Synthesis and structure-activity relationships of fibrate-based analogues inside PPARs

Article abstract of DOI:10.1016/j.bmcl.2012.09.111

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic groups derived from natural products chalcone and stilbene were synthesised. Some of them were found to be active at micromolar concentrations only on PPARα or PPARγ, while others were identified as dual agonists PPARα/γ.

Full text of DOI:10.1016/j.bmcl.2012.09.111

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7662–7666
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and structure–activity relationships of fibrate-based analogues inside
PPARs
Letizia Giampietro, Alessandra D’Angelo, Antonella Giancristofaro, Alessandra Ammazzalorso,
Barbara De Filippis, Marialuigia Fantacuzzi, Pasquale Linciano, Cristina Maccallini, Rosa Amoroso
⇑
Dipartimento di Farmacia, Università degli Studi ‘G. d’Annunzio’, via dei Vestini 31, 66100 Chieti, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2012
Revised 26 September 2012
Accepted 29 September 2012
Available online 6 October 2012
In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new
compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic
groups derived from natural products chalcone and stilbene were synthesised. Some of them were found
to be active at micromolar concentrations only on PPAR
agonists PPAR
a
or PPAR
c, while others were identified as dual
a/c.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
PPARs
Transactivation assay
Fibrates
Chalcone
Stilbene
Gene expression
The PPARs (peroxisome proliferator activating receptors) are a
subfamily of ligand-activated nuclear hormone receptors that are
highly expressed in metabolically active tissues which regulate
genes encoding lipid and glucose metabolism, and overall energy
homeostasis.1 PPARs are activated by fatty acids and cyclooxygen-
ase-derived eicosanoids;2 similar to other nuclear hormone recep-
tors, they bind their ligand in the cytoplasm and translocate to the
cell nucleus. Once within the nucleus, PPARs form a heterodimer
with RXR (retinoid X receptor) and bind to specific DNA-response
elements in the promoter of target genes. Binding of ligands to
PPARs leads to a conformational change in the receptor, resulting
in the recruitment of coactivators and chromatin remodelling,
which allows the initiation of DNA transcription.3
still the least defined of all the PPARs; however, several studies
have suggested that PPARd regulates fatty acid catabolism, insulin
sensitivity, and energy homeostasis in muscle and adipose tissue.6
Two classes of compounds, namely fibrates,7 as antihyperliped-
imic agents, and thiazolidinediones,8 as antidiabetic agents, are
currently marketed and are PPAR
There are, however, factors that limit the use of these drugs:
fibrates are poor activators of PPAR and their subtype selectivity
a and c agonists, respectively.
a
is not high. Probably due to the high doses requested to exert ther-
apeutic effect, therapy with fibrates is associated with increased
risk for myopathy and hepatotoxicity.9 Frequent side effects of
thiazolidinediones are weight gain, edema, and heart failure.10 In
the last years, a number of approaches directed towards the devel-
opment of new potent agonists specific for PPAR subtypes repre-
sented the logical evolution in the field of metabolic disorders
Three PPAR subtypes, commonly designated as PPARa, PPARc,
and PPARb/d, have been identified; they have different tissue
distribution, binding of ligands, and recruitment of co-activators
treatment.11 In addition, also PPAR
a/c dual agonists, termed
or co-repressors. PPAR
by decreasing both serum triglycerides and free fatty acid levels,
and increasing HDL (high-density lipoproteins) level.4 The PPAR
has a critical role in fatty acid storage and glucose metabolism
by coordinating the expression of genes involved in lipid metabo-
lism, adipogenesis and inflammation.5 PPARb/d functional roles are
a
plays a pivotal role in lipid metabolism
as ‘glitazars’, have been identified as very attractive candidates in
the treatment of metabolic disorders, by combining the beneficial
effects of two different subtype receptors (Fig. 1).12 Currently, none
of new PPAR agonists has been approved by FDA due to the toxic
side effects, although some of them have reached different stages
of clinical trials.13 So, the safety concerns seem to discourage
research in this field; however, the importance of metabolic dis-
eases and the fact that the reasons of failure of various PPAR ago-
nists are quite different from each other require the development
of newer and safer drugs, by evaluating the adverse effects case
by case.
c
⇑
Corresponding author. Address: Dipartimento di Farmacia, Università di Chieti,
via dei Vestini, 66100 Chieti, Italy. Tel.: +39 0871 3554686; fax: +39 0871 3554911.
