A common building block for the syntheses of amorfrutin and cajaninstilbene acid libraries toward efficient binding with peroxisome proliferator-activated receptors

Article abstract of DOI:10.1021/ol503135u

A common building block for the synthesis of amorfrutin and cajaninstilbene acid derivatives has been developed. The library of synthesized compounds has enabled identification of new nontoxic ligands of peroxisome proliferator-activated receptors (PPAR) and potential inhibitors of the transcriptional corepressor protein NCoR. The biological data holds promise in identification of new potential leads for the antidiabetic drug discovery process.

Full text of DOI:10.1021/ol503135u

Letter
pubs.acs.org/OrgLett
A Common Building Block for the Syntheses of Amorfrutin and
Cajaninstilbene Acid Libraries toward Efficient Binding with
Peroxisome Proliferator-Activated Receptors
Indrapal S. Aidhen,* Ramesh Mukkamala, Christopher Weidner, and Sascha Sauer*
,†
†
‡
,‡
†
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
‡
Otto-Warburg Laboratory, Max-Planck-Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany
S Supporting Information
*
ABSTRACT: A common building block for the synthesis of amorfrutin and cajaninstilbene acid derivatives has been developed.
The library of synthesized compounds has enabled identification of new nontoxic ligands of peroxisome proliferator-activated
receptors (PPAR) and potential inhibitors of the transcriptional corepressor protein NCoR. The biological data holds promise in
identification of new potential leads for the antidiabetic drug discovery process.
he peroxisome proliferator-activated receptors alpha,
T
beta/delta, and gamma (PPARα, PPARβ/δ, and
PPARγ) are important transcriptional regulators of the nuclear
1
receptor family. These nuclear receptors like other gene-
2
regulating enzymes such as chromatin modifiers are highly
3
relevant drug targets, in particular for metabolic diseases.
4
Amorfrutin A (1), a member of the so far largely unexplored
isoprenoid-substituted benzoic acid derivatives, has been
Figure 1. Amorfrutin A (1), stilbenoids (2), and cajaninstilbene acid
(3).
isolated from the two dietary legumes Glycyrrhiza foetida
5
(
licorice) and Amorpha fruticosa. Recently, it was shown that
12
the naturally occurring amorfrutins A and B exert strong
followed by hydrogenation, (b) benzylic metalation followed
5
,6
13
antidiabetic and lipid-lowering effects in vivo. The physio-
logical effects of natural amorfrutins appeared to be mainly
mediated by highly selective activation of PPARγ due to
by alkylation, (c) Sonogashira coupling for coupling of aryl-
5
triflate with phenyl-acetylene. A recent biomimetic approach
uses 2,2,6-trimethyl-4H-1,3-dioxin-4-one as starting material to
inhibited interaction with the nuclear receptor corepressor
synthesize amorfrutin A through decarboxylative prenylation,
7
14
(
NCoR) protein. In a number of preclinical tests, amorfrutin A
migration, and aromatization sequence. Alternatively, amor-
and B did not show any side effects known from strong PPARγ-
frutin A can be produced by tandem Michael addition−
5
,6
intramolecular Claisen condensation followed by oxidative
targeting drugs of the thiazolidinedione family. However,
nature only offers a very limited pool of amorfrutin structures,
and rather low amounts of amorfrutins were found in relatively
15
aromatization. The synthesis of prenylated stilbenoid 3 is
currently based on the Horner−Wadsworth−Emmons ap-
16
8
proach for the C−C double bond formation or alternatively
uncommon plants. So far, no systemic endeavors have been
17
olefination of aromatic aldehydes with thiophthalides. The
relatively narrow substrate scope in the available methods, for
both prenylated bibenzyl 1 and stilbenoid 3, was the key
limiting factor in efficiently developing analogues.
made to tailor synthetic routes for these promising natural
products.
9
In general, hydroxy-substituted stilbenes 2 display beneficial
biological activities encompassing various therapeutic areas. For
10
Given the great biomedical potential of compounds 1 and 3,
the need to develop a general efficient strategy for generating
example, the stilbenoid 3, known as cajaninstilbene acid, has
11
shown strong antioxidant activity (Figure 1).
The synthesis of prenyl-substituted bibenzyl derivative 1
usually applies the following protocols for C−C bond
formation between two benzyl residues: (a) Wittig reaction
Received: October 30, 2014
©
XXXX American Chemical Society
A
DOI: 10.1021/ol503135u
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
libraries from a common building block became urgent.
Therefore, we designed the common building block 4 for the
synthesis of both types of compounds (1 and 3) to achieve
efficient synthesis of prenylated bibenzyls 5 and prenylated
stilbenoids 6, containing a functionalized aromatic ring (Figure
the sulfide 12 with 30% H O /Na WO ·2H O in methanol
furnished the desired building block 4 in good yield (88%), as a
white crystalline solid (Scheme 1).
2
2
2
4
2
Besides the NMR spectral analysis, the structure and position
of the prenyl moiety in sulfone 4 was confirmed unambiguously
using single-crystal X-ray diffraction analysis (see Supporting
1
8
2). This building block 4 enables synthesis of bibenzyl
22
Information 1).
