Altered activity profile of a tertiary silanol analog of multi-targeting nuclear receptor modulator T0901317

Article abstract of DOI:10.1016/j.bmcl.2016.02.031

We report the design, synthesis, and physicochemical/biological evaluation of novel silanol derivative 6 (sila-T) as a silanol analog of multi-target nuclear receptor modulator T0901317 (5). Compound 6 showed intermediate hydrophobicity between the corres

Full text of DOI:10.1016/j.bmcl.2016.02.031

Accepted Manuscript
Altered activity profile of a tertiary silanol analog of multi-targeting nuclear
receptor modulator T0901317
Hirozumi Toyama, Shoko Sato, Hitoshi Shirakawa, Michio Komai, Yuichi
Hashimoto, Shinya Fujii
PII:
S0960-894X(16)30143-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.02.031
BMCL 23585
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
22 January 2016
9 February 2016
12 February 2016
Please cite this article as: Toyama, H., Sato, S., Shirakawa, H., Komai, M., Hashimoto, Y., Fujii, S., Altered activity
profile of a tertiary silanol analog of multi-targeting nuclear receptor modulator T0901317, Bioorganic & Medicinal
Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.02.031
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Bioorganic & Medicinal Chemistry Letters
Altered activity profile of a tertiary silanol analog of multi-targeting nuclear
receptor modulator T0901317
Hirozumi Toyamaa, Shoko Satob, Hitoshi Shirakawac, Michio Komaic, Yuichi Hashimotoa , Shinya Fujii a,*
a Institute of Molecular and Cellular Biosciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-0032 Tokyo, Japan
b Department of Biological Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan
c Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
We report the design, synthesis, and physicochemical/biological evaluation of novel silanol
derivative 6 (sila-T) as a silanol analog of multi-target nuclear receptor modulator T0901317 (5).
Compound 6 showed intermediate hydrophobicity between the corresponding alcohol 13 and
perfluoroalcohol 5. While 5 exhibited potent activities toward liver X receptor α and β, farnesoid
X receptor, pregnane X receptor (PXR) and retinoic acid receptor-related orphan receptor (ROR)
γ, silanol 6 exhibited activity only toward PXR and RORs. Incorporation of silanol instead of
perfluoroalcohol is a promising option for developing novel target-selective, biologically active
compounds.
Keywords:
Silanol
Sila-substitution
Nuclear receptor
2009 Elsevier Ltd. All rights reserved.
Pregnane X receptor (PXR)
Retinoic acid receptor-related orphan receptor (ROR)
T0901317
The alcoholic hydroxy group is one of the most important
functional groups in biologically active compounds.1 It can be
involved in hydrogen bonding and other polar contacts, functions
as a nucleophilic reactive species, and markedly influences the
absorption, distribution, metabolism, excretion, and toxicity
(ADMET) profiles of compounds. Physicochemical properties
such as the acidity of the hydroxy group and the hydrophobicity
of a neighboring group also affect the biological activity. For
example, in nuclear receptor ligands such as vitamin D receptor
(VDR) ligands,2,3 liver X receptor (LXR) ligands and pregnane X
receptor (PXR) ligands,4 modification of the acidity or
hydrophobicity of the tertiary alcohol therein significantly affects
the biological activities. Therefore, the use of novel substitutes
for the alcoholic hydroxy group is a promising approach for
structural development of drug candidates.
silanol as a hydrophilic structure. A representative example is a
series of silanediol-based protease inhibitors, such as 1 and 2.17-19
Silanediols in these compounds function as mimics of the
transition state in substrate hydrolysis. Another example is
provided by cyclic silanol derivatives including sila-venlafaxine
(3) and sila-haloperidol (4) (Figure 1).20-22 In the case of sila-
haloperidol, dehydration to afford the toxic pyridinium
metabolite is blocked, because the Si=C double bond is
intrinsically thermodynamically instable.21 Although other
examples have also been reported, utilization of silanol in
medicinal chemistry is still quite limited compared to other
hydrophobic substructures.
One possible approach for exploiting novel isosteric structures
of alcoholic hydroxy groups is utilization of heteroatom
functionalities. In the case of acidic carboxy groups, application
of several heteroatom-hydroxy functionalities, such as sulfonic
acid, phosphonic acid, hydroxamic acid and boronic acid, has
been intensively investigated in the field of medicinal
chemistry.1,5 Regarding development of alternatives to the
alcoholic hydroxy group, incorporation of heteroatoms is also
useful, and silanol has potential as an isosteric substructure of
alcoholic hydroxy groups.6-8 The silicon atom is isoelectronic
with carbon, and therefore various silicon/carbon exchanges
(sila-substitutions) of biologically active compounds have been
investigated, particularly for optimization of hydrophobic
moieties.9-16 There have also been some studies on the use of
Figure 1. Examples of silanol-based biologically active
compounds.

