.7 mg, 71%). H-NMR (500 MHz, CDCl
(
3
)

δ 8.15 (s, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.68 (d, 1H, J = 7.4 Hz), 7.63 (d, 1H, J = 6.9 Hz), 7.57 (d,
1
8
1
1
H, J = 7.4 Hz), 7.46 (dd, 1H, J = 10.9, 4.6 Hz), 7.30 (t, 1H, J = 7.2 Hz), 3.60 (s, 1H), 1.38-1.24 (m,
1
3
H), 0.95 (t, 4H, J = 8.0 Hz), 0.83 (t, 6H, J = 6.9 Hz). C-NMR (125 MHz, CDCl ) δ 149.0, 147.5,
3
40.7, 138.0, 133.5, 133.4, 131.1, 130.3, 127.8, 125.0, 123.9, 121.7, 121.1, 118.7, 60.6, 26.5, 26.1,
-
OSi 459.1579; found: m/z 459.1587 (M-H) .
3.7, 11.9. HRMS (FAB) calcd for C23
H
25
F
6
2-(5,5-Dimetyl-5H-dibenzosilol-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (25)
A mixture of 22 (38.7 mg, 0.0830 mmol) and 10% Pd/C (7.4 mg) in MeOH (5.5 mL) was stirred at
2
room temperature. The reaction vessel was evacuated and back-filled with H , and the mixture was
stirred vigorously. Stirring was continued overnight, and then the mixture was filtered over a pad of
Celite (hexane and EtOAc eluent). The filtrate was extracted with hexane, and the organic solution
4
was washed with brine, dried over MgSO and concentrated. The residue was purified by silica gel
column chromatography (n-hexane/EtOAc = 5:1) to give 25 as a colorless oil (8.3 mg, 17%).
1
H-NMR (500 MHz, CDCl
3
) δ 8.16 (s, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.70 (d, 1H, J = 7.4 Hz), 7.65
(
(
d, 1H, J = 7.4 Hz), 7.61-7.59 (m, 1H), 7.47 (tt, 1H, J = 7.4, 2.2 Hz), 7.31 (t, 1H, J = 7.2 Hz), 0.44
13
s, 6H). C-NMR (125 MHz, CDCl
3
) δ 147.0, 139.1, 133.0, 131.3, 133.5, 129.1, 129.0, 128.0,
1
3
13 6
27.4, 125.2, 121.2, 118.7, -3.3. HRMS (FAB) calcd for C17H F OSi 375.0640; found: m/z
-
75.0654 (M-H) .
2
-(5,5-Diethyl-5H-dibenzosilol-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (26)
A mixture of 23 (2.7 mg, 5.46 µmol) and 10% Pd/C (0.5 mg) in MeOH (0.25 mL) was stirred at
room temperature. The reaction vessel was evacuated and back-filled with H . The mixture was
2
stirred vigorously overnight, and then filtered over a pad of Celite (hexane and EtOAc eluent). The
filtrate was extracted with hexane, and the organic solution was washed with brine, dried over
MgSO
4
and concentrated. The residue was purified by silica gel column chromatography
1
n-hexane/EtOAc = 10:1) to give 26 as a colorless oil (0.9 mg, 41%). H-NMR (500 MHz, CDCl
(
3
)
δ 8.15 (s, 1H), 7.87 (d, 1H, J = 7.4 Hz), 7.69 (d, 1H, J = 7.4 Hz), 7.63 (d, 1H, J = 7.4 Hz), 7.57 (d,
1H, J = 7.4 Hz), 7.46 (td, 1H, J = 7.6, 1.3 Hz), 7.30 (t, 1H, J = 6.9 Hz), 1.02-0.99 (m, 6H),
1
.97-0.94 (m, 4H). C-NMR (125 MHz, CDCl
3
0
3
) δ133.4, 130.4, 127.8, 121.2, 7.6, 3.7. HRMS
-
OSi 403.0953; found: m/z 403.0975 (M-H) .
(
FAB) calcd for C19
H
17
F
6
2-(2-Benzyloxy-1,1,1,3,3,3-hexafluoropropan-2-yl)-5-butyl-5-methyl-5H-dibenzosilole (28)
To a solution of 20 (109 mg, 0.165 mmol) in dry tetrahydrofuran (1.5 mL) was added t-BuLi in

