CN109810017B - Amazonia sparsa acid derivative and preparation method and application thereof - Google Patents

Amazonia sparsa acid derivative and preparation method and application thereof Download PDF

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CN109810017B
CN109810017B CN201910151981.2A CN201910151981A CN109810017B CN 109810017 B CN109810017 B CN 109810017B CN 201910151981 A CN201910151981 A CN 201910151981A CN 109810017 B CN109810017 B CN 109810017B
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silvestris
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dichloromethane
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CN109810017A (en
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曹建国
冯妮平
张晟
王明龙
王全喜
黄国正
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Shanghai Normal University
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Abstract

The invention relates to a silvestris acid derivative and a preparation method and application thereof, the silvestris acid is taken as a substrate, the silvestris acid reacts with various primary amines or secondary amines under the action of a condensing agent, the silvestris acid derivative is obtained by separation, the synthesized derivative is subjected to antibacterial and antitumor cell activity tests, and the antibacterial result shows that most compounds show antibacterial activity and the antibacterial activity to staphylococcus aureus is more obvious; the antitumor results show that most of the compounds show obvious antitumor activity and IC of 4 different human cancer cell lines50All are about 10 mu M. Compared with the prior art, the synthesis process is simple and convenient, the synthesis efficiency is high, the purity of the separated compound is high, the method is an effective way for synthesizing a new compound by modifying the structure of the meadow fern acid, and the prepared meadow fern acid derivative is expected to be applied to the field of preparing antibacterial and antitumor drugs.

Description

Amazonia sparsa acid derivative and preparation method and application thereof
Technical Field
The invention relates to preparation and application of a compound, in particular to a silvestris acid derivative and a preparation method and application thereof.
Background
Silvery meadow fern (Aleuritopteris argentea (Gmhel.) F é e), also known as menstrual flow grass, cupressus paniculatus, Ceratopteris argentea, Chrysopogon indicus, and the like, is a plant of the genus of meadow fern in the family of Pteridaceae in China, and is distributed in most areas of China. The Chinese medicinal preparation is commonly applied to minority regions of Tibetan, Mongolian and Korean nationalities in China, such as Mongolian medicine for treating sore injury, fracture, injury of pulse and tendon and irregular menstruation; tibetan medicine can be used for treating common cold, fever, and removing toxic substance; she medicine can treat irregular menstruation, amenorrhea, pulmonary tuberculosis hemoptysis, etc. However, it is not widely used in clinical practice of traditional Chinese medicine, and is not available in hospital. In modern clinical research, the clinical reports of the radix clematidis are few, and the Mongolian medicine eyesight improving seven-ingredient pills and the eyesight improving small preparations are observed to have the treatment effect on 70 cases of postoperative late glaucoma patients, so that the Mongolian medicine eyesight improving seven-ingredient pills and the eyesight improving small preparations are considered to have short treatment course and remarkable treatment effect on postoperative late glaucoma. (Dynasty, Alatantaya, Mongolian medicine for treating postoperative late glaucoma [ J ]. Proc. Med. Pharmacology 2005,23(10):1918-
The silvery meadow fern contains terpenoid compounds such as meadow fern acid and the like, a plurality of flavonoid compounds, chlorogenic acid, alkaloid, polysaccharide and the like. The structures of the meadowfoam fern acid are identified, and the content of the meadowfoam fern acid in different producing areas is found to be remarkably different. (New compound [ J ] in the silver Stellaria delavayi Diels leaves, pharmaceutical research (day), 1960, 32 (5): 354 ] in Gangtian Bo, Yantian Zhongzhi, Dazhu Liang Happy. the diterpene compound Stellaric acid in silver Stellaria delavayi has a structure [ J ]. Central journal of medicine (day), 1964, 195 (3): 287.) in Zhaoyanchun, etc., the separation, purification and structural identification of Stellaria delavayi acid in silver Stellaria delavayi Diels are carried out, and the content of Stellaria delavayi acid in silver Stellaria delavayi Diels is determined by adopting an HPLC method, wherein the result shows that the content of Stellaria delavayi acid in silver Stellaria delavayi Diels in Shandong reaches 3.75%. (Zhaoyingchun, Wangxiao Li, Zhaoyanli, et al, Nephragmites communis leaf Pink fern acid separation and content determination [ J ]. Shenyang pharmaceutical science university report, 2008, 25 (1): 52-55.) The laboratory also separated a large amount of Pink fern acid from Aleurites argentea purchased from Henan, and content determination was carried out, wherein, Pink fern acid accounts for 0.35%.
