Synthesis and evaluation of several 3,4-Seco-derivatives of myricerone as endothelin receptor antagonists

Article abstract of DOI:10.1007/s10600-014-0989-6

3,4-Seco-derivatives of myricerone were prepared by the Baeyer-Villiger oxidation of myricerone, and their structures were elucidated based on NMR and MS analyses. The synthesized compounds were evaluated as endothelin receptor antagonists and exhibited s

Full text of DOI:10.1007/s10600-014-0989-6

Chemistry of Natural Compounds, Vol. 50, No. 3, July, 2014 [Russian original No. 3, May–June, 2014]
SYNTHESIS AND EVALUATION OF SEVERAL 3,4-SECO-DERIVATIVES
OF MYRICERONE AS ENDOTHELIN RECEPTOR ANTAGONISTS
Junyi Hu, Chengfei Liu, Yingqian Xu,*
Yun Gao, and Guoyong Xiao
3,4-Seco-derivatives of myricerone were prepared by the Baeyer–Villiger oxidation of myricerone, and their
structures were elucidated based on NMR and MS analyses. The synthesized compounds were evaluated as
endothelin receptor antagonists and exhibited significant binding affinity for the ET receptor.
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Keywords: myricerone, seco-derivative, endothelin receptor antagonist.
Cardiovascular diseases have been designated as a global health problem, with the number of reported cases increasing
rapidly each year throughout the world in the populations of both developing and developed countries [1].
Endothelin-1 (ET-1) is a potent vasoconstrictor protein composed of 21 amino acids and was first isolated byYanagisawa
et al. [2] in 1988 from porcine aortic endothelial cells. ET-1 exhibits selective binding affinity for the ET receptor, which has
A
been shown to mediate vasoconstriction as well as the proliferation of vascular smooth muscle cells. One of the most important
factors in the regulation of blood pressure is the vasoconstrictory action of vascular smooth muscle cells, which is caused by
ET receptor antagonists.
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Several research groups have been involved in the search for novel endothelin receptor antagonists from natural
sources. Myricerone is an ET receptor antagonist isolated from Myrica cerifera, and several synthetic analogues of this
A
compound have been developed as potent and specific ET receptor antagonists [3]. In this paper, we report our work on the
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modification of myricerone with the aim of developing novel ET receptor antagonists with improved levels of activity.
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It was envisaged that a series of novel 3,4-seco-derivatives of myricerone (1) could be constructed according
to the synthetic strategy shown in Scheme 1, with the Baeyer–Villiger oxidation reaction being used as the key step.
30
29
20
21
19
O
13
11
9
25
10
26
17
CO Bn
2
d
CO H
2
CO Bn
1
2
a, b
c
28
15
3
7
27
OH
OAc
O
O
OAc
O
O
5
1
2
3
23
24
O
O
25
CO Bn
25
9
2
3
CO Bn
2
CO Bn
2
MeO C
2
9
e
f
HO C
2
1
1
10
3
O
7
5
HO
7
OAc
OAc
HO
OAc
O
5
5
6
4
24
23
24
23
a. Ac O; b. BnBr; c.O ; d. m-CPBA; e. K CO ; f. NaOH
2
3
2
3
Scheme 1
Center of Separation Technology, School of Chemical Engineering, University of Science and Technology Liaoning,
114051, Liaoning Anshan, P. R. China, fax: +86 412 5929627, e-mail: hjy741110@yahoo.com.cn. Published in Khimiya
Prirodnykh Soedinenii, No. 3, May–June, 2014, pp. 407–409. Original article submitted August 7, 2012.
470
0009-3130/14/5003-0470 02014 Springer Science+Business Media New York