E-mail address: ramoroso@unich.it (R. Amoroso).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.111

L. Giampietro et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7662–7666
7663
S
COOH
Cl
O
COOi-Pro
Cl
O
COOH
O
N
H
N
O
clofibric acid (2)
fenofibrate (1)
(active metabolite of clofibrate)
GW7647 (3)
(highly specific and potent
PPARα activator)
S
S
O
O
N
H
O
O
N
O
O
N
H
HO
pioglitazone (4)
troglitazone (5)
N
O
O
O
O
O
O
S
COOH
HN
O
COOH
tesaglitazar (7)
activators, thiazolidinones and ‘glitazars’.
O
farglitazar (6)
Figure 1. Chemical structures of representatives fibrates, specific and potent PPAR
a
The chemical structures of synthetic PPAR agonists are referable
to a general pharmacophore, including a carboxylic acid head, an
aromatic ring, and a lipophilic cyclic tail, connected by linkers;
the nature of these fragments affects the potency and subtype
selectivity. In the search for new PPAR ligands that fit these
common structural features, ‘nutraceuticals’ and natural products
derived from plants, like stilbenes14 and chalcones15 have attracted
attention as novel scaffolds because of their health benefits includ-
ing antioxidant, antilipidemic and antiplatelet properties. It was
envisaged that structures containing these moieties may show
PPAR agonist activity with enhanced pharmacological effects. In
linker between the aromatic centre and the lipophilic tail (Fig. 2).
The new compounds were in vitro bioevaluated for their PPAR
and PPAR agonistic activity using the reporter gene assay and a
preliminary screening of gene activation by RTqPCR (real-time
quantitative PCR analysis) was performed.
All compounds were easily obtained in good yields by standard
esterification procedures followed by hydrolysis.17 Esters 11–13
were obtained by SN2 reaction of phenols 8–10 with ethyl
2-bromo-2-methylpropanoate, in the presence of dry K2CO3 in
DMF at reflux. The basic hydrolysis of 11–13 with 1 N NaOH gave
the acids 14–16. Esters 17–34 were synthesized by Mitzunobu
reaction between 11–13 and the appropriate commercial phenols.
Only the phenol (2E)-1-(4-hydroxyphenyl)-3-phenylprop-2-en-1-one,
not commercially available, was synthesized according to well
established procedures.18 Hydrolysis of 17–34 with 1 N NaOH gave
desired acids 35–52 (Scheme 1).
a
c
this field, we have recently reported the synthesis and PPAR
vation of a series of molecules derived by the combination of anti-
lipidemic drug gemfibrozil with natural -asarone, stilbene,
a acti-
a
chalcone, and other bioisosteric modifications.16 In continuation
of these studies, and in order to gain more insight on the struc-
ture–activity relationship, we herein describe the synthesis and
in vitro evaluation of new compounds based on a combination of
two key pharmacophores: the classical clofibric acid, the active
metabolite of clofibrate, and lipophilic groups derived from natural
products chalcone and stilbene. We kept unalterate the clofibrate
scaffold and systematically varied the cyclic tail and the length of
All new compounds were assessed for their PPAR
functional activity by transactivation assay using the
GAL4–PPAR and GAL4-responsive luciferase reporter in HEK293
(human embryonic kidney 293 cells).19 As control for PPAR
, clofi-
bric acid (2), the active metabolite of clofibrate, and GW7647 (3), a
highly specific and potent PPAR
activator,20 were used; the PPAR
a and PPARc
a
c
a
a
c
activity was examined in comparison with pioglitazone (4). The
results are shown in Table 1.
As depicted in Figure 2, our strategy was based on the combina-
tion of clofibric acid with lipophilic groups derived from natural
products and their modifications. Also the length of the linker
between the aromatic centre and the lipophilic tail (one, two or
three carbons) was investigated. In general, the tested compounds
Linker
Linker
Acidic head
group
Aromatic
center
Cyclic tail
Aliphatic
chain
Lipophylic groups derived
from chalcone and stilbene
displayed a very different profile of efficacy from PPAR
Most of the PPAR agonists had an efficacy superior to clofibrate;
in contrast, none of the compounds active on PPAR was able to
a to PPARc.
