Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists

Article abstract of DOI:10.1016/j.bmcl.2015.05.045

Abstract We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds.

Full text of DOI:10.1016/j.bmcl.2015.05.045

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of silicon-containing fatty acid amide
derivatives as novel peroxisome proliferator-activated receptor
(
PPAR) agonists
a
a
b
a
a
Daisuke Kajita , Masaharu Nakamura , Yotaro Matsumoto , Minoru Ishikawa , Yuichi Hashimoto ,
Shinya Fujii
a
a,
⇑
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we inves-
tigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and syn-
thesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing
Received 28 April 2015
Revised 14 May 2015
Accepted 20 May 2015
Available online xxxx
PPARa
agonist, and evaluated their PPAR
a/d/c agonistic activity. We found that diethylsilyl derivative
20 exhibited PPAR
a
/d agonistic activity, and we also obtained a PPARd-selective agonist, 32. Our results
suggest that incorporation of silyl functionality is a useful option for structural development of biologi-
cally active compounds.
Keywords:
Sila-substitution
Silicon
Ó 2015 Elsevier Ltd. All rights reserved.
cis-Olefin mimetic
Peroxisome proliferator-activated receptor
PPAR
In the field of medicinal chemistry, introduction of a silicon
atom in place of a carbon atom (sila-substitution) is employed as
a strategy to alter the activity, selectivity and pharmacokinetics
of compounds, due to the different properties of carbon and silicon,
acids, such as leukotriene B4 (6), arachidonic acid (7), and an acid
amide oleoylethanolamide (OEA: 8), function as peroxisome prolif-
–11
erator-activated receptor
a (PPARa
) agonists (Fig. 3).9
PPAR is a member of the nuclear receptor superfamily of ligand-
1
–4
12–14
such as atomic size, electronegativity and hydrophobicity.
In
dependent transcriptional factors.
PPAR, namely PPAR , PPAR and PPARd (b). PPAR
the endogenous agonists, and regulates various physiological
processes, including lipid metabolism. Therefore, PPAR is an
attractive target of drugs for metabolic disorders, and synthetic
PPAR agonists such as fibrates have been used for treatment of
hyperlipidemia. Though the endogenous PPAR
considered as lead compounds for novel PPAR
There are three subtypes of
recent years, various silicon-containing bioactive compounds have
a
c
a
is activated by
been reported, such as BNP1350 (1), sila-haloperidol (2) and
5
–7
TAC101 (3) (Fig. 1),
and clinical studies have supported the idea
a
that sila-substitution can improve the selectivity, potency and
pharmacokinetics of drug candidates. We previously designed
and synthesized diphenylsilane derivatives of the anticancer drug
combretastatin A-4 (CA-4) (4) by replacing the cis-olefin with a
silyl functionality (Fig. 2).8 We found that silicon-containing 5
exhibited potent antitumor activity, together with much greater
stability in aqueous solution compared with CA-4 (4), which iso-
merized to inactive form under the same conditions. Based on
these findings, we planned to further investigate the utility of silyl
functionality as an aliphatic cis-olefin mimetic. There are myriad
cis-olefin-containing fatty acids and their derivatives in biological
systems, and many of them function as biological factors or sig-
nal-transducing molecules. For instance, some endogenous fatty
a
1
5
a
a
agonists can be
modulators, the
chemical instability of the cis-olefinic bond is an undesirable
feature for structural development. In this Letter, we described
the design and synthesis of novel PPAR-modulating fatty acid
derivatives containing a silyl functionality as a cis-olefin mimetic.
In order to develop suitable derivatives, we focused on OEA (8).
It was previously reported that administration of OEA caused a
1
1
reduction of food intake in mice. In addition to its agonistic
activity toward PPAR , OEA promotes the secretion of GLP-1, a
a
gut hormone controlling insulin secretion, insulin sensitivity, and
appetite, by stimulating G-protein coupled receptor GPR119.16
Furthermore, it was suggested that OEA activates TRPV1 (transient
receptor potential cation channel subfamily V member 1), also
⇑
Corresponding author. Tel.: +81 3 5841 7848; fax: +81 3 5841 8495.