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TABLE 1. Effects of the 3,4-Seco-derivatives of Myricerone on [ I]endothelin-1 Binding
Compound
IC50, M
Compound
IC50, M
6. 10–5
4.9 10–4
3
4
5
6
ꢂ
ꢂ
8.7 10–7
1.6 10–3
ꢂ
ꢂ
Thus, compound 1 was subjected to sequential protection reactions to give the C-27/C-28 protected myricerone 2, which
was treated with ozone [4] to afford the corresponding epoxide 3. Subsequent treatment of compound 3 with m-CPBA gave
the ring-expanded lactone 4. It is noteworthy that this Baeyer–Villiger reaction required a large excess of m-CPBA over an
extended reaction time to proceed to completion, and chromatographic purification was also required to give the pure
product. Treatment of lactone 4 with K CO in aqueous MeOH gave the 3,4-seco-derivative 5, which was hydrolyzed to the
2
3
corresponding carboxylic acid 6 with sodium hydroxide. Interestingly, the 27-acetoxy groups in compounds 4–6 were
stable to the basic conditions used in the hydrolysis step. This stability can be understood in terms of the steric hindrance
provided by the myricerone skeleton, with the 27-acetoxy groups in compounds 4–6 being shielded from hydrolysis by the
surrounding molecular framework.
The synthesized compounds were evaluated as ET receptor agonists in a competitive binding affinity assay using a
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previously published procedure [5], and the antagonistic effects of these compounds are shown in Table 1. Compound 4
exhibited a high level of affinity for the ET receptor.
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EXPERIMENTAL
General Experimental Procedures. NMR analyses were performed on a JEOL ECA300 instrument (JEOL, Tokyo,
1
Japan) at 300 MHz for the H spectra. The spectra were recorded in deuterated solvents containing tetramethylsilane as an
internal reference standard. ESI-MS data were obtained on a Bruker Esquire LC instrument (Bruker, USA). Column
chromatography (CC) was performed on silica gel (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China). Myricerone (1)
was prepared as previously described in the literature [6].
27-O-Acetylmyricerone Benzyl Ester (2). Myricerone (1) (2.5 g, 5.3 mmol) was dissolved in a mixture of pyridine
(20 mL) and Ac O (10 mL), and the resulting mixture was stirred for 3 h at 0ꢀC. The reaction mixture was then diluted with
2
water (50 mL) and extracted with CH Cl (30 mL). The organic layer was collected and washed with a saturated aqueous
2
2
KHSO solution (20 mL) before being dried over anhydrous Na SO . The solvent was evaporated under vacuum to give a
4
2
4
residue, which was dissolved in anhydrous THF (20 mL). BnBr (1.7 g, 10 mmol) and K CO (1.1 g, 8 mmol) were added to the
2
3
THF solution, and the resulting mixture was stirred for 16 h at room temperature. The solvent was then evaporated under
vacuum to give a residue, which was purified by CC over silica gel using a mixture of petroleum ether–EtOAc (7:1) as the eluent
to give 2. White amorphous solid, C H O , yield 2.3 g (72%), R 0.6 (petroleum ether–EtOAc, 4:1), mp 223–225ꢀC. Mass
39 54
5
f
+
spectrum ESI, m/z 625 [M + Na] . PMR spectrum (300 MHz, CDCl , ꢁ, ppm, J/Hz): 7.33 (5H, br.s, Bn), 5.57 (1H, t, J = 3.3,
3
H-12), 5.10 (1H, d, J = 12.7, Bn), 5.04 (1H, d, J = 12.7, Bn), 4.18 (1H, d, J = 12.7, H-27), 4.02 (1H, d, J = 12.7, H-27), 2.96 (1H,
dd, J = 4.1, 13.7), 1.98 (3H, s, OAc), 1.07, 1.02, 0.98, 0.92, 0.86, 0.59 (each 3H, s).
12,13-Epoxide-27-O-acetylmyricerone Benzyl Ester (3). Compound 2 (0.8 g, 1.3 mmol) was dissolved in EtOAc
(50 mL), and ozone gas was bubbled through the resulting solution at –50ꢀC until 2 could no longer be detected by TLC
analysis. The ozonolysis process was then suspended, and N gas was bubbled through the mixture to remove any residual
2
ozone. The reaction mixture was then concentrated under vacuum to give a residue, which was purified by CC over silica gel
using a mixture of CH Cl in EtOAc (30:1) to give 3. White amorphous solid, C H O , yield 778 mg (97%), R 0.5 (petroleum
2
2
39 54
6
f
+
ether–EtOAc, 4:1), mp 263–267ꢀC. Mass spectrum ESI, m/z 619 [M + H] . PMR spectrum (300 MHz, CDCl , ꢁ, ppm, J/Hz):
3
7.35 (5H, br.s, Bn), 5.16 (1H, d, J = 12.7, Bn), 5.04 (1H, d, J = 12.7, Bn), 4.50 (1H, d, J = 12.7, H-27), 4.04 (1H, d, J = 12.7,
H-27), 3.04 (1H, s), 2.07 (3H, s, OAc), 1.04, 0.98, 0.93, 0.89, 0.79, 0.67 (each 3H, s).
3,4-Seco-3,4-lactone-12,13-epoxide-27-O-acetylmyricerone Benzyl Ester (4). Finely ground NaHCO (17 mg,
3
0.2 mmol) was added to a solution of 3 (63 mg, 0.1 mmol) and m-CPBA (35 mg, 0.2 mmol) in CH Cl (5 mL), and the
2
2
resulting suspension was concentrated under vacuum to a solid residue, which was analyzed by TLC. If the reaction had not
reached completion after 3 h, a small volume of CH Cl was added, and the resulting mixture was concentrated to a solid. This
2
2
471