Amazonic acid belongs to labdane diterpenoid substances, and generally has various activities such as marrubiin having activities of relaxing blood vessels, protecting heart and relieving spasm and pain. Diterpene compounds which are separated from Copaifera by Erika Izumi and the like and have a structure similar to that of meadow fern acid have the function of resisting trypanosoma cruzi. (Izumi E., Ueda-Nakamura T., Veiga V.F., et al. Terphenes from Copaiferae purified in Vitro analytical and synthetic Activity [ J ]. Journal of Medicinal Chemistry 2012,55(7):2994-
Disclosure of Invention
The present invention aims to overcome the defects of the prior art and provide a silvestris acid derivative, a preparation method and an application thereof.
The technical scheme of the invention is as follows: the method comprises the following steps of taking silvestris acid separated from silvestris in the laboratory as a substrate, and reacting with different primary amines or secondary amines respectively to obtain 15 kinds of silvestris acid derivatives. After separation and structure identification, the derivatives thereof are researched for antibacterial and anticancer activities.
The purpose of the invention can be realized by the following technical scheme:
the sildenafil acid derivative has the following structural formula:
Figure BDA0001981814360000021
compound FB 1: (E) -N, N-diethyl-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-enamide;
Figure BDA0001981814360000022
compound FB 2: (E) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-1- (4-methylpiperazin-1-yl) pent-2-en-1-one;
Figure BDA0001981814360000031
compound FB 4: (E) -1- ([1,4 '-piperidin ] -1' -yl) -5- ([1R,4aS,6R,8aS ] -6-hydroxy 5,5,8a trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-en-1-one;
Figure BDA0001981814360000032
compound FB7 is (E) -1- (4- [ dimethylamino ] piperidin-1-yl) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-en-1-one;
Figure BDA0001981814360000033
compound FB 8: (E) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-N-propylpent-2-enamide;
Figure BDA0001981814360000034
compound FB 9: (E) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-N- (prop-2-) yn-1-yl) pent-2-enamide;
Figure BDA0001981814360000035
compound FB 10: (E) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-N-octylpent-2-enamide;
Figure BDA0001981814360000041
compound FB 11: (E) -N, N-dibenzyl-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-enamide;
Figure BDA0001981814360000042
compound FB 12: (E) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-N- (p-tolyl) pent-2-enamide;
Figure BDA0001981814360000043
compound FB 16: (E) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-1- (piperidin-1-onyl) pent-2-en-1-one;
Figure BDA0001981814360000044
compound FB 17: (E) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-1- (pyrrolidin-1-yl) pent-2-en-1-one;
Figure BDA0001981814360000045
compound FB 19: (E) -N- (4-chlorophenyl) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpentene-2-enamide;
Figure BDA0001981814360000051
compound FB 21: (E) -N-ethyl-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-enamide;
Figure BDA0001981814360000052
compound FB 22: (E) -5- ([1R,4aS,6R,8aS ] - -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -N, 3-dimethylpent-2-enamide;
Figure BDA0001981814360000053
compound FB23 was (E) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-1- (4-methylpiperazin-1-yl) pent-2-en-1-one.
The preparation method of the silvestris acid derivative comprises the following synthetic route:
Figure BDA0001981814360000054
wherein R1 and R2 are alkyl.