Skeleton of clofibrate
a
c
O
COOH
exhibit full agonist activity and all appear partial agonists. Initial
SAR was focused on the introduction of chalcone and its analogues
obtained by removing the double bond (benzoylphenoxy) and
replacing the carbonyl function with the oxygen (phenoxyphenoxy).
Almost all compounds of this series showed a selective activation of
O
R
1-3
Figure 2. General features of synthetic PPAR agonists and structural development
of presented compounds.

7664
L. Giampietro et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7662–7666
OH
O
COOEt
O
COOH
a
b
HO
HO
HO
1-3
1-3
1-3
11-13
14-16
8-10
c
O
COOH
O
COOEt
b
O
O
R
1-3
R
1-3
35-52
17-34
Scheme 1. (a) Ethyl 2-bromo-2-methylpropanoate, dry K2CO3, DMF, reflux; (b) 1 N NaOH, EtOH, rt; (c) appropriate phenol (ROH), DIAD, Ph3P, dry THF, N2, rt.
Table 1
In vitro transactivation activity of compounds with various lipophilic tails and linkers
O
COOH
O
R
n
Compound
R
n
hPPAR
nad
a
EC50
(
l
M)a (% max)b,c
hPPAR
c EC50 (lM) (% max)
35
36
1
2
na
64.0 0.9 (118)
5.9 0.8 (21)
37
3
na
0.8 0.04 (21)
O
38
39
1
2
na
na
5.4 0.2 (19)
54.6 1.0 (12)
40
3
na
5.8 0.3 (33)
O
O
41
42
43
1
2
3
na
na
na
0.8 0.04 (13)
6.9 0.3 (13)
75.2 1.2 (5)
44
45
1
2
40.5 3.1 (156)
11.6 0.4 (81)
6.0 0.2 (36)
12.6 0.5 (18)
46
3
9.9 0.2 (125)
0.8 0.1 (32)
47
48
1
2
5.6 0.3 (350)
0.6 0.01 (158)
21.0 0.9 (19)
1.4 0.02 (21)
49
3
42.8 0.4 (81)
10.0 0.7 (36)
N
N
S
N
50
51
1
2
3
1
2
3
44.6 0.6 (125)
18.3 0.7 (169)
32.0 0.7 (35)
39.3 0.3 (8)
7.9 0.1 (23)
52
14
15
16
2
45.8 0.8 (100)
34.5 1.0 (119)
75.1 1.3 (94)
30.6 0.8 (181)
55.0 3.9 (100)
0.2 0.02 (164)
na
H
H
H
30.0 0.3 (6)
na
na
na
na
3
4
0.8 0.01 (100)
a
b
c
Compounds were tested in at least three separate experiments at five concentrations ranging from 1 to 150
Compounds were tested in at least two separate experiments at concentration of 150
Efficacy values were calculated as percentage of the maximum obtained fold induction with the clofibric acid (2) and pioglitazone (4).
l
M. The results are expressed with SEM.
l
M. Only GW7647 was tested at 1 lM. The results are expressed with SEM.
d
Not active.
PPAR
c
receptor, while they are inactive on PPAR
a
. The linker length
groups, showed an EC50 = 0.8 lM. Among the compounds contain-
influences the activity in a different way depending on the lipophilic
group in the molecule. For chalcone derivatives, a spacer of one car-
ing the benzoylphenoxy group those with a spacer of one (38) or
three carbon atoms (40) were active, while the intermediate chain
leads to an almost inactive compound (39). The molecules with a
bon leads to a molecule completely inactive (35), while the PPAR
c
activity gradually reaches a value approximately equal to that of
phenoxyphenoxy lipophilic tail (41–43) show values of PPAR
cactiv-
pioglitazone; compound 37, containing a linker of three methylenic
ity decreasing with the increasing of chain spacer. Among them,

L. Giampietro et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7662–7666
7665
acting as a PPARa agonist for regulating the expression of PPARa
CPT1A (HepG2. 24h)
target gene CPT1A involved in lipid metabolism in hepatocytes.
6.0
5.0
4.0
3.0
2.0
1.0
0.0
In summary, we have investigated new molecules designed
from the general pharmacophore for PPAR agonists, based on clo-
fibric acid (carboxylic acid head and aromatic ring) and a lipophilic
tail derived from natural products chalcone and stilbene and their
modifications, connected by a linker of one, two or three methylen-
ic groups. Compounds 37 and 41 were found to be PPAR
with the same potency of pioglitazone, and compounds 46 and 48
were identified as dual PPAR agonists, although the values of
c agonists
a/c
DMSO
2 (150uM)
3 (1uM)
48
efficacy seem to indicate a behaviour as partial agonists. All new
molecules were tested in vitro with the transactivation assay and
a preliminary test of gene expression was performed on compound
48. This molecule is candidate as new lead compound for the
design of more potent and selective PPARac agonists analogues
of fibrates.