process of dissolution and evaporation was repeated every 3 h until the reaction reached completion. When the reaction
reached completion, the residue was purified by CC over silica gel using a mixture of CH Cl and EtOAc (20:1, v/v) as the
2
2
eluent to give 4. White amorphous solid, C H O , yield 30 mg (46%), R 0.6 (petroleum ether–EtOAc, 3:1, v/v), mp 254–257ꢀC.
39 54
7
f
+
Mass spectrum ESI, m/z 657 [M + Na] . PMR spectrum (300 MHz, CDCl , ꢁ, ppm, J/Hz): 7.36 (5H, br.s, Bn), 5.18 (1H, d,
3
J = 12.4, Bn), 5.06 (1H, d, J = 12.4, Bn), 4.50 (1H, d, J = 13.1, H-27), 4.04 (1H, d, J = 13.1, H-27), 3.05 (1H, s), 2.08 (3H, s,
OAc), 1.44, 1.34, 1.09, 0.94, 0.79, 0.65 (each 3H, s).
3,4-Seco-3-methoxycarbonyl-4-hydroxy-12,13-epoxide-27-O-acetylmyricerone Benzyl Ester (5). Powdered
potassium carbonate (3.9 mg, 0.03 mmol) was added to a solution of compound 4 (18 mg, 0.03 mmol) in 10% aqueous
methanol (3 mL), and the resulting mixture was stirred at room temperature for 48 h. The mixture was then reduced in volume
under vacuum and extracted with ethyl acetate (4 ꢂ 10 mL). The combined organic layers were concentrated to give the crude
product as a residue, which was purified by CC over silica gel using a mixture of CH Cl in EtOAc (7:1, v/v) as the eluent to
2
2
give compound 5. White amorphous solid, C H O , yield 10 mg (53%), R 0.4 (petroleum ether–EtOAc, 2:1, v/v), mp 212–215ꢀC.
40 58
8
f
+
Mass spectrum ESI, m/z 689 [M + Na] . PMR spectrum (300 MHz, CDCl , ꢁ, ppm, J/Hz): 7.36 (5H, br.s, Bn), 5.18 (1H, d,
3
J = 12.4, Bn), 5.06 (1H, d, J = 12.4, Bn), 4.53 (1H, d, J = 12.7, H-27), 4.04 (1H, d, J = 12.7, H-27), 3.65 (3H, s, OMe), 3.06 (1H,
s), 2.09 (3H, s, OAc), 1.26, 1.19, 1.04, 0.94, 0.79, 0.66 (each 3H, s).
3,4-Seco-3-carboxy-4-hydroxy-12,13-epoxide-27-O-acetylmyricerone Benzyl Ester (6). A solution of compound 5
(45 mg, 0.07 mmol) in a mixture of CH OH and THF (2:3, v/v, 3 mL) was treated with 4 N NaOH (0.5 mL), and the resulting
3
mixture was stirred for 16 h. The solution was then neutralized with 2 N HCl and the volatiles removed under vacuum to give
an aqueous mixture, which was extracted with EtOAc (4 ꢂ 10 mL). The combined organic layers were concentrated under
vacuum to give a residue, which was purified by CC over silica gel using a mixture of CH Cl and EtOAc (4:1, v/v) as the
2
2
eluent to give compound 6. White amorphous solid, C H O , yield 28 mg (64%), R 0.4 (petroleum ether–EtOAc, 1:1, v/v),
39 56
+
8
f
mp 228–231ꢀC. Mass spectrum ESI, m/z 691 [M + K] . PMR spectrum (300 MHz, CDCl , ꢁ, ppm, J/Hz): 7.36 (5H, br.s, Bn),
3
5.25 (1H, d, J = 12.7, Bn), 5.08 (1H, d, J = 12.7, Bn), 4.53 (1H, d, J = 12.7, H-27), 4.04 (1H, d, J = 12.7, H-27), 2.97 (1H, d,
J = 3.4), 2.10 (3H, s, OAc), 1.28, 1.23, 1.02, 0.98, 0.87, 0.86 (each 3H, s).
Procedure of Bioassay. Preliminary biological evaluation was performed according to a previously reported
procedure and showed significant binding affinity for the ET receptor. The synthesized compounds were screened using
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125
an ET receptor competitive binding test. I-ET-1 was used as a radioactive ligand in the current study to evaluate the ET
A
A
receptor antagonist activity of the synthesized compounds, and rat aortic smooth muscle A7r5 cells were selected as the
carrier to screen the compounds. The inhibitory effects of the synthesized compounds are shown in Table 1.
ACKNOWLEDGMENT
This project was supported financially by the Higher Education Department of the Liaoning Province Research
Foundation (Grant No. LJQ2013034). The project is sponsored by Liaoning BaiQianWan Talents Program (Grant
No. 2013921057) and the Science and Technology Department of Liaoning Province Science Foundation (Grant 2010226003).
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