n-hexane (1.63 M, 0.304 mL, 0.496 mmol) under an Ar atmosphere at -78 °C. The mixture was
stirred at the same temperature for 20 min, and then warmed to room temperature. Stirring was
continued at the same temperature for 30 min. The reaction mixture was cooled to -78 °C,
n-butyltrichlorosilane (89.2 µL, 0.545 mmol) was added to it, and stirring was continued at room
temperature overnight. A solution of methylmagnesium bromide (0.436 mL, 0.397 mmol) in dry
tetrahydrofuran was then added under an Ar atmosphere at -78 °C, and stirring was continued at
room temperature overnight. The reaction was quenched with H
2
O and the mixture was extracted
. The
with EtOAc. The extract was successively washed with H O and brine, and dried over MgSO
2
4
solvent was evaporated, and the residue was purified by silica gel column chromatography using
1
hexane to give 28 (26.5 mg, 32%) as a colorless oil. H-NMR (500 MHz, CDCl
3
) δ 8.02 (s, 1H),
7.70 (d, 1H, J = 8.0 Hz), 7.64 (t, 2H, J = 7.2 Hz), 7.56-7.47 (m, 1H), 7.44-7.36 (m, 6H), 7.30 (t, 1H,
J = 7.4 Hz), 4.71 (s, 2H, J = 8.6 Hz), 1.42 (tt, 2H, J = 9.5, 3.6 Hz), 1.37-1.29 (m, 2H), 0.96-0.93 (m,
1
H), 0.86 (t, 3H, J = 7.2 Hz), 0.44 (s, 3H). C-NMR (125 MHz, CDCl
3
2
3
) δ 138.6, 133.4, 133.2,
130.4, 129.0, 128.8, 128.3, 128.0, 127.5, 127.2, 126.8, 121.1, 120.3, 68.3, 26.5, 26.1, 13.7, 13.3,
-
5.1. MS (FAB [M]) m/z 508, (FAB [M-nBu] ) m/z 451, (FAB [M-nBu-Me+H] ) m/z 437.
-
-
2-(5-Butyl-5-methyl-5H-dibenzosilol-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (29)
A mixture of 28 (15.1 mg, 0.0300 mmol) and 10% Pd/C (3.0 mg) in MeOH (0.149 mL) and acetic
acid (15 µL) was stirred at room temperature. The reaction vessel was evacuated and back-filled
with H
hexane and EtOAc eluents). The filtrate was extracted with hexane, and the organic solution was
washed with brine, dried over MgSO and concentrated. The residue was purified by silica gel
2
. The mixture was stirred vigorously overnight, and then filtered over a pad of Celite
(
4
column chromatography (n-hexane/EtOAc = 5:1) to give 29 as a colorless oil (11.1 mg, 90%).
1
H-NMR (500 MHz, CDCl
d, 1H, J = 6.3 Hz), 7.58 (d, 1H, J = 7.4 Hz), 7.46 (td, 1H, J = 7.6, 1.3 Hz), 7.31 (t, 1H, J = 7.7 Hz),
.43-1.36 (m, 2H), 1.34-1.29 (m, 2H), 0.94 (td, 2H, J = 5.6, 4.2 Hz), 0.85 (t, 3H, J = 7.2 Hz), 0.43
3
) δ 8.15 (s, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.63
(
1
1
3
s, 3H). C-NMR (125 MHz, CDCl
(
3
) δ 148.7, 141.2, 138.6, 133.2, 131.2, 130.4, 127.9, 125.1,
OSi 417.1109; found:
1
21.1, 118.7, 26.4, 26.1, 13.7, 13.3, -5.1. HRMS (FAB) calcd for C19H F
17 6
-
m/z 417.1120 (M-H) .
4.2 Reporter gene assay
PcDNA3.1(-)-hRORα1, pcDNA3.1(-)-hRORβ1, pcDNA3.1(-)-hRORγ1 and RORE-TK-Luc were
provided by Itsuu Laboratory. CMX-β-GAL was provided by Professor Dr. Makoto Makishima

(
Nihon University School of Medicine). Human embryonic kidney (HEK) 293 cells were cultured in
DMEM containing 5% FBS, penicillin and streptomycin mixture at 37 °C in a humidified
2
atmosphere of 5% CO in air. Cells were seeded at a density of 20% confluence/96-well plate 24 h
prior to transfection. Cells in each well were cotransfected with 150 ng of a nuclear receptor
expression plasmid, 500 ng of a luciferase reporter and 10 ng of CMX-β-GAL expression vector.
Transfections were performed by the calcium phosphate co-precipitation method. After 8 h,
transfected cells were treated with test compounds or dimethyl sulfoxide (DMSO) for 16 h. Treated
cells were assayed for luciferase activity with a luminometer. The luciferase activity of each sample
was normalized by the level of β-galactosidase activity. Each transfection was carried out in
triplicate.
4.3. Docking simulation
Structure of LBD of RORγ was prepared from the Protein Data Bank accession 4NB6. The
structure added for polar hydrogens, and partial atomic charges were assigned using
1
AutoDockTools (ADT). Molecular docking was performed using AutoDock 4.2 with Genetic
4
Algorithm. Autodock parameters for silicon atom Rii = 4.30 and εii = 0.402 were used.
Acknowledgements
The work partially supported by “Platform for Drug Discovery, Informatics, and Structural Life
Science”, and “Grants-in-Aid for Scientific Research from The Ministry of Education Culture,
Sports, Science and Technology, Japan, and the Japan Society for the Promotion of Science
(
KAKENHI Grant No. 26293025 (YH) and No. 25460146 (SF))”.
References and notes
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