Table 1.
Determined and calculated physicochemical properties of
compounds 5, 6 and 13.
5
6
13
a
logPo/w
5.38
170.7
7.5
4.23
154.4
12.5
3.70
141.3
14.6
partial volume (PhXR2OH) (Å3)b
pKac
a Determined by HPLC method.30 b Calculated by MOPAC software
(methods: PM3 EF)31. c Estimated by ACD/Chemsketch software32.
Figure 2. Design scheme of the silanol analog of T0901317 (sila-
T; 6).
In order to investigate the structure-activity relationship, the
corresponding alcohol derivative 13 was also synthesized as
shown in Scheme 2. Reaction with ethyl 4-aminobenzoate (10)
and benzenesulfonyl chloride gave sulfonamide 11, which was
N-alkylated to afford compound 12. Treatment of compound 12
with methylmagnesium bromide gave the desired alcohol 13
(Scheme 2).
To expand the utility of silanols, we focused on the similarity
between silanol and perfluoroalcohol. Perfluoroalcohols show
higher acidity and hydrophobicity than the corresponding
hydrocarbon-based alcohols, owing to the differences of
electronegativity and molecular volume between alkyl groups
and the corresponding perfluoroalkyl groups. Silanols also show
somewhat higher acidity and hydrophobicity than the
corresponding alcohols because of the differences of electronic
properties and molecular volume between silanols and the
We next investigated the physicochemical properties of the
synthesized
compounds
and parent T0901317 (5).
corresponding
alcohols.23
The
1,1,1,3,3,3-hexafluoro-2-
Hydrophobicity was determined in terms of the octanol−water
partition coefficient (Po/w), using an HPLC method.30 Silanol 6
exhibited a logPo/w value of 4.23, which is larger than that of
corresponding alcohol 13 (logPo/w; 3.70). Previous results
indicated that C/Si-exchange of alkylsilanes increases the
hydrophobicity of the compounds by 0.5-0.7 in logPo/w value,16
and the present result suggests that this is also the case with
silanols. Compound 5 exhibited a logPo/w value of 5.38,
significantly larger than that of corresponding alcohol 13, and the
hydrophobicity of silanol is intermediate between those of the
alcohol and perfluoroalcohol. The difference of hydrophobicity
can be mainly attributed to the difference of molecular volume,
and the calculated values of partial volume of the compounds
(PhXR2OH) are consistent with the order of hydrophobicity. The
acidity of the compounds was also calculated. The estimated pKa
value of compound 6 (12.5) is smaller than that of alcohol 13
(14.6), while both values are considerably larger than that of
compound 5 (7.5). Though the acidity of silanols may be larger
than that of corresponding alcohols, it is considerably smaller
than that of perfluoroalcohols.
hydroxypropyl group, one of the perfluoroalcoholic
functionalities, is a key structural motif of T0901317 (5), which
is a benzenesulfonamide-based compound that exhibits agonistic
activity toward multiple nuclear receptors, including LXRα and
LXRβ,24 PXR (also SXR; steroid and xenobiotic receptor),4,25
farnesoid X receptor (FXR),26 and inverse agonistic activity
toward retinoic acid receptor-related orphan receptors (RORs).27
Previous researches revealed that the substituents around the
hydroxy group have a significant influence on the activity and
selectivity.4,28 So, we planned to investigate the activity profile of
silanol 6 (named sila-T), a silanol analog of perfluoroalcohol-
based T0901317 (5) (Figure 2).
Scheme 1 shows the synthesis of the designed silanol
derivative 6. Sulfonamide formation using 4-bromoaniline (7)
and benzenesulfonyl chloride gave sulfonamide 8, and then N-
alkylation with 2,2,2-trifluoroethyl triflate afforded compound 9.
The bromo group of 9 was converted to dimethylsilanol using
Denmark’s conditions;29 namely, in the presence of PdCl2 and 2-
(di-tert-butylphosphino)biphenyl (BPTBP), compound 9 reacted
with 1,2-diethoxy-1,1,2,2-tetramethyldisilane to afford
a
ethoxydimethylsilyl derivative as an intermediate, and then
removal of the ethyl group gave the desired silanol 6 (Scheme 1).
Scheme 1. Synthesis of silanol derivative 6 (sila-T). Reagents and conditions: (a) benzenesulfonyl chloride, pyridine, THF, rt, 93%; (b)
NaH, CF3CH2OTf, DMF, 80°C, 68%; (c) i) PdCl2, BPTBP, i-Pr2EtN, (Me2SiOEt)2, NMP, 60°C; ii) AcOH, MeCN, Me2N(CH2)2SH-
HCl, 26%.
Scheme 2. Synthesis of alcohol derivative 13. Reagents and conditions: (a) benzenesulfonyl chloride, pyridine, THF, rt; (b) NaH,
CF3CH2OTf, DMF, 80°C, 33% from 10; (c) MeMgBr, THF, 0°C, 77%.