0.1uM 1uM 10uM 50uM 100uM 150uM
Figure 3. CPT1A expression in HepG2 following treatment. HepG2 cells were
treated with vehicle (DMSO), 2 (150 M), 3 (1 M), 48 (0.1–150 M) for 48 h.
RTqPCR was performed to measure CPT1A mRNA levels.Values shown represent
mean SEM for four independent determinations performed in duplicate.
Cyclophilin was used as reference gene and values were normalised to data
obtained from vehicle treated cells.
l
l
l
Acknowledgments
The authors gratefully acknowledge the Italian MIUR for finan-
cial support and Dr. David J. Mangelsdorf (Dallas, TX) for the PPAR
plasmids and Dr. Antonio Moschetta for helpful comments and
suggestions.
compound 41 showed equipotent PPAR
compared to pioglitazone. The introduction of stilbene scaffold
and the related phenyldiazenyl derivative completely changes the
profile of activity. All the analogues are active on PPARa and PPARc.
c activity (EC50 = 0.8 lM)
Analogues with stilbene were found to have an increasing potency
for both receptors with the length of the spacer chain. Compound
Supplementary data
44 activated the PPAR
a weak dual PPAR activator. The analogue with the three-carbon
linker (46) showed an EC50 = 0.8 M; it was also a dual PPAR acti-
vator (EC50 = 9.9 M). The replacement of double bond of stilbene
c receptor better than PPARa, while 45 was
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.09.
111.
a/c
l
a
l
with a diazenyl function substantially does not change the trend
of activity. However, a considerable increase of activity against
References and notes
PPAR
which was also a good activator of PPAR
PPAR EC50 = 1.4 M); this molecule probably fits better into the
a
was observed for compound 48 (linker of two carbon atoms),
1. (a) Issemann, I.; Green, S. Nature 1990, 347, 645; (b) Chinetti, G.; Fruchart, J.-C.;
Staels, B. Inflamm. Res. 2000, 49, 497; (c) Varga, T.; Czimmerer, Z.; Nagy, L.
Biochim. Biophys. Acta 2011, 8, 1007.
c
(PPAR EC50 = 0.6 M,
a
l
c
l
receptor pockets than the other two analogues (47 and 49). Further
modifications involved the introduction of a benzothiazole and the
total removal of the lipophilic tail. In the series of benzothiazole
derivatives, all compounds (50–52) did not show improvements in
2. Harmon, G. S.; Lam, M. T.; Glass, C. K. Chem. Rev. 2011, 111, 6321.
3. Kota, B. P.; Huang, T. H.-W.; Roufogalis, B. D. Pharmacol. Res. 2005, 51, 85.
4. (a) Zandbergen, F.; Plutzky, J. Biochim. Biophys. Acta 2007, 1771, 972; (b)
Fruchart, J.-C. Atherosclerosis 2009, 205, 1.
5. Lehrke, M.; Lazar, M. A. Cell 2005, 123, 993.
6. Wagner, K.-D.; Wagner, N. Pharmacol. Ther. 2010, 125, 423.
7. (a) Backes, J. M.; Gibson, C. A.; Ruisinger, J. F.; Moriarty, P. M. Pharmacotherapy
2007, 27, 412; (b) Lalloyer, F.; Staels, B. Arterioscler. Thromb. Vasc. 2010, 30, 894;
(c) Wierzbicki, A. S. Curr. Opin. Cardiol. 2009, 24, 372.
8. (a) Rizos, C. V.; Liberopoulos, E. N.; Mikhailidis, D. P.; Elisaf, M. S. Expert Opin.
Pharmacother. 2008, 9, 1087; (b) Quinn, C. E.; Hamilton, P. K.; Lockhart, C. J.;
McVeigh, G. E. Br. J. Pharmacol. 2008, 153, 636.
9. Florentin, M.; Liberopoulos, E. N.; Mikhailidis, D. P.; Elisaf, M. S. Curr. Pharm.
Des. 2008, 14, 574.