The method comprises the following specific steps:
(1) dissolving the meadowrue acid powder in dichloromethane, then sequentially adding diisopropylethylamine, a condensing agent and various primary amines or secondary amines, stirring at room temperature, after complete conversion, quenching with water for reaction, extracting, and evaporating to dryness;
(2) and (2) separating and purifying the substance obtained by evaporation in the step (1) by using a silica gel column chromatography, or dissolving the substance by using methanol, and separating and purifying by using a semi-preparative liquid phase to obtain a target product.
Preferably, in step (1): the condensing agent is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU).
Preferably, in step (1): the primary amine or the secondary amine is one of diethylamine, 4-methylpiperidine, 4-piperidylpiperidine, 4-dimethylaminopiperidine, N-propylamine, propynylamine, N-octylamine, dibenzylamine, p-toluidine, piperidine, pyrrolidine, p-chloroaniline, ethylamine, methylamine and N-methylpiperazine.
Preferably, in step (1): the reaction was checked for complete conversion using TLC plates.
Preferably, in step (1): the extraction was carried out using methylene chloride as solvent.
Use of the derivative of Amaranthus altissima acid in preparing antibacterial drugs and antitumor drugs is provided.
The invention has the following beneficial effects:
1. the synthesis process is simple and convenient, the synthesis efficiency is high, and the purity of the separated compound is high;
2. in the screening of antibacterial activity, most compounds show antibacterial activity, and the antibacterial activity to staphylococcus aureus is more obvious. FB1, FB4, FB7, FB9, FB10, FB11, FB23 (the inhibition zone is more than 8mm) have obvious antibacterial activity to colibacillus; FB1, FB2, FB7, FB9, FB12, FB16, FB17, FB21, FB22 (the inhibition zone is more than 8mm) have obvious antibacterial activity on staphylococcus aureus;
3. in the anticancer activity screening, most compounds show obvious antitumor activity, and FB4 and FB7 have good effects, and the IC of the compounds is used for 4 different human cancer cell lines including non-small cell lung cancer A549, breast cancer MCF-7, prostate cancer PC-3 and cervical cancer Hela50Both are about 10. mu.M, wherein the IC of compound FB5 on Hela cells507.39 μ M; FB19 IC of Hela against 3 different cancer cell lines, non-small cell lung carcinoma A549, breast carcinoma MCF-7, and cervical carcinoma50All have a concentration of about 10 μ M and have a toxicity of more than 100 μ M to human normal liver cell HL-7702, and FB22 has IC values for 3 different cancer cell lines, namely non-small cell lung cancer A549, breast cancer MCF-7 and prostate cancer PC-350Also all are about 10 mu M;
4. the silvestris acid derivative is expected to be applied to the preparation of antibacterial and antitumor drugs.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1
(E) Preparation of-N, N-diethyl-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-enamide (compound FB 1):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 22mL of diethylamine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, rotatably evaporating dichloromethane phase to dryness, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.78-5.74(m,1H,14-H),4.88-4.84(m,1H,17-H),4.53(s,1H,17-H),3.46-3.36(m,2H,a-C 2H),3.32(q,J＝7.1Hz,2H,a-C 2H),3.24(dt,J＝10.1,3.9Hz,1H,3-H),2.41(ddd,J＝12.8,4.1,2.4Hz,1H,7-H),2.23(ddd,J＝14.0,9.9,4.2Hz,1H,12-H),1.95(td,J＝14.9,13.6,6.0Hz,2H,7-H,12-H),1.90-1.88(d,J＝0.9Hz,3H,16-C 3H),1.81-1.48(m,7H,1-H,6-H,2-C 2H,11-C 2H,9-H),1.39(qd,J＝12.9,4.2Hz,1H,6-H),1.18(dd,J＝13.3,3.8Hz,1H,1-H),1.14(t,J＝7.1Hz,6H,2×b-C 3H),1.07(dd,J＝12.5,2.7Hz,1H,5-H),0.99(s,3H,18-H),0.77(s,3H,19-H),0.69(s,3H,20-H)；13C NMR(125MHz,CDCl3)δ168.05(C-15),149.52(C-13),147.95(C-8),118.02(C-14),106.92(C-17),78.96(C-3),55.99(C-9),54.82(C-5),42.64(a-CH2),39.64(C-12),39.54(C-10),39.29(C-4),38.76(a-CH2),38.33(C-7),37.22(C-1),28.46(C-18),28.07(C-2),24.17(C-6),21.74(C-11),18.59(C-16),15.54(C-19),14.66(C-20),14.53(b-CH3),13.34(b-CH3)。
yield: 65 percent. Melting point: 135-137 ℃. Mass spectrometry data: c24H41NO2[M+H]+Calculating the value: 376.3216, found: 376.3205.