Table 2.
Biological activities of compounds toward nuclear receptors.
compd
hLXRα
hLXRβ
hFXR
EC50 (μM)
hPXR
EC50 (μM)
hRORα
IC50
(μM)
hRORβ
IC50 (μM) IC50
(μM)
hRORγ
EC50 (μM)
IC50 (μM) a
EC50 (μM)
IC50 (μM) b
0.40
N.A.
N.A.
-
0.23
N.A.
N.A.
-
3.4
0.27
N.A.
N.A.
60
N.A.
3.0
43
N.A.
5
6
13
N.A.
N.A.
N.A.
N.A.
11 (23%)c
N.A.
0.88 (61%)d 53
N.A.
N.A.
a Compounds were treated with 0.30 μM T0901317 (5). b Compounds were treated with 0.10 μM T0901317 (5). c Percentage with respect to the response to 10
μM T0901317 (5). d Percentage with respect to the response to 1.0 μM T0901317 (5). N.A.: No significant activity.
Next, the ligand potencies of the compounds toward hLXRα,
hLXRβ, hFXR, hPXR (SXR), and hRORα, β and γ were
evaluated by means of luciferase reporter gene assay in HEK293
cells. Compound 5 exhibited significant agonistic activity toward
LXRα and β, FXR and PXR, and inverse agonistic activity
toward RORγ.33 On the other hand, compound 13 bearing a
hydrocarbon-based alcohol instead of the perfluoroalcohol
moiety of 5 exhibited no significant activity toward any of these
nuclear receptors. These results indicate that high hydrophobicity
and/or potent acidity of compound 5 is essential for biological
activity toward these nuclear receptors. As for the silanol
derivative 6, it exhibited neither agonistic nor antagonistic
activity toward LXRs, and showed only modest partial agonistic
activity toward FXR. In contrast to the case of LXRs and FXR,
compound 6 exhibited inverse agonistic activity toward RORs. In
addition, silanol 6 exhibited significant agonistic activity toward
PXR. The PXR agonistic activity of silanol 6 is comparable to
that of representative PXR agonist rifampicin (EC50 value for
PXR; 1.1 μM, maximum efficacy is 75% compared to 5 in the
same assay system). This result suggests that the silanol group
could function as an isoster of the perfluoroalkyl group in the
case of PXR ligands. The silanol functionality may be a useful
option for development of other target-selective bioactive
compounds.
therefore shows selectivity for PXR over LXRs. Although the
reason of the
X-Ray crystal structures of compound 5 complexed with
hLXRα,34 hLXRβ,35 hPXR4 and hRORγ28 have been reported,
and we conducted docking simulations using the crystal
structures.36 In the co-crystal structures with RORγ, the
hexafluorohydroxypropyl group of compound 5 does not form a
hydrogen bond to any amino acid residue of the receptor. In the
docked structure with RORγ, the hydroxy group of silanol 6 also
shows no notable hydrogen bonding (Figure 3). These results
suggest that hydrophobic interaction around the hydroxy moiety
of the compound and the receptor surface of RORγ is rather more
important than polar interaction for the activity. It is possible that
silanol 6 exhibited inverse agonistic activity towards RORs due
to its relatively high hydrophobicity compared with that of the
corresponding alcohol 13.
In the cases of LXRα, LXRβ and PXR, the
hexafluorohydroxypropyl group of compound 5 forms a key