10. Lieb, D. C.; McCall, A. L. Curr. Diab. Rep. 2010, 10, 116.
11. (a) Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. J. Med. Chem. 2000,
43, 527; (b) Etgen, G. J.; Mantlo, N. Curr. Top. Med. Chem. 2003, 3, 1649; (c) Pirat,
C.; Farce, A.; Lebègue, N.; Renault, N.; Furman, C.; Millet, R.; Yous, S.; Speca, S.;
Berthelot, P.; Desreumaux, P.; Chavatte, P. J. Med. Chem. 2012, 55, 4027.
12. (a) Balakumar, P.; Rose, M.; Ganti, S. S.; Krishan, P.; Singh, M. Pharmacol. Res.
2007, 56, 91; (b) Adeghate, E.; Adem, A.; Hasan, M. Y.; Tekes, K.; Kalasz, H. Open
Med. Chem. J. 2011, 5, 93.
13. Rubenstrunk, A.; Hanf, R.; Hum, D. W.; Fruchart, J.-C.; Staels, B. BBA-Mol. Cell.
Biol. L. 2007, 1771, 1065.
14. (a) Rimando, A. M.; Nagmani, R.; Feller, D. R.; Yokoyama, W. J. Agric. Food Chem.
2005, 53, 3403; (b) Mizuno, C. S.; Ma, G.; Khan, S.; Patny, A.; Avery, M. A.;
Rimando, A. M. Bioorg. Med. Chem. 2008, 16, 3800; (c) Li, W.; He, X.; Shi, W.;
Haoyan Jia, H.; Zhong, B. ChemMedChem 1977, 2010, 5.
15. (a) Jung, S. H.; Park, S. Y.; Kim-Pak, Y.; Lee, H. K.; Park, K. S.; Shin, K. H.; Ohuchi,
K.; Shin, H.-K.; Keum, S. R.; Lim, S. S. Chem. Pharm. Bull. 2006, 54, 368; (b) Li, X.-
h.; Zou, H.-j.; Wu, A.-h.; Ye, Y.-l.; Shen, J.-h. Acta Pharmacol. Sin. 2007, 28, 2040;
(c) Matin, A.; Gavande, N.; Kim, M. S.; Yang, N. X.; Salam, N. K.; Hanrahan, J. R.;
Roubin, R. H.; Hibbs, D. E. J. Med. Chem. 2009, 52, 6835; (d) Shukla, P.;
Srivastava, S. P.; Srivastava, R.; Rawat, A. K.; Srivastava, A. K.; Pratap, R. Bioorg.
Med. Chem. Lett. 2011, 21, 3475.
16. De Filippis, B.; Giancristofaro, A.; Ammazzalorso, A.; D’Angelo, A.; Fantacuzzi,
M.; Giampietro, L.; Maccallini, C.; Petruzzelli, M.; Amoroso, R. Eur. J. Med. Chem.
2011, 46, 5218.
activity even if the EC50 values on both PPAR
Also in the series of alcohols, modifications of linker length did not
influence the PPAR activation very much. The acid 14 containing
the methanol group in para at the aromatic ring and the ethanol ana-
logue 15 activated the PPAR slightly better than clofibric acid;
than, the introduction of propanol group (16) caused a little worsen-
ing of activity. Only 14 was a weak activator of PPAR . The transac-
aand PPARcwere good.
a
a
c
tivation studies reported in Table 1 show that the lipophilic tail and
the length of linker seem to be correlated to activity; indeed, there
were remarkable differences when varying these two fragments
regarding the potency and the isoform selectivity. Among all the
compounds tested, stand out as PPARc agonists molecules 37 and
41,21 while dual agonists may be represented by 46 and 48.22
In the liver, the import of fatty acids into hepatocyte mitochon-
dria is regulated by the mitochondrial key enzyme CPT1A (carnitine
palmitoyl acyl-CoA transferase 1).23 The expression pattern of this
gene is a well established in vitro model to study PPAR
On the basis of the transactivation assay results, we selected com-
pound 48 for the preliminary in vitro analysis of CPT1 expression
a
activation.24
a
in HepG2 (human hepatocellular liver carcinoma cell line) by using
RTqPCR. The expression level of CPT1A was measured in the
presence of various concentrations of compound 48. Cells were
stimulated with increasing amounts of selected compound 48 (from
0.1 to 100 lM) and compared with 2 and 3; control cells were
treated with DMSO alone. As shown in Figure 3, our molecule led
to a significant and concentration-dependent increase of mRNA
levels; its activity was comparable with that of superagonist 3,

7666
L. Giampietro et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7662–7666
17. Giampietro, L.; Ammazzalorso, A.; Giancristofaro, A.; Lannutti, F.; Bettoni, G.;
De Filippis, B.; Fantacuzzi, M.; Maccallini, C.; Petruzzelli, M.; Morgano, A.;
Moschetta, A.; Amoroso, R. J. Med. Chem. 2009, 52, 6224.