E-mail address: fujiis@iam.u-tokyo.ac.jp (S. Fujii).
http://dx.doi.org/10.1016/j.bmcl.2015.05.045
960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Kajita, D.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.045

2
D. Kajita et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Si
COOH
O
Cl
F
O
Si
N
H
N
Si
N
O
HO
N
O
Si
O
OH
BNP1350 (1)
topoisomerase inhibitor
sila-haloperidol (2)
antipsychotic agent
TAC101 (3)
retinoic acid receptor agonist
Figure 1. Examples of silicon-containing bioactive compounds.
MeO
MeO
X
OH
CH
d = 3.214 ഺ
CH
3
CH
d = 3.132 ഺ
CH
3
H
3
C
C
CH3
3
H C
Si
C
d = 2.579 ഺ
OMe
H
3
3
H C
CH
3
OMe
3
3
4
5
: X = cis-CH=CH IC50 (MCF-7) = 0.004 µM
: X = SiHCH IC50 (MCF-7) = 0.007 µM
9
10
11
3
H
N
H
N
R
R
OH
OH
Figure 2. Structure of tubulin polymerization inhibitors. Silyl derivative 5, in which
cis-olefin is replaced by a silyl group, exhibited potent activity.
Si
O
O
R = Me, Et, n-Pr, n-Bu
silyl analogs of OEA
OEA (8)
OH
OH
O
Figure 4. Design rationale of silicon-containing fatty acid derivatives. Calculated
distances (d) between the two indicated carbon atoms in compounds 9, 10 and 11
OH
(
top) are shown. Structures of the designed compounds (bottom).
leukotriene B4 (LTB4: 6)
O
OH
summarized in Scheme 2. The hydroxyl group of 23 was protected
with a PMB group to give compound 24. Disubstitution of
dichlorodiethylsilane (15b) using compound 24 and 1-octyne, or
compound 14 and 1-heptyne afforded tetraalkylsilanes 25 and
arachidonic acid (7)
H
N
OH
2
9, respectively. Catalytic hydrogenation of 25 and 29 gave alcohol
O
derivatives 26 and 30, respectively. Oxidation of alcohol 26 and 31
gave carboxylic acid derivatives 27 and 31, and finally, condensa-
tion of the carboxylic acids 27 and 32 with ethanolamine gave
compounds 28 and 32, respectively (Scheme 2). N-(2-Hydroxyethyl)
stearamide (34), a saturated fatty acid amide derivative of OEA,
was also prepared from stearic acid (33) (Scheme 3).
oleoylethanolamide (OEA: 8)
Figure 3. Structures of endogenous PPAR
a
agonists containing a cis-olefin moiety.
known as capsaicin receptor.17 Thus, the physiological roles of this
endogenous fatty acid amide are interesting.
The PPAR-agonistic activities of the synthesized silyl derivatives
of OEA were evaluated by means of PPAR reporter gene assays.
Initially, in order to examine the structural similarity of alipha-
tic cis-olefin and silyl group, we conducted molecular orbital calcu-
lations for cis-olefin (Z)-3-hexene (9), diethyldimethylsilane (10)
and 3,3-dimethylpentane (11). As shown in Figure 4, the distance
Figure 5A shows the PPARa-agonistic activity of compounds
19–22 bearing different dialkylsilyl functionalities and saturated
fatty acid amide 34. As reported, OEA exhibited agonistic activity
toward PPAR
significant PPAR
cis-olefin is a key substructure for PPAR
Regarding silyl derivatives, compounds 20 bearing a diethylsilyl
group showed moderate PPAR -agonistic activity. Dimethylsilyl
derivative 19 and di-n-propyl derivative 21 also exhibited
PPAR -agonistic activity somewhat more potent than that of satu-
a
. On the other hand, compound 34 did not exhibit
-agonistic activity. This result indicated that
-agonistic activity.