As projected in the conceived strategy for substituted
prenylated stilbenoids 6, various substituted aromatic aldehydes
1
3a−13l were now subjected to modified Julia olefination
reaction with building block 4 using sodium hydride as the base
for initial generation of carbanion in DMF as the solvent.
Functionalized stilbenes 14a−14l were obtained in good yields
Figure 2. Common building block for prenylated bibenzyls and
stilbenoids.
(
62−83%), as the E-isomer only, which was confirmed by the
3
vicinal coupling constant value ( J = 15.5−16.5 Hz) between
the olefinic protons in their H NMR spectrum (Scheme 2).
HH
1
derivatives 5 through a sequence comprising benzylation with
various substituted benzyl bromides, followed by desulfonyla-
tion and hydrolysis, whereas synthesis of 6 involves Julia
olefination with various substituted aromatic aldehydes,
followed by hydrolysis.
Scheme 2. Synthesis of Cajaninstilbenes Acid and Its
Analogues (15a−15l)
18
The synthesis of the common building block 4 is presented
19
in Scheme 1. Starting with 7, thio-alkylation of 2-mercapto-
Scheme 1. Synthesis of the Key Building Block (4)
The acetate and methyl ester protections in stilbenes 14a−14l
were conveniently removed by using NaOH/H O/THF at 50
2
°
C for 32 h to provide the targeted cajaninstilbenes acid 6
analogues 15a−15l in good to excellent yields (76−90%)
Scheme 2). The results are summarized in Table 1. The ability
(
Table 1. Cajaninstilbenes Acid and Its Analogues
a
a
s.n.
Ar 13a−m
13a (C H )
14a−m (yield)
15a−m (yield)
1
2
3
4
5
6
7
8
9
14a (83%)
14b (74%)
14c (77%)
14d (80%)
14e (83%)
14f (65%)
14g (62%)
14h (76%)
14i (76%)
14j (77%)
14k (65%)
14l (80%)
14m (74%)
15a (90%)
15b (81%)
15c (88%)
15d (85%)
15e (85%)
15f (88%)
15g (80%)
15h (87%)
15i (81%)
15j (76%)
15k (88%)
15l (83%)
6
5
13b (4-MeOC H )
6
4
13c (3,5-MeO C H )
2
6
3
13d (3,4,5-MeO C H )
3
6
2
13e (2,3,4-MeO C H )
3
6
2
13f (3,4-OCH OC H )
2
6
3
13g (4-FC H )
6
4
13h (2,4-F C H )
benzothiazole with the bromide 7 in dichloromethane using
triethylamine as a base resulted in the formation of the sulfide 8
in good yield (79%). For installation of the prenyl moiety on
the aromatic ring, compound 8 was deacetylated and a
2
6
3
13i (3,4-Cl C H )
2
6
3
1
0
1
13j (2-pyridyl)
13k (3-pyridyl)
13l (4-pyridyl)
1
2
0
12
̈
procedure reported by Furstner and Gastner for C-
b
1
3
13m (6-pyronyl)
15m (84%)
prenylation was applied on the phenolic compound 9. The
reaction using sodium hydride as the base and prenyl bromide
as the electrophile in toluene at 35 °C was very sluggish and
generated very low yield of the desired C-prenylated compound
a
b
Yield of products after column chromatography. Precisely:
(4‑methoxy-2H-pyran-2-one)-6-yl.
11 (15%), whereas the major product under these conditions
of sulfone 4 to olefinate aldehydes was not restricted to
23
was the O-prenylated compound 10 in 60% yield. These two
compounds were easily separable using column chromatog-
raphy over silica gel. In order to improve the yield of desired
compound 11, we relied on rearrangement of the O-prenyl
ether 10 to ortho-prenyl phenol 11. To achieve this, the O-
prenylated product 10 was initially obtained in high yield
aromatic aldehydes alone. The pyrone based aldehyde 13m,
as an illustrative example (entry 13, Table 1), could be used to
generate the corresponding product 14m in equally good yields
(74%). By anticipating the pyrone moiety to be incompatible
with the hydrolytic conditions, selective removal of acetyl
protection in 14m was achieved with K CO in MeOH and the
2
3
(
90%) using DMF as a solvent and subjected to rearrangement.
product 15m with methyl ester was obtained in good yields
(84%), thereby illustrating the usefulness of the synthetic route.
The use of aqueous NaOH solution on 14m, for hydrolysis,
indeed leads to extensive degradation of the compound.
