Synthesis, modification, and evaluation of (R)-de-O-methyllasiodiplodin and analogs as nonsteroidal antagonists of mineralocorticoid receptor

Article abstract of DOI:10.1016/j.bmcl.2010.12.101

Macrolide (R)-de-O-methyllasiodiplodin (1), discovered to be a potent nonsteroidal antagonist of the mineralocorticoid receptor (MR), was synthesized via an efficient method and evaluated for MR antagonistic activity together with its analogs. Among all the tested compounds, compounds 18a, 18b and 18c, exhibited more potent antagonistic activity against MR with IC₅₀ values ranging from 0.58 to 1.11 μM. Generally, it was obviously demonstrated that acetylation at phenolic hydroxyl groups and the ring size in analogs of 1 were very important for MR antagonist activity.

Full text of DOI:10.1016/j.bmcl.2010.12.101

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1171–1175
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, modification, and evaluation of (R)-de-O-methyllasiodiplodin
and analogs as nonsteroidal antagonists of mineralocorticoid receptor
Cheng-Shi Jiang a, , Rong Zhou b, , Jing-Xu Gong a, , Li-Li Chen a, , Tibor Kurtán c, Xu Shen a,b, Yue-Wei Guo a,
⇑
⇑
⇑
a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
b East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China
c Department of Organic Chemistry, University of Debrecen, PO Box 20, 4010 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Macrolide (R)-de-O-methyllasiodiplodin (1), discovered to be a potent nonsteroidal antagonist of the
mineralocorticoid receptor (MR), was synthesized via an efficient method and evaluated for MR
antagonistic activity together with its analogs. Among all the tested compounds, compounds 18a, 18b
and 18c, exhibited more potent antagonistic activity against MR with IC50 values ranging from 0.58 to
Received 30 August 2010
Revised 16 December 2010
Accepted 21 December 2010
Available online 25 December 2010
1.11
lM. Generally, it was obviously demonstrated that acetylation at phenolic hydroxyl groups and
the ring size in analogs of 1 were very important for MR antagonist activity.
Keywords:
Macrolide
Ó 2010 Elsevier Ltd. All rights reserved.
(R)-De-O-methyllasiodiplodin
Mineralocorticoid receptor
Antagonist
Ring-closing-metathesis reaction
The mineralocorticoid receptor (MR), also called aldosterone
receptor, is a member of the super family of nuclear receptor. MR
is activated by steroids including aldosterone, cortisol and cortico-
sterone.1–4 MR activation results in sodium transport, increasing
blood pressure, urinary protein excretion and potassium levels.5
However, abnormal activation of MR by elevated level of aldoste-
rone and salt imbalance cause hypertension and other effects det-
rimental to the cardiovascular system. Thus, MR antagonists are
expected to be beneficial to patients with hypertension and other
cardiovascular diseases, such as heart failure.6
Despite the great achievements in exploring MR ligand in
50 years, only two steroidal MR antagonists, spironolactone and
eplerenone, have been brought to the market for the treatment
of hypertension and heart failure. Results of randomized aldactone
evaluation study (RALES) has demonstrated that spironolactone in
standard therapy reduced risk of death by 30% and improved car-
diac function of patients with severe heart failure.7 Other results
from Eplerenone Post Acute Myocardial Infarction Heart Failure
Efficacy and Survival Study (EPHESUS) indicated that eplerenone,
when added to optimal medical therapy, resulted in improved
survival and reduced hospitalization among patients with acute
myocardial infarction complicated by left ventricular dysfunction
and heart failure.8
However, spironolactone lacks selectivity against other steroid
nuclear homone receptors, primarily androgen receptor and
progesterone receptor, and has undesirable side effect, such as
gynecomastia in men and menstrual irregularity in women, that
limited its long term use.9 In contrast, eplerenone is more selective,
but less potent than spironolactone in vitro.10 Meanwhile, steroidal
MR antagonists were developed slowly due to complexity in chem-
ical synthesis, lacking of selectivity and unwanted side effects. In
recent years novel classes of nonsteroidal MR antagonists have just
begun to emerge.6,11
A great number of macrolide compounds with remarkable bio-
activities have been isolated and synthesized to date.12 The twelve-
membered macrolides, (R)-de-O-methyllasiodiplodin (1) and (R)-
lasiodiplodin (1a) (see Fig. 1), which were isolated from plants13
as well as from fungus,14 exhibit efficient inhibition of prostaglan-
din biosynthesis,13c,15,16 antimicrobial activities14b and significant
antitumor activities.16 Recently, 1 was reported to be a potent
inhibitor of pancreatic lipase (PL), an enzyme playing a key role
in the efficient digestion of triglycerides and being a target for
treating obesity,17 with an IC50 value of 4.73 M.18
l
In our screening program to search for nonsteroidal MR antag-
onist, 1 was found to exhibit potent antagonistic effect against MR
with an IC50 value of 8.93 lM (unpublished data). The compound 1
⇑
Corresponding authors. Tel.: +86 21 50805813; fax: +86 21 50807088.