example 2
(E) Preparation of 5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-1- (4-methylpiperazin-1-yl) pent-2-en-1-one (compound FB 2):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 12mg of 4-methylpiperidine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.70(s,1H,14-H),4.85(d,J＝1.6Hz,1H,17-H),4.57(d,J＝13.3Hz,1H,a-H),4.52(d,J＝1.6Hz,1H,17-H),3.88(d,J＝13.2Hz,1H,a-H),3.23(dd,J＝12.0,4.3Hz,1H,3-H),2.95(t,J＝12.5Hz,1H,a-H),2.58(t,J＝12.8Hz,1H,a-H),2.40(dd,J＝9.3,2.6Hz,1H,7-H),2.22(ddd,J＝13.9,9.7,3.8Hz,1H,12-H),1.98-1.87(m,2H,7-H,12-H),1.86(s,3H,16-C 3H),1.80-1.50(m,12H,1-H,2-C 2H,6-H,9-H,11-C 2Hand 2×b-C 2H,c-H),1.43(qd,J＝12.9,4.3Hz,1H,6-H),1.19-1.12(m,1H,1-H),1.07(dd,J＝12.5,2.5Hz,1H,5-H),0.98(s,3H,19-C 3H),0.94(d,J＝6.5Hz,3H,d-C 3H),0.77(s,3H,19-C 3H),0.68(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ167.53(C-15),148.04(C-13),147.92/147.89(C-8),118.39(C-14),106.94(C-17),78.95(C-3),56.03/55.97(C-9),54.84(C-5),46.84(C-12),41.75(a-CH2),39.53(C-10),39.28(C-4),38.37(a-CH2),38.32(C-7),37.23(C-1),35.09/34.97(b-CH2),34.03(b-CH2),31.34(c-CH2),28.46(C-18),28.06(C-2),24.15(C-6),21.91(d-CH2),21.67/21.62(C-11),18.68/18.63(C-16),15.53(C-19),14.66(C-20).
yield: 70%, melting point: 148 ℃ -150 ℃, mass spectrometry data: c26H43NO2[M+H]+Calculating the value: 402.3372, found: 402.3344.
example 3
(E) Preparation of-1- ([1,4 '-piperidin ] -1' -yl) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-en-1-one (compound FB 4):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 25.3mg of 4-piperidyl piperidine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation drying on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.71(s,1H,14-H),4.85(s,1H,17-H),4.67(d,J＝12.8Hz,1H,a-H),4.52(s,1H,17-H),3.96(d,J＝13.5Hz,1H,a-H),3.23(dd,J＝11.7,4.4Hz,1H,3-H),2.95(t,J＝12.8Hz,1H,a-H),2.59-2.37(m,7H,a-H,7-H,c-H,2×d-C 2H),2.22(ddd,J＝14.1,9.6,4.1Hz,1H,12-H),1.99-1.33(m,23H,7-H,12-H,1-H,16-CH3,6-CH2,9-H,11-CH2,2×b-C 2H,c-H,2×e-C 2H,f-C 2H),1.15(t,J＝13.4Hz,1H,1-H),1.06(dd,J＝2.5,2.7Hz,1H,5-H),0.98(s,3H,18-C 3H),0.76(s,3H,19-C 3H),0.68(s,3H,20-C 3H).13C NMR(126MHz,CDCl3)δ167.41(C-15),148.62/148.51(C-13),147.91(C-8),118.08/117.93(C-14),106.94(C-17),78.92(C-3),62.81(c-CH2),56.05/55.98(C-9),54.86(C-5),50.41(2×d-CH2),46.17(C-12),41.14(a-CH2),39.54(C-10),39.28(C-4),38.43/38.38(a-CH2,38.33(C-7),37.25(C-1),29.28/29.20(b-CH2),28.46(C-18),28.07(C-2),27.89/27.83(b-CH2),26.51(2×e-CH2),24.88(f-CH2),24.15(C-6),21.68/21.63(C-11),18.72/18.67(C-16),15.54(C-19),14.66(C-20).