hydrogen bond to a His residue of the receptor (His 421, His435
and His407, respectively). In the docked structure with PXR, the
hydroxy group of silanol 6 also forms a hydrogen bond to
His407. Structure-activity relationship study of T0901317
derivatives indicates that introduction of bulky hydrophobic
substituents, as well as perfluoroalkyl groups, at the tertiary
alcohol moiety is effective for potent PXR agonistic activity,
whereas LXR agonistic activity strictly requires perfluoroalkyl
substituents. We speculate that high hydrophobicity around the
hydroxy moiety is important for PXR agonistic activity, whereas
both hydrophobicity and high polarization of the hydroxy moiety
may be essential for LXR agonistic activity. It is possible that
silanol 6 exhibited PXR agonistic activity due to its relatively
high hydrophobicity, but did not exhibit LXR ligand potency
because of its lower polarization compared to compound 5, and
Figure 3. Docking simulations of compound 6 using the crystal
structures of hRORγ (PDB-ID: 4NB6, upper) and hPXR (PDB-
ID: 2O9I, bottom). The protein surface is indicated as a light-blue
mesh. The native ligand T0901317 (5) in the crystal structures is
shown in green.
inactivity of compound 6 toward LXRs is unclear, alcohol/silanol
exchange appears to be a promising option for modifying the
activity profile of bioactive compounds.
In summary, in order to expand the utility of silanols in
medicinal chemistry, we designed and synthesized silanol 6 (sila-
T), a novel silanol derivative of T0901317 (5), focusing on the
silanol functionality as an isosteric structure of perfluoroalcohol,
and we compared the physicochemical properties and biological
activities of 5 and 6. In contrast to the parent compound 5, which
exhibited potent activities toward LXRα and β, FXR, PXR and
RORγ, the synthesized silanol 6 exhibited only agonistic activity
toward PXR and inverse agonistic activity toward RORs. The
difference in activity could be attributed to the similarity of

hydrophobicity and the difference of polarization between silanol
and perfluoroalcohol. Silanol appears to be promising option for
development of novel, target-selective, biologically active
compounds. Further structural development and structure-activity
relationship studies are in progress.
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Acknowledgments
This work was 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 (Y.H.), No. 25460146 (S.F.), Nos. 20380071 and
23380070 (H.S.)). We thank Dr. Shuichi Mori (Tokyo Medical
and Dental University) for helpful discussions.
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Supplementary Material
Supplementary data associated with this article can be found,
in the online version.
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Altered activity profile of a tertiary silanol
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Hirozumi Toyama, Shoko Sato, Hitoshi Shirakawa, Michio Komai, Yuichi Hashimoto, Shinya Fujii