E-mail addresses: jxgong@mail.shcnc.ac.cn (J.-X. Gong), lilichen@mail.shcn-
c.ac.cn (L.-L. Chen), ywguo@mail.shcnc.ac.cn (Y.-W. Guo).
These authors contributed equally to the study.
is the first macrolide compound found to behave as MR antagonist
to date, different from the other nonsteroidal MR antagonists.6,11
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.101

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C.-S. Jiang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1171–1175
afforded (R)-4 in 85% yield under Mitsunobu conditions,24 then
was converted to 3, mixture of geometrical isomers
4
a
[(E):(Z) = 1.5:1], in 80% yield by the classical RCM reaction cata-
lyzed by the second generation Grubbs catalyst (10, 3 mol %) in
refluxing CH2Cl2 for 1 h.20 A subsequent catalytic hydrogenation
of the double bond provided (R)-2 in 94% yield in EtOH at room
temperature overnight. Then 2 was treated with BBr3 in dry
CH2Cl2 at 0 °C for 15 min and quenched with H2O under reduced
pressure to afford the target compound 1,25 the physical and spec-
tral data of which were in agreement with the literature data.13,19
By performing the quenching under reduced pressure, the yield of
the last step was increased to 57%, a remarkable increase from the
17% yield of the literature procedure.19
In order to discover initial information about SAR of 1 and find
more potent MR antagonists than 1, 20 derivatives (1b–1u) of 1
were synthesized (see Scheme 1 and Table 1). Compound 1b was
prepared from 1 by reacting with CH2N2/Et2O in methanol at room
temperature.26 Treatment of 1 (1 equiv) with ethyl iodide or
bromoalkane (1.5 equiv) catalyzed by potassium carbonate in
acetone provided 1c–1l,27 with anhydride (2.5 equiv) catalyzed
by triethylamine in dichloromethane provided 1n–1q, and with
acyl chloride catalyzed by triethylamine in dichloromethane at
room temperature provided 1r–1u, respectively.28 Compound 1m
was obtained by treating 1 epichlorohydrin (2.5 equiv) catalyzed
by potassium carbonate in refluxing acetone.29
Figure 1. Structures of (R)-de-O-methyllasioplodin (1) and (R)-lasiodiplodin (1a).
The MR antagonistic activity of 1 sparked our great interest in its
further investigation and optimization, but the low amount of
the available sample from natural sources is a bottle-neck for addi-
tional structural derivatization/modification and structure–activity
relationship (SAR) studies.
The first asymmetric total synthesis of 1, a precursor in the syn-
thesis of 1a, was published in 1990 with 18 steps in 0.8% overall
yield19 but the synthetic route was too complicated and low yield-
ing. Especially, the yield of the last demethylation step was only
17%. In 1996, a shorter route, using the Ring-closing-metathesis
(RCM) reaction as the key step, was reported by Alois Fürstner
and Kindler.20 However, the carboxylation step via a Kolbe–
Schmitt reaction under CO2 (40 atm) and 120 °C for 12 h can not
be considered a routine procedure for an average synthetic labora-
tory. Herein we report a more facile and efficient route for the
preparation of 1 with higher yield and simple synthetic steps.