22. Spectral data for 46 and 48. 2-Methyl-2-[4-(3-{4-[(E)-2- phenylvinyl]phenoxy}
propyl)phenoxy]propanoic acid (46): white solid, 86% yield, mp 258 °C dec, IR
(KBr) 3423, 1703 cmÀ1 1H NMR (CD3OD) d 1.49 (s, 6H, C(CH3)2), 2.02 (m, 2H,
;
18. Yeap, G. Y.; Susanti, I.; Teoh, B. S.; Mahmood, W. A. K.; Harrison, W. T. A. Mol.
Cryst. Liq. Cryst. 2005, 442, 133.
19. Matthews, J. M.; Chen, X.; Cryan, E.; Hlasta, D. J.; Rybczynski, P. J.; Strauss, K.;
Tang, Y.; Xu, J. Z.; Yang, M.; Zhouk, L.; Demarest, K. T. Bioorg. Med. Chem. Lett.
2007, 17, 6773.
20. Brown, P. J.; Stuart, L. W.; Hurley, K. P.; Lewis, M. C.; Winegar, D. A.; Wilson, J.
G.; Wilkison, W. O.; Ittoop, O. R.; Willson, T. M. Bioorg. Med. Chem. Lett. 2001,
11, 1225.
J1 = 6.3 Hz, J2 = 7.2 Hz, OCH2CH2CH2Ph), 2.71 (t, 2H, J = 7.2 Hz, OCH2CH2CH2Ph),
3.95 (t, 2H, J = 6.3 Hz, OCH2CH2CH2Ph), 6.82–6.89 (m, 4H, CH Ar), 6.97–7.08 (m,
4H, CH Ar), 7.17–7.22 (m, 1H, CH Ar), 7.29–7.34 (m, 2H, CH Ar), 7.44–7.52 (m,
4H, CH Ar); 13C NMR (CD3OD) d 25.31 (C(CH3)2), 31.04 (OCH2CH2CH2Ph), 31.19
(OCH2CH2CH2Ph), 66.77 (OCH2CH2CH2Ph), 80.37 (C(CH3)2), 114.51, 118.76,
126.04 (CH Ar), 126.18 (CH Vin), 126.91 (CH Ar), 127.56 (CH Ar), 128.12 (CH
Vin), 128.44 and 128.60 (CH Ar), 130.25, 133.71, 138.04, 154.91 and 159.10 (C
Ar), 180.97 (COOH). Anal. Calcd for C27H28O4: C, 77.86; H, 6.78. Found: C, 77.75;
H, 6.80. 2-Methyl-2-[4-(2-{4-[(E)-phenyldiazenyl]phenoxy}ethyl)phenoxy]prop-
anoic acid (48): orange solid, 91% yield, mp 239–240 °C. IR (KBr) 3423,
21. Spectral data for 37 and 41. 2-Methyl-2-[4-(3-{4-[(2E)-3-phenylprop-2-enoyl]
phenoxy}propyl)phenoxy] propanoic acid (37): yellow solid, 53% yield, mp 121–
123 °C. IR (KBr) 3420, 1735, 1662 cmÀ1
;
1H NMR (CDCl3) d 1.58 (s, 6H, C(CH3)2),
1705 cmÀ1 1H NMR(CD3OD) d 1.50 (s, 6H, C(CH3)2), 3.02 (t, 2H, J = 6.9 Hz,
;
2.11 (m, 2H, J1 = 6.3 Hz, J2 = 7.8 Hz, OCH2CH2CH2Ph), 2.78 (t, 2H, J = 7.8 Hz,
OCH2CH2CH2Ph), 4.04 (t, 2H, J = 6.3 Hz, OCH2CH2CH2Ph), 6.87 (d, 2H, J = 8.5 Hz,
CH Ar), 6.95 (d, 2H, J = 9.0 Hz, CH Ar), 7.11 (d, 2H, J = 8.5 Hz, CH Ar), 7.40–7.42
(m, 3H, CH Ar), 7.54 (d, 2H, J = 15.6 Hz, CH Vin), 7.63–7.66 (m, 2H, CH Ar), 7.81
