Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD1 and 13-epi-dinor-PGD1 are peroxisome proliferator-activated receptor α/γ dual agonists

Article abstract of DOI:10.1016/j.bmcl.2013.03.024

2,3-Dinorprostaglandins (dinor-PGs) have been regarded as β-oxidation products of arachidonic-acid-derived prostaglandins, but their biological activities in mammalian cells remain unclear. On the other hand, C18 polyunsaturated fatty acids (PUFAs), such

Full text of DOI:10.1016/j.bmcl.2013.03.024

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3013–3017
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Bioorganic & Medicinal Chemistry Letters
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Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD1
and 13-epi-dinor-PGD1 are peroxisome proliferator-activated
receptor a/c dual agonists
Ayato Sato a,b, Kosuke Dodo a,b, Makoto Makishima c, Yuichi Hashimoto d, Mikiko Sodeoka a,b,
⇑
a Sodeoka Live Cell Chemistry Project, ERATO, JST, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
b RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
c Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
d Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
2,3-Dinorprostaglandins (dinor-PGs) have been regarded as b-oxidation products of arachidonic-acid-
Received 17 November 2012
Revised 27 February 2013
Accepted 7 March 2013
Available online 21 March 2013
derived prostaglandins, but their biological activities in mammalian cells remain unclear. On the other
hand, C18 polyunsaturated fatty acids (PUFAs), such as c-linolenic acid (GLA), have various biological
activities, and dinor-PGs are speculated to be biosynthesized from GLA. Here, we synthesized dinor-
PGs that may possibly be derived from GLA and examined their activities towards peroxisome prolifer-
ator-activated receptors (PPARs). Dinor-PGD1 (1) and its epimer 13-epi-dinor-PGD1 (epi-1) were found
Keywords:
to be dual agonists for PPAR
a
/
c
, whereas PGD2 derived from arachidonic acid is selective for PPAR
c
. Thus,
2,3-Dinorprostaglandin
Prostaglandin
Fatty acid
GLA-derived dinor-PGs may have unique biological roles.
Ó 2013 Elsevier Ltd. All rights reserved.
PPAR
c
-Linolenic acid
Polyunsaturated fatty acids (PUFAs) and their derivatives are in-
volved in a variety of biological signaling pathways. Among these
compounds, C20 PUFAs, arachidonic acid (AA), dihomo- -linolenic
from a-linolenic acid act as injury signaling factors in the plant
kingdom.17,18 But, as far as we know, no detailed biological studies
on GLA-derived dinor-PGs have yet been reported. Therefore, we
c
acid (DGLA), and eicosapentaenoic acid (EPA), are converted to a
variety of lipid mediators, such as prostaglandins and leukotri-
enes,1 that play critical roles in smooth muscle contraction,2 sleep,3
platelet aggregation,4 tumor suppression5 and inflammation6 in
mammals.
started
dinor-PGs. Here, we report the syntheses of 2,3-dinorprostaglandin
D1 (dinor-PGD1) and 13-deoxy-
10,12-2,3-dinorprostaglandin J1
(13-deoxy-dinor-PGJ1), and the evaluation studies of their activities
towards peroxisome proliferator-activated receptor (PPAR)
subtypes.
a project to examine the chemistry and biology of
D
c-Linolenic acid (GLA), a representative C18 PUFA, has antitumor
activity7 and transcriptional activation activity.8–11 GLA is generally
recognized as a precursor in the biosynthesis of AA, but its biological
activities are not always the same as those of AA, suggesting that GLA
itself and/or its metabolites also act as physiological modulators.
Interestingly, C18 PG-like molecules have been identified in plasma
and urine.12–14 Although they had been assumed to be formed by
auto-oxidation of C18 PUFAs or b-oxidation of C20 PGs, they may
themselves have significant biological activity. Indeed, biological
activities of some dinor–isoprostanes have been reported.15
Furthermore, GLA serves as a substrate of human prostaglandin-
endoperoxide H synthases, raising the possibility that dinor-PGs
having 18 carbon atoms may be enzymatically produced from
GLA, at least in part.16 It is noteworthy that C18 prostanoids derived
Peroxisome proliferator-activated receptors (PPARa, d, and c),
which belong to the nuclear receptor superfamily of transcription
factors, are key regulators of lipid metabolism and are considered
to be important drug targets.19 Various fatty acids, such as AA
and GLA, are known to bind and activate PPARs.20,21 Furthermore,
the relationship between the chain length of fatty acids and their
PPAR agonistic activities has been discussed.8,21 In 1995,
prostaglandin D2 (PGD2) and its dehydrated metabolites (Fig. 1)
were found to be potent activators of PPARs, and among them,
15-deoxy-D
12,14-PGJ2 was significantly more potent than its pre-
cursors, AA and PGD2.22,23 Therefore, we speculated that GLA
may also be directly transformed into dinor-PGs and that some
of these molecules may activate PPARs. To test this hypothesis,
we planned to synthesize and evaluate dinor-PGs correspon-
ding to PGD2, PGJ2 and 15-deoxy-
dinorprostaglandin D1 (dinor-PGD1) (1), 2,3-dinor-prostaglandin
D
12,14-PGJ2, namely 2,3-
⇑
Corresponding author. Tel.: +81 48 467 9373; fax: +81 48 462 4666.