Scheme 1 shows the synthetic route for the preparation of
macrolide 1. Compound 8 was prepared from the commercially
available orcinol monohydrate (9) in two steps with 99% overall
yield by following procedures described in the literature.21 The
lithiation of the bromo derivative 8 by n-BuLi in dry THF at
ꢀ78 °C followed by treatment with isobutyl chloroformate gave
the required ester 7 in 89% yield,21 which was converted to 6 in
90% yield with 3-chloropropene in dry THF at ꢀ78 °C catalyzed
by LDA.22 Saponification of 6 with KOH in refluxing EtOH (90%)
for 12 h afforded the carboxylic acid 5 in 98% yield. Esterification
of 5 with (S)-hept-6-en-2-ol obtained in a Grignard reaction,23
To evaluate the antagonistic activity of these derivatives against
MR, yeast two-hybrid assay was preformed according to our previ-
ously published papers.30,31 The pGADT7-hSRC-1(aa.613-773) and
pGBKT7-rMR-LBD (aa.725-981) were constructed and transformed
into AH109 yeast cells. To assess the reliability of the yeast two-hy-
brid system, we firstly determined the activity of corticosterone in
stimulating MR_LBD/SRC1 interaction with EC50 of 33 nM. Then
the activities of the derivatives were determined using the same
assay.
The results are shown in Table 1. Only four compounds were
found to have MR antagonistic effect besides 1, and compound
1n was the most potent antagonist with an IC50 value of
2.78 lM. Among compounds 2–4, only Z-3 was active against
Scheme 1. Reagents and conditions: (a) reaction conditions of the two steps are specified in Ref.9, 99% over two steps; (b) n-BuLi, isobutyl chloroformate, dry THF, ꢀ78 to 0 °C,
3 h, 89%; (c) LDA, 3-chloropropene, dry THF, ꢀ78 to 0 °C, 3 h, 90%; (d) KOH, 90% EtOH, reflux, 12 h, then 10% HCl, 98%; (e) EtOOC–N@N–COOEt, PPh3, (S)-hept-6-en-2-ol, THF,
rt, 1.5 h, 85%; (f) 10 (3 mol %), CH2Cl2, reflux, 1 h, 80%; (g) H2 (1 atm), 10% Pd/C, EtOH, rt, overnight, 94%; (h) BBr3, dry CH2Cl2, 0 °C, 15 min, 57%; (i) CH2N2/Et2O, MeOH, rt,
overnight for 1b, 73%; EtI, K2CO3, acetone, rt, overnight for 1c, 45% and 1d, 46%; bromoalkane, K2CO3, acetone, reflux, 2.5 h for 1e–1i, 23–48%, and rt, overnight for 1j–1l, 33–
86%; epichlorohydrin, K2CO3, acetone, reflux, 4 h for 1m, 46%; anhydride or acyl chloride, Et3N, CH2Cl2, rt, overnight for 1n–1u, 66–93%.

C.-S. Jiang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1171–1175
1173
Table 1
Inhibitory activity of 1 and its analogs presented as IC50 (lM)
Compounds
R1
R2
Compounds
R1
R2
a
4
E-3
Z-3
2
1a
1
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
H
H
H
Et
n-Bu
H
Me
Me
Me
Me
H
H
Me
Et
—
—
1i
1j
1k
1l
1m
1n
1o
1p
1q
1i
CH2@CHCH2
H
Bn
p-NO2-Bn
H
Ac
CH2@CHCH2
Bn
Bn
p-NO2-Bn
CH2OCHCH2
Ac
—
—
—
—
—
2.78
31.72
—
—
—
—
—
16.55
—
—
8.93
—
—
EtCO
EtCO
n-ProCO
i-ProCO
Bz
p-Br-Bz
p-Cl-Bz
p-Ts
n-ProCO
i-ProCO
Bz
p-Br-Bz
p-Cl-Bz
p-Ts
Et
n-Bu
Pr
—
—
—
1s
1t
1u
1g
1h
Pr
H
Pr
—
—
CH2@CHCH2
6.51
a
Inactive.