(d) in the silyl derivative 10 is similar to that of the cis-olefin 9.
a
On the other hand, the distance in the corresponding alkane 11 is
significantly shorter than those in 9 and 10. This result suggests
that replacement of the cis-olefin of OEA with a silyl functionality
would be a reasonable conversion, and therefore we designed silyl
derivatives of OEA (Fig. 4).
a
a
a
Synthesis of silyl derivatives 19–22 bearing n-octyl and
n-octanoyl moieties is illustrated in Scheme 1. Alkyne zipper reac-
tion of 3-octyn-1-ol (12) gave the terminal alkyne 13, then the
hydroxyl group of 13 was protected with p-methoxybenzyl
rated fatty acid amide 34. Compound 22 bearing a di-n-butylsilyl
moiety showed no activity. Figure 5B shows the agonistic activity
of compounds 18–22 toward PPARd. Diethylsilyl derivative 20
exhibited PPARd-agonistic activity with similar potency to that of
OEA. Compounds 19 and 21 also exhibited PPARd-agonistic activ-
ity, whereas compound 22 exhibited no activity. No agonistic
(
PMB) group to afford compound 14. Disubstitution of dichlorosi-
lanes 15a–d using compound 14 and 1-octyne in the presence of
n-butyllithium afforded tetraalkylsilanes 16a–d, respectively.
Reduction of alkyne moieties and removal of the PMB group of
activity was observed toward PPARc (data not shown). These
results suggested that dialkylsilyl substitution of the cis-olefin of
OEA at least partially retains the biological activity. Alkyl groups
on the silicon atom considerably affected the activity (Fig. 5).
Next, we investigated the structure–activity relationship of
diethylsilyl derivatives. Compound 28 bearing heptanoyl structure
and compound 32 bearing an n-heptyl group exhibited quite low
1
6a–d by catalytic hydrogenation gave alcohol derivatives 17a–d,
respectively. The isolate yield of 17a and 17d was low because
the alkylating step gave multiple products and there was difficulty
in purification. Oxidation of the alcohols 17a–d using Dess–Martin
periodinane gave carboxylic acid derivatives 18a–d, respectively.
Finally, condensation of the carboxylic acids 18a–d with ethanola-
mine via acid anhydride gave the designed OEA derivatives 19–22,
respectively (Scheme 1). Synthesis of silyl derivatives 28 and 32 is
activity toward PPAR
in a decrease of PPAR
of the chain length also affected the agonistic activity toward
a. Modification of the chain length resulted
a
-agonistic activity (Fig. 6A). Modification
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D. Kajita et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
a
OH
b
OPMB
OH
H
H
12
13
14
OPMB
R
OH
R
Cl
R
Cl
c
R
R
d
14
Si
Si
Si
R
1
5a (R = Me)
16a (R = Me)
16b (R = Et)
16c (R = n-Pr)
16d (R = n-Bu)
17a (R = Me)
17b (R = Et)
17c (R = n-Pr)
17d (R = n-Bu)
1
1
1
5b (R = Et)
5c (R = n-Pr)
5d (R = n-Bu)
H
N
R
Si
R
OH
R
e
f
OH
Si
O
R
O
1
9 (R = Me)
1
8a (R = Me)
8b (R = Et)
8c (R = n-Pr)
1
1
1
20 (R = Et)
21 (R = n-Pr)
2 (R = n-Bu)
2
8d (R = n-Bu)
Scheme 1. Synthesis of compounds 19–22. Reagents and conditions: (a) NaH, ethylenediamine, 65 °C, 72%; (b) CSA, 4-methoxybenzyl trichloroacetimidate, CH
2
Cl
2
, rt, 34%;
(
c) 1-octyne, n-BuLi, THF, À78 °C to rt, 44% or crude; (d) H
2
, Pd/C, ethyl acetate, rt, 42% or 1.4–44% (2 steps); (e) DMP, CH
, rt, 14–40% or 34% (2 steps).
2
Cl
2
, rt, 56–70% or crude; (f) triethylamine, methyl
chloroformate, ethanolamine, CH
Cl
2 2
OPMB
a
b
Et
Et
OH
OPMB
Si
H
c
H
2
3
24
25
O
O
Et
Et
d
Et
Et
e
Et
OH
OH
OH
N
H
Si
Si
Si
Si
Et
26
27
28
OPMB
OPMB
f
Et
Et
c
Et
OH
Si
H
Et
14
29
30
H
N
d
Et
Et
OH
e
Et
OH
Si
Si
O
O
Et
31
32
Scheme 2. Synthesis of compounds 28 and 32. Reagents and conditions: (a) CSA, 4-methoxybenzyl trichloroacetimidate, CH
dichlorodiethylsilane, THF, À78 °C to rt, crude; (c) H , Pd/C, ethyl acetate, rt, 14–15% (2 steps); (d) DMP, CH Cl , rt, 19–50%; (e) triethylamine, methyl chloroformate,
ethanolamine, CH Cl
, rt, 40–68%; (f) 1-heptyne, n-BuLi, dichlorodiethylsilane, THF, À78 °C to rt, crude.