E-mail address: sodeoka@riken.jp (M. Sodeoka).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.024

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A. Sato et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3013–3017
COOH
COOH
arachidonic acid (AA)
γ-linolenic acid (GLA)
?
dinor-prostaglandin (dinor-PG)
HO
O
COOH
HO
COOH
OH
PGD2
metabolism
O
OH
(β-oxidation,
reduction)
dinor-PGD1 (1)
COOH
COOH
O
OH
PGJ2
O
OH
dinor-PGJ1 (2)
COOH
COOH
O
15-deoxy-Δ12,14-PGJ2
O
13-deoxy-Δ10,12-dinor-PGJ1 (3)
endogenous ligand for PPARγ
Figure 1. Hypothetical metabolic pathway of GLA in parallel to the AA cascade.
O
AcO
AcO
J1 (dinor-PGJ1) (2), and 13-deoxy-
J1 (13-deoxy-dinor-PGJ1) (3) (Fig. 1).
D
10,12-2,3-dinor-prostaglandin
O
c - e
f
CO2Et
For the synthesis of these molecules, we used Corey’s lactone as
the starting material.24 As shown in Scheme 1, after sequential pro-
tection of its alcohols with t-butyldiphenylsilyl (TBDPS) and eth-
oxyethyl (EE) groups, 4 was converted to the lactol by reduction
OR1
EEO
EEO
OTBDPS
OTBDPS
R2O
Corey's lactone (R1, R2 = H)
4 (R1 = TBDPS, R2 = EE)
5
6
a, b
with diisobutyl-aluminum hydride (DIBAL). To construct the
a-
AcO
EEO
AcO
g, h
chain, we first attempted to introduce the C-3 unit directly into
CO2Et
CO2Et
i, j
the lactol by means of a Wittig reaction,25,26 but this was unsuc-
OH
cessful. Therefore, we next tried to construct the a-chain in a step-
wise manner. A C1 unit was successfully introduced by using
Ohira–Bestmann homologation27 in 69% yield over two steps, then
acetylation of the resulting secondary alcohol gave alkyne 5 in 86%
yield. Next, introduction of a C2 unit was achieved by a Cu-medi-
ated coupling reaction with ethyl iodoacetate to give ester 6 in
89% yield.28 Hydrogenation of 6 followed by removal of the TBDPS
group afforded primary alcohol 7 in 94% yield over two steps.
Swern oxidation of 7 and Horner–Wadsworth–Emmons reaction
of the resulting aldehyde gave enone 8 in 69% yield over two steps.
The diastereoselective reduction of 8 with (S)-BINAL-H29 was
examined, but the stereoselectivity was low (37% de). Other stere-
oselective reductions of 8 employed previously in prostaglandin
synthesis30,31 also gave unsatisfactory results. Therefore, we
decided to employ Luche conditions for large-scale preparation.
The reaction proceeded smoothly to give 9a and 9b in 49% and
47% yields, respectively.32 The diastereomers were separated for
use in subsequent reactions.
EEO
O
7
8
AcO
k
AcO
CO2Et
CO2Et
+
EEO
EEO
OH
9a
OH
9b
Scheme 1. Preparations of 9a and 9b. Reagents and conditions: (a) TBDPSCl,
imidazole, DMF, À40 °C, 2 h, 84%; (b) ethyl vinyl ether, PPTS, CH2Cl2, 0 °C, 1.5 h then
rt, 1 h, 84%; (c) DIBAL, toluene, À78 °C, 30 min; (d) MeCOCN2PO(OMe)2, K2CO3,
MeOH, rt, 14 h then 45 °C, 5 h, 69% over two steps; (e) Ac2O, Et3N, DMAP, CH2Cl2, rt,
1.5 h, 86%; (f) ICH2CO2Et, CuI, MeCN, rt, 24 h, 89%; (g) PtO2, H2, AcOEt, rt, 3 h; (h)
TBAF, THF, 0 °C to rt, 22.5 h, 94% over two steps; (i) (COCl)2, DMSO, À78 °C, 15 min;
Et3N, 0 °C, 45 min; (j) dimethyl-2-oxoheptyl phosphonate, NaH, THF, 0 °C to rt, 69%
over two steps; (k) NaBH4, CeCl3Á7H2O, MeOH, À20 °C, 10 min, 49% for 9a, 47% for 9b.