MR, indicating that to some extent the configuration of lactonic
ring had an impact on the antagonistic activity against MR. By
comparison with compounds 1a, 1, 1b, and 2, it was found that
not only dimethylates but also monomethylates led to inhibitory
effect loss, and only compound 1 without methylate was active
ent ring size of the lactone without chiral methyl moiety. The syn-
thetic route is shown in Scheme 2. The compounds 11 were reacted
with tert-butyldimethylsily (TBS) chloride in CH2Cl2 to result in the
protected derivatives 12 in 90–96% yield,32 which were converted
to 13 with 7 in dry THF at ꢀ78 °C catalyzed by LDA.22 The com-
pounds 14 were obtained from 13 by TBS-deprotection of hydroxyl
groups using concentrated HCl at room temperature in acetone33
in 60–70% overall yield for two steps. Saponification of 14 with
KOH in refluxing EtOH (90%) for 12 h afforded the carboxylic acid
15 in 74–81% yield, which were converted to 16 in 52–62% yield
under Mitsunobu conditions.24 Then 16 were treated with BBr3
in dry dichloromethane at 0 °C for 15 min and quenched with
H2O under reduced pressure to afford 17 in 35–44% yield. Treat-
ment of 17 with acetic anhydride catalyzed by triethylamine at
room temperature in CH2Cl2 provided 18 in 80–88% yield.28
The activity results of 17 and 18 are shown in Table 2. Except for
17, all compounds 18 were active against MR. Clearly, diacetylation
can increase antagonistic effect against MR. It was speculated that
the permeability change caused by the acetyl group leads to
increase the antagonistic activity of 1n and 18. The compounds
18a, 18b and 18b were more potent active than 1n, indicating
that the chiral methyl moiety was unnecessary for the MR antago-
nistic effect. The removal of methyl moiety can promote antagonis-
tic activity against MR, most probably because of decreasing steric
with an IC50 value of 8.93 lM. The reason was speculated that
maybe methylate of phenolic hydroxyl group decreased its hydro-
philicity and affinity to MR consequently, and the similar results
were obtained from 1c–1m without inhibitory activity against
MR. Intriguingly, compound 1n, diacetylate of compound 1, exhib-
ited a more potent antagonistic effect against MR than 1, with an
IC50 value of 2.78 lM. So it was decided to continue acetylation
of 1 with the purpose of finding more potent derivatives. However,
the activity of derivatives from 1o to 1t decreased or lost with in-
crease in the amount of carbon atoms or steric hindrance of substi-
tuent groups. It is interesting to note that although p-toluene
sulfonyl group causes large steric effect, 1u had potent antagonistic
effect against MR with an IC50 value of 6.51 lM. Possible explana-
tion is that the sulphur or oxygen atoms in substituent groups are
helpful to increase affinity to MR.
Base on this information in hand and in order to investigate the
impact of different ring size of the lactone on the MR inhibitory ef-
fect, another synthesis program was initiated to further explore
this series by preserving diacetylate moiety and introducing differ-
Scheme 2. Reagents and conditions: (a) TBSCl, DMAP, Et3N, CH2Cl2, rt, 5 h, 90–96%; (b) LDA, 7, dry THF, ꢀ78 to 0 °C, 3 h; (c) concd HCl, acetone, rt, 10 min, 60–70% for two
steps b and c; (d) KOH, 90% EtOH, reflux, 12 h, then 10% HCl, 74–81%; (e) EtOOC–N@N–COOEt, PPh3, THF, rt, 1.5 h, 52–62%; (f) BBr3, dry CH2Cl2, 0 °C, 15 min, 35–44%; (g) Ac2O,
Et3N, dry CH2Cl2, rt, overnight, 80–88%.

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C.-S. Jiang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1171–1175
Table 2
30730108, 40976048, 81072572), STCSM Project (09ZR1438000,
10540702900), CAS Key Project (SIMM0907KF-09), and partially
funded by grant from CAS (KSCX2-YW-R-18).