2 2
Cl , rt, 70%; (b) 1-octyne, n-BuLi,
2
2
2
2
2
H
N
the hydrophobic pocket of the LBD, and ethanolamide moiety
shows a polar interaction. It was also suggested that the diethylsi-
lyl group improves hydrophobic interaction with the LBD. On the
other hand, it was suggested that the diethylsilyl group of com-
pound 20 could sterically interfere with the receptor surface
OH
OH
O
O
33
34
Scheme 3. Synthesis of compound 34. Reagents and conditions: triethylamine,
methyl chloroformate, ethanolamine, CH Cl , rt, 74%.
(
Fig. 7B). This might be a possible reason why compound 32 exhib-
ited potent PPARd agonistic activity in comparison with compound
0.
2
2
2
PPARd. Interestingly, n-heptylsilyl derivative 32, which had quite
low PPAR -agonistic activity, exhibited potent PPARd-agonistic
activity, indicating that modification of the silyl moiety caused
In conclusion, based on the hypothesis that an alkylsilyl group
a
can function as a mimic of aliphatic cis-olefin, we designed and
synthesized a series of silicon-containing fatty acid amide deriva-
tives. In PPAR reporter gene assays, several compounds showed
selectivity switching (Fig. 6B). These compounds showed no ago-
nistic activity toward PPAR
c
(data not shown).
PPARa- and/or PPARd-agonistic activity. Among them, diethyl-
We performed docking studies of diethyl-n-heptylsilyl deriva-
n-octyl derivative 20 exhibited PPARa/d-dual agonistic activity,
tive 32 and diethyl-n-octylsilyl derivative 20 with the reported
and diethyl-n-heptyl derivative 32 exhibited potent and selective
PPARd-agonistic activity. Thus, introduction of a dialkylsilyl group
in place of aliphatic cis-olefin is an effective strategy to modify bio-
logical activity and selectivity. In addition, tetraalkylsilyl structure
is more stable to isomerization and oxidation than cis-olefin. These
18
crystal structure of PPARd (PDB ID: 3SP9), using the AutoDock
.2 docking program.19,20 Figure 7A shows the docking form of
4
compound 32 in the PPARd ligand-binding domain (LBD). In the
docking structure, the fatty acid chain of compound 32 occupies
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D. Kajita et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
H
R
R
N
1
9: R = Me
OH
Si
20: R = Et
O
21: R = n-Pr
22: R = n-Bu
Figure 5. Biological evaluation of OEA (8) and compounds 19–22 and 34. (A) Agonistic activity toward PPAR
a. Activities are indicated as percent of maximum activity of
GW7647. (B) Agonistic activity toward PPARd. Activities are indicated as percent of maximum activity of GW501516.
m
H
N
20: m = 7, n = 7
28
Et
Et
OH
:
m = 6, n = 7
Si
O
32: m = 7, n = 6
n
Figure 6. Biological evaluation of OEA (8) and compounds 20, 28, 32 and 34. (A) Agonistic activity toward PPAR
GW7647. (B) Agonistic activity toward PPARd. Activities are indicated as percent of maximum activity of GW501516. Compound 32 exhibited cytotoxicity at 30
a. Activities are indicated as percent of maximum activity of
*
l
M.
Figure 7. (A) Binding model of compound 32 at the LBD of PPARd. The protein surface is indicated by light blue mesh. (B) Superimposition of binding models of compound 20
magenta) and compound 32 (atom color) at the PPARd-LBD.
(
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D. Kajita et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
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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,
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Supplementary data
Supplementary data (analytical data and experimental proce-
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tational studies) associated with this article can be found, in the
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