Having successfully achieved synthesis of highly function-
alized C-prenylated stilbene derivatives 15a−m, the utility of
the building block 4 was now explored toward the synthesis of
Among various possible reagents, use of Montmorillonite
2
1
K10 led to the desired C-prenylated product 11 in modest
yield (40%). Although the major side product was the
deprenylated compound 9, the cyclic sequence (9 → 10 →
1
1) ensured no loss of material and assured regular supplies of
compound 11. Acetylation of compound 11 and oxidation of
B
DOI: 10.1021/ol503135u
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
targeted bibenzyl compounds 5, i.e. amorfrutin A and its
analogues. To our delight, in a model reaction, sulfone 4
underwent clean benzylation at the benzylic site, through the
generation of the carbanion with sodium hydride as the base,
and with benzyl bromide 16a as the electrophile, at 0 °C to
room temperature, in 3 to 4 h.
in the nanomolar range (Supporting Information 2, Supple-
mentary Table 1), in particular for cajaninstilbene acid
derivative 15f we observed a K value of 30 nM. As recently
i
described for the naturally occurring amorfrutin A, also the
synthesized compounds induced efficient dissociation of NCoR
from PPARγ up to for example 72% for 15f compared to
rosiglitazone. Inhibitory concentrations (IC50) of 20 nM could
be detected for this compound (Supporting Information 2,
Supplementary Figure 1d and Table 2).
The desired monobenzylated product 17a was obtained in
good yield (78%). This procedure was generalized with various
other substituted benzyl bromides 16b−i for alkylation with
building block 4. Desired monobenzylated products 17b−i
were obtained in good to excellent yields (69−95%) (Scheme
In summary, the first library of synthetic analogues of natural
amorfrutins produced in our synthetic endeavor contains a
number of promising binders of PPARs and efficient inhibitors
3).
26
of NCoR. Notably, none of the compounds showed relevant
induction of toxic effects (Supporting Information 2,
Supplementary Table 3 and Supplementary Figure 2).
Scheme 3. Synthesis of Amorfrutin A (19a) and Its
Analogues (19b−i)
In conclusion, the here presented common building block 4
has enabled convenient access to initial libraries of synthetic
5,8
18
analogues of recently described antidiabetic amorfrutins
and cajaninstilbene acids. The synthetic analogues reported
herein point to promising prospects of amorfrutins and
cajaninstilbene acids toward biomedical applications. Relevant
applications may include development of drug candidates with
improved safety profiles and provision of new chemical tools
for mechanistic PPAR research.
The monobenzylated compounds 17a−i were subjected to
ASSOCIATED CONTENT
Supporting Information
■
desulfonylation with inexpensive reagents such as sodium
*
S
24
amalgam (10%) in methanol or Mg/AcOH/AcONa in
2
5
Experimental details and further results are available as
Supporting Information 1 and 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
DMF. Under both conditions, desulfonylation resulted in a
complex reaction mixture as reflected by multiple spots on
25
TLC. The use of SmI (0.1M) solution in THF, along with
2
HMPA (5 equiv) and t-BuOH (20 equiv) at 0 °C to room
temperature, enabled clean desulfonylation and resulted in the
formation of products 18a−i in moderate to good yields (see
Table 2). Finally, hydrolysis of these compounds 18a−i
provided the targeted amorfrutin A 19a and its analogues
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: isingh@iitm.ac.in.
*E-mail: sauer@molgen.mpg.de.
Author Contributions
19b−i in good to excellent yields (73−90%).
All authors contributed equally to this work.
Notes
Table 2. Amorfrutin A (19a) and Its Analogues (19b−i)
a
a
s.n.
Ar 16a−j
16a (C H )
18a−i (yield)
19a−i (yield)
The authors declare no competing financial interest.
1
2
3
4
5
6
7
8
9
18a (76%)
18b (63%)
18c (83%)
18d (64%)
18e (71%)
18f (66%)
18g (88%)
18h (88%)
18i (78%)
19a (73%)
19b (90%)
19c (85%)
19d (84%)
19e (88%)
19f (85%)
19g (83%)
19h (85%)
19i (90%)
6
5
16b (4-MeOC H )
6
4
ACKNOWLEDGMENTS
■
16c (3,5-MeO C H )
2
6
3
I.S.A. thanks BRNS for the project and IIT-M for infrastructure.
R.M. thanks CSIR for an SRF award. S.S. was supported by the
BMBF (Grant Number 0315082 (01EA1303)). We thank Dr.
Florenz Sasse and Aman Bhasin (both at Department of
Chemical Biology, Helmholtz Centre for Infection Research,
Germany) for support and discussions.
16d (3,4,5-MeO C H )
3
6
2
16e (2,3,4-MeO C H )
3
6
2
16f (3,4-OCH OC H )
2
6
3
16g (4-FC H )
6
4
16h (2,4-F C H )
2
6
3
16i (3,4-Cl C H )
2
6
3
a
Yield of products after column chromatography.
DEDICATION
■
Dedicated to Professor Richard R. Schmidt on the occasion of
his 80th birthday.
To determine binding of the synthesized compounds to
PPARs, we performed in vitro competitive binding studies with
all three PPAR subtypes namely PPARα, β/δ, and γ. In general,
for PPARα, the compounds revealed binding affinity constants
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DOI: 10.1021/ol503135u
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Organic Letters
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DOI: 10.1021/ol503135u
Org. Lett. XXXX, XXX, XXX−XXX