With compounds 9a and 9b in hand, we moved to the synthesis
of 1–3 (Fig. 1). As shown in Scheme 2, protection of 9a with TBDPS
gave 10a in 93% yield, then hydrolysis of the acetyl group and ethyl
ester gave hydroxyacid 11a in 96% yield. Protection of the second-
ary alcohol and carboxylic acid with t-butyldimethylsilyl triflate
(TBSOTf) afforded stable bis-TBS ether ester, and consecutive treat-
ment with acetic acid afforded carboxylic acid 12a in quantitative
yield over two steps. It was unexpected that the ethoxyethyl group
was tolerated under these conditions, and selective removal of this
group from 12a in the presence of the TBS group was troublesome.
After investigation of several reaction conditions, selective removal
of the ethoxyethyl group was accomplished by treatment of 12a
with CeCl3Á7H2O in MeOH at 10 °C for 2 d, affording the desired
secondary alcohol 13a in 84% yield. Oxidation of 13a using Dess–
Martin periodinane (DMP) gave protected dinor-PGD1 14a (67%),
and subsequent removal of TBS and TBDPS groups employing
aqueous HF solution afforded 1 in 37% yield. By using the same
conditions, 13-epi-dinor-PGD1 (epi-1) was similarly synthesized
from 9b.33

A. Sato et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3013–3017
3015
AcO
EEO
HO
α
δ
γ
CO2Et
COOH
COOH
COOH
a
b
20
15
10
5
6
4
2
0
9a (α-OH)
9b (β-OH)
6
4
2
0
EEO
OTBDPS
10a
OTBDPS
11a
11b
10b
TBSO
EEO
TBSO
HO
COOH
c, d
e
g
OTBDPS
12a
12b
OTBDPS
0
13a
13b
fenofibric acid
GW501516
ciglitazone
Figure 2. PPAR-agonistic activities of fenofibric acid (10
GW50516 (100 nM, PPARd agonist) and ciglitazone (10 M, PPAR
l
M, PPARa agonist),
TBSO
O
HO
O
l
c
agonist).
COOH
f
To evaluate the activities of these synthetic dinor-PGs towards
PPARs, PPAR reporter assay using HEK293 cells was conducted
according to a previous report.36 As controls, we first evaluated
the known subtype-selective PPAR ligands, fenofibric acid,
GW501516, and ciglitazone. These synthetic PPAR ligands showed
the expected subtype-selective activations (Fig. 2). Then, we exam-
ined the effects of the synthesized C18 dinor-PGs, compared with
those of the parent C20 prostaglandins (Fig. 3). Dinor-PGD1 (1)
and its epimer 13-epi-dinor-PGD1 (epi-1) both showed PPAR
nistic activity, whereas PGD2 activated PPAR more strongly than
PPAR
or d. According to previous reports,22,23 PGD2 is transformed
to PGJ2 and 15-deoxy-PGJ2 in cells, and 15-deoxy-PGJ2 shows the
most potent PPAR activation among them. In contrast, 13-
deoxy-dinor-PGJ1 (3), which is the dinor-PG corresponding to 15-
deoxy-PGJ2, showed only weak activity towards PPAR , as well
as towards PPAR /d.