(d, 2H, J = 15.6 Hz, CH Vin), 8.02 (d, 2H, J = 9.0 Hz, CH Ar); 13C NMR (CDCl3) d
25.17 (C(CH3)2), 30.83 (OCH2CH2CH2), 31.50 (OCH2CH2CH2), 67.26
(OCH2CH2CH2), 78.18 (C(CH3)2), 114.55 and 121.27 (CH Ar), 122.09 (C@OCH
Vin), 128.61, 129.16, 129.58, 130.60 and 131.10 (CH Ar), 131.26, 135.29 and
136.68 (C Ar), 144.32 (CH Vin), 158.03 and 163.14 (C Ar), 189.13 (COOH),
201.01 (ArC@O). Anal. Calcd for C28H28O5: C, 75.65; H, 6.35. Found: C, 75.58; H,
6.37. 2-Methyl-2-{4-[(4-phenoxyphenoxy)methyl]phenoxy}propanoic acid (41):
OCH2CH2), 4.22 (t, 2H, J = 6.9 Hz OCH2CH2), 6.87 (d, 2H, J = 8.7 Hz CH Ar), 7.04
(d, 2H, J = 9.0 Hz CH Ar), 7.15 (d, 2H, J = 8.7 Hz CH Ar), 7.44–7.54 (m, 3H, CH Ar),
7.83–7.87 (m, 2H, CH Ar), 7.88 (d, 2H, J = 9.0 Hz CH Ar); 13C NMR (CD3OD) d
25.31 (C(CH3)2), 34.67 (OCH2CH2), 69.33 (OCH2CH2), 80.41 (C(CH3)2), 114.71,
118.70, 122.29, 124.55, 128.97, 129.17 and 130.34 (CH Ar), 131.85, 147.02,
154.75, 155.86 and 163.75 (C Ar), 175.21 (COOH). Anal. Calcd for C24H24N2O4:
C, 71.27; H, 5.98; N, 6.93. Found: C, 71.33; H, 5.96; N, 6.97.
23. (a) Britton, C. H.; Mackey, D. W.; Esser, V.; Foster, D. W.; Burns, D. K.; Yarnall, D.
P.; Froguel, P.; McGarry, J. D. Genomics 1997, 40, 209; (b) Bonnefont, J.-P.;
Djouadi, F.; Prip-Buus, C.; Gobin, S.; Munnich, A.; Bastin, J. Mol. Aspects Med.
2004, 25, 495; (c) Lee, K.; Kerner, J.; Hoppel, C. L. J. Biol. Chem. 2011, 286, 25655.
24. (a) Lawrence, J. W.; Chen, S.; De Luca, J. G.; Berger, J. P.; Umbenhauer, D. R.;
Moller, D. E.; Zhou, G. J. Biol. Chem. 2001, 276, 31521; (b) Westerbacka, J.; Kolak,
M.; Kiviluoto, T.; Arkkila, P.; Sirén, J.; Hamsten, A.; Fisher, R. M.; Yki-Järvinen, H.
Diabetes 2007, 56, 2759; (c) Rakhshandehroo, M.; Hooiveld, G.; Muller, M.;
Kersten, S. PLoS One 2009, 4, e6796.
white solid, 78% yield, mp 115–116 °C. IR (KBr) 3224, 1703 cmÀ1 1H NMR
;
(CD3OD) d 1.56 (s, 6H, C(CH3)2), 4.98 (s, 2H, OCH2), 6.87–7.04 (m, 9H, CH Ar),
7.26–7.37 (m, 4H, CH Ar); 13C NMR (CD3OD) d 24.57 (C(CH3)2), 69.95 (OCH2Ph),
79.05 (C(CH3)2), 115.90, 117.42, 119.15, 120.49, 122.37, 128.69, 129.51 (CH Ar),
131.08, 150.60, 155.38, 155.52 and 158.74 (C Ar), 161.03 (COOH). Anal. Calcd
for C23H22O5: C, 73.00; H, 5.86. Found: C, 73.15; H, 5.83.