Inhibitory activity of 17 and 18
Compounds
n
IC50 (lM)
a
17a
18a
17b
18b
17c
18c
17d
18d
4
4
5
5
6
6
7
7
—
0.58
—
1.11
—
0.82
—
2.90
A. Supplementary data
Supplementary data (Experimental details and 1H and 13C NMR
spectra of compounds) associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.12.101.
a
Inactive.
References and notes
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a and PR
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IC50
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(lM)
GR
a
PR
a
1n
18a
18b
18c
18d
—
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—
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8.36
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>10
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—
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18a-18c were better than 18d, and especially the compound 18a,
bearing 11-membered lactonic ring, had the best antagonistic ef-
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fect against MR with an IC50 value of 0.58 lM, 14.4- and 3.8-fold
increase in inhibitory effect compared with 1 and 1n, respectively.
In order to test the antagonistic activity of compounds 1n and
18 against other panel of related steroid nuclear hormone recep-
tors including glucocorticoid receptor (GR), estrogen receptor
(ERa) and progestogen receptor (PR), mammalian one-hybrid as-
say was performed according to our previous methods.34,35 The
plasmids including UAS-TK-Luc, pRL-SV40 and pGAL4-nuclear
receptor (GR, ERa or PR)-LBD were transiently co-transfected into
HEK293T cells. Relative activities were measured using Dual-Lucif-
erase Assay System kit (Promega). The results are shown in Table 3.
From the data shown below, compounds 1n and 18d exhibited
antagonistic activity against ERa, 18c and 18d exhibited antago-
nism against PR, but 18a and 18b had no effects on PR and ERa,
and none of them had effects on GR.
In summary, (R)-de-O-methyllasiodiplodin (1) was synthesized
via an efficient route with nine steps in 28.3% overall yield, and
evaluated for MR antagonist activity together with its analogs.
Some more potent MR antagonists were found, such as 18a, 18b
and 18c with IC50 values ranging from 0.58 to 1.11 lM, providing
20. Fürstner, A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005.
21. Mondal, M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007, 72, 2068.
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24. Mitsunobu, O. Synthesis 1981, 1, 1.
a novel MR antagonist chemtype. Initial evaluation of antagonistic
activity against MR indicated that the acetylation at phenolic hy-
droxyl groups in analogs of 1 can increase the antagonistic effect
against MR and the ring size of the lactone was also very crucial
for its activity. The further study on SAR about this new class of
MR antagonists is ongoing.
25. Experimental section and spectral data for (R)-de-O-methyllasioplodin (1): To a
stirred solution of 2 (1.00 g, 3.26 mmol) in anhydrous dichloromethane under
nitrogen, BBr3 (25 mmol, 2.41 mL) was added at 0 °C and stirred for 15 min at the
same temperature. To the resulting mixture, then H2O (15 mL) was added and it
was evacuated for 5 min. The residue was extracted with CH2Cl2 (3 ꢁ 30 mL). The
organic layer was dried with MgSO4 and concentrated. The residue was subjected
to chromatography with petroleum ether/acetone (3:1) to give the desired
Acknowledgments
products 1 as a white solid (0.52 g, 57%). ½a D20
ꢂ
+29.2 (c 0.25, CHCl3). 1H NMR
This research work was financially supported by National S & T
Major Project (Nos. 2009ZX09301-001, 2009ZX09103-060),
National Marine 863 Programme for Druggability Evaluation
(2011-2013), Natural Science Foundation of China (Nos.
(300 MHz, CDCl3): d 1.36 (3H, d, J = 6.2 Hz), 1.40–1.99 (12H, m), 2.50 (1H, m,
benzylic H), 3.28 (1H, td, J = 3.7, 11.4 Hz benzylic H), 5.17 (1H, m, HCOCO), 6.22
(1H, d, J = 2.6 Hz,), 6.27 (1H, d, J = 2.6 Hz), 11.98 (1H, s, 2-OH). 13C NMR (100 MHz,
CDCl3): d 20.1 (CH3), 21.1 (CH2), 24.1 (CH2), 24.6 (CH2), 27.2 (CH2), 30.7 (CH2), 31.0

C.-S. Jiang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1171–1175
1175
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