We next examined the dose-dependent activations of PGD2, 1,
and epi-1 (Fig. 4). Both 1 and epi-1 showed stronger PPAR and
weaker PPAR agonistic activities relative to PGD2. These results
OTBDPS
OH
dinor-PGD1 (1)
13-epi-dinor-PGD1 (epi-1)
14a
14b
Scheme 2. Syntheses of dinor-PGD1 (1) and 13-epi-dinor-PGD1 (epi-1). Reagents
and conditions: (a) TBDPSCl, imidazole, DMAP, DMF/Et3N (5:1), 93% for 10a and 86%
for 10b; (b) NaOH, MeOH/H2O (10:1), 96% for 11a and 78% for 11b; (c) TBSOTf, 2,6-
lutidine, CH2Cl2, À60 °C, 15 min; (d) THF/AcOH/H2O (4:1:1), quant. over two steps
for both 12a and 12b; (e) CeCl3Á7H2O, MeOH/H2O (20:1), 10 °C, 2 d, 84% for 13a and
86% for 13b; (f) DMP, CH2Cl2, 0 °C, 6 h, 67% for 14a and 98% for 14b; (g) HF, MeCN/
H2O (20:1), À10 °C, 6 d, 37% for 1 and 57% for epi-1.
a ago-
c
a
Next we examined the synthesis of dinor-PGJ1 (2) and 13-
c
deoxy-D
10,12-dinor-PGJ1 (3). Unfortunately, attempts to synthesize
2 and 3 directly from 14a or 1 by elimination of either silanol or
water were unsuccessful. Therefore we decided to try the macro-
lactone method reported by Bundy et al. (Scheme 3).34 Lactoniza-
tion of 11a gave eight-membered lactone 15 in 72% yield.
Removal of the ethoxyethyl group gave the secondary alcohol
(80%), and subsequent Dess–Martin oxidation afforded dinor-
PGD1 lactone 16 in quantitative yield. Treatment of 16 with silica
gel resulted in b-elimination to give the desired carboxylic acid
17 in 67% yield. However, deprotection of the TBDPS group using
HF did not give the desired dinor-PGJ1 2, and further dehydration
c
a
a
c
indicate the change of subtype selectivity from
c to a in 1 and
epi-1.
Based on the reported crystal structures of PPAR
a
-LBD complex
with synthetic ligand AZ 24237 and PPAR
c-LBD complex with 15-
38
deoxy-PGJ2 (Fig. 5a), we speculated that the reason for the
proceeded to afford 13-deoxy-D
10,12-dinor-PGJ1 (3) in 68% yield.
PPAR
tion, the hydrophobic
enter the cavity of PPARs, where it is surrounded by hydrophobic
amino acid residues. The carboxylic acid moiety of the -chain
a
-selectivity of dinor-PGD1 is as follows. During PPAR activa-
All attempts to synthesize 2 were unsuccessful due to rapid elim-
ination of the hydroxyl group at C13. Interestingly, when the same
reactions were performed starting from the epimer 11b, 13-epi-
dinor-PGJ1 was obtained as a minor product (34%), though again
3 was formed as the major product (62%).35
x
-chain of PGs and dinor-PGs is thought to
a
interacts with hydrophilic amino acids (His and Tyr in Fig. 5a)
and changes the position of helix-12. The movement of helix-12 in-
duces conformational change and recruitment of coactivators,
leading to gene expression. Therefore, the position of the carboxyl-
ate should be critical for the activation. Distances between the
O
O
O
O
a
b, c
11a
α
δ
γ
6
4
2
0
EEO
O
OTBDPS
15
OTBDPS
16
COOH
COOH
e
d
O
O
OTBDPS
17
13-deoxy-Δ10,12-dinor-PGJ1 (3)
15-deoxy
PGJ2
control
PGD2
PGJ2
1
epi-1
3
Scheme 3. Synthesis of 13-deoxy-
D
10,12-dinor-PGJ1 (3). Reagents and conditions:
(a) PySSPy, PPh3, benzene; benzene (4 mM), reflux, 72%; (b) THF/H2O/AcOH (2:1:6),
80%; (c) DMP, CH2Cl2, quant.; (d) silica gel (5000 wt %), n-hexane/AcOEt (7:3), 67%;
(e) HF, MeCN/H2O (20:1), 0 °C, 1 week, 68%.
Figure 3. PPAR-agonistic activities of PGD2 (10
(3
l
M), PGJ2 (3
l
M), 15-deoxy-PGJ2
l
M), and dinor-PG compounds 1, epi-1, and 3 (10 lM).

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A. Sato et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3013–3017
hydrophobic pocket and the hydrophilic amino acid residues are
different between the two crystal structures, presumably reflecting
the conformation required for activation. Dinor-PGD1 (1) having a
through hydrogen bonding (Tyr464, Tyr314 and Ser280), support-
ing our binding model of 1.
In this study, we have succeeded in synthesizing dinor-PGD1
(1), 13-epi-dinor-PGD1 (epi-1) and 13-deoxy-dinor-PGJ1 (3), and
we examined their effects on the activity of PPARs. Dinor-PGD1
(1) and its epimer, 13-epi-dinor-PGD1 (epi-1), were found to be
shorter
parison to AZ 242. On the other hand, the shorter
to be too short to interact with the hydrophilic amino acid residues
of helix-12 in PPAR . As a result, dinor-PGD1 clearly showed stron-
ger agonistic activity for PPAR while at the same time weaker
activity for PPAR , compared to PGD2.
Finally, to confirm the binding model, we conducted a docking
study of PPAR
(PDB ID 1I7G) and 1 with AutoDock 4.2 software39
(Fig. 6). As predicted above, the results indicate that the carboxylic
acid moiety of 1 can access the hydrophilic pocket of PPAR
a
-chain, fits comfortably into the pocket of PPAR
a in com-
a
-chain appears
c
PPAR
tain PGs were not applicable to dinor-PGs, even though there is
only a two-carbon difference in the -chain. Our new synthetic
a/c dual agonists. Synthetic methods previously used to ob-
a
c
a
routes should be applicable for the synthesis of other dinor-PGs.
Further synthetic and biological studies are under way.
a
a
PPARα with dinor-PGD1
α
δ
γ
10
8
6
4
Tyr464
2
Ser280
Tyr314
0
1
3
10
30
1
3
10
30
1
3
10
30
epi-1 (µM)
PGD2 (µM)
1 (µM)
Figure 4. Dose-dependent PPAR-agonistic activities of PGD2, 1, and epi-1.
Figure 6. Docking study of dinor-PGD1 (1) with PPARa. Calculated model of PPARa
with 1 constructed by AutoDock 4.2. The image was drawn with PyMOL.
(a)
PPARα
O
S
O
Helix-11
O
His440
His440
O
O
O
O
Ser280
Tyr464
Helix-12
Tyr464
Tyr314
Ser280
Tyr314
PPARγ
Helix-11
His449
Cys285
His449
S
O
O
Tyr473
Helix-12
O
Ser289
His323
Tyr473
(b)
PPARα
PPARγ
Helix-11
His449
Helix-11
OH
His440
O
too far
to interact
O
HO
O
HO
O
OH
Tyr473
Helix-12
Tyr464
O
Ser289
His323
Helix-12
Ser280
O
Tyr314
Figure 5. (a) Reported X-ray crystal structures of PPAR
model of dinor-PGD1 (1) with PPAR and PPAR
a (PDB ID 1I7G) and PPARc (PDB ID 2ZK1) complexed with agonists. The images were drawn by PyMOL; (b) binding
a
c.

A. Sato et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3013–3017
3017
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Acknowledgment
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6717.
We thank Dr. M. Ishikawa (The University of Tokyo) for helpful
discussions about the docking study.
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(dd, J = 15.4, 8.1 Hz, 1H), 4.41 (m, 1H), 4.01 (ddd, J = 13.0, 6.4, 6.4 Hz, 1H), 2.68
(dd, J = 11.7, 8.1 Hz, 1H), 2.49 (dd, J = 18.6, 6.4 Hz, 1H), 2.27–2.30 (m, 3H), 1.98
(m, 1H), 1.32–1.68 (m, 16H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 216.4, 179.0, 135.9, 125.9, 74.4, 68.5, 54.3, 48.5, 37.8, 33.9, 31.7, 27.5, 27.0,
26.7, 24.9, 24.3, 22.5, 14.0; HRMS (ESI) (m/z) calcd for C18H29O5 [MÀH]À:
325.2020, found: 325.2010; 13-epi-dinor-PGD1 (epi-1): 1H NMR (500 MHz,
CDCl3) d 5.51 (dd, J = 15.4, 6.6 Hz, 1H), 5.20 (dd, J = 15.4, 8.2 Hz, 1H), 4.35 (m,
1H), 4.10 (ddd, J = 13.9, 6.4, 6.4 Hz, 1H), 2.60 (dd, J = 11.8, 8.2 Hz, 1H), 2.33 (dd,
J = 18.6, 6.4 Hz, 1H), 2.28–2.32 (m, 3H), 1.98–1.94 (m, 2H), 1.34–1.72 (m, 15H),
0.80 (t, J = 9.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 216.2, 172.0, 136.1, 125.8,
74.0, 68.6, 54.1, 48.6, 37.7, 31.7, 27.7, 27.0, 26.7, 25.7, 24.9, 24.3, 19.3, 14.0;
HRMS (ESI) (m/z) calcd for C18H29O5 [MÀH]À: 325.2020, found: 325.2024.
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