yield: 65%, melting point: 146 ℃ to 148 ℃, mass spectrometry data: c30H50N2O2[M+H]+Calculating the value: 471.3951, found: 471.3927.
example 4
(E) Preparation of-1- (4- [ dimethylamino ] piperidin-1-yl) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-en-1-one (compound FB 7):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 19.3mg of 4-dimethylaminopiperidine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.69(s,1H,14-H),4.83(s,1H,17-H),4.61(d,J＝13.3Hz,1H,a-H),4.50(s,1H,17-H),3.93(d,J＝13.1Hz,1H,a-H),3.20(dd,J＝11.7,4.4Hz,1H,3-H),3.01-2.91(m,1H,a-H),2.59(t,J＝12.4Hz,1H,a-H),2.38(d,J＝12.6Hz,1H,7-H),2.32(ddt,J＝11.2,7.7,3.5Hz,1H,c-H),2.25(s,6H,2×d-C 3H),2.20(ddd,J＝13.9,4.4Hz,1H,12-H),1.91-1.82(m,3H,7-H,12-H,1-H),1.81(s,3H,16-CH3),1.79-1.45(m,9H,6-H,9-H,11-CH2and 2×b-CH2,c-H),1.41-1.31(m,1H,6-H),1.13(t,J＝13.2Hz,1H,1-H),1.04(d,J＝11.1Hz,1H,5-H),0.96(s,3H,18-C 3H),0.74(s,3H,19-C 3H),0.66(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ167.40(C-15),148.78/148.64(C-13),147.84(C-8),117.92/117.77(C-14),106.86(C-17),78.74(C-3),62.27(c-CH2),55.95(C-9),54.82(C-5),45.67(C-12),41.73(2×a-CH2),40.64(d-CH2),39.48(C-10),39.23(C-4),38.37/38.32(d-CH2),38.27(C-7),37.20(C-1),29.50/29.42(b-CH2),28.43(C-18),28.12/28.04(C-2),28.01(b-CH2),24.10(C-6),21.62/21.57(C-11),18.67/18.60(C-16),15.51(C-19),14.60(C-20).
yield: 63%, melting point: 131 ℃ -133 ℃, mass spectrometry data: c27H46N2O2[M+H]+Calculating the value: 431.3638, found: 431.3624.
example 5
(E) Preparation of-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-N-propylpent-2-enamide (Compound FB 8):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 8.9mg of n-propylamine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.49(s,1H,14-H),5.38(s,1H,NH),4.85(s,1H,17-H),4.51(s,1H,17-H),3.28-3.20(m,3H,3-H,a-C 2H),2.40(d,J＝13.0Hz,1H,7-H),2.27-2.18(m,1H,12-H),2.13(s,3H,16-CH3),1.99-1.85(m,2H,7-H,12-H),1.81-1.65(m,4H,1-H,6-H,2-C 2H),1.65-1.46(m,5H,9-H,11-C 2H,b-C 2H),1.42-1.35(m,1H,6-H),1.20-1.11(m,1H,1-H),1.07(dd,J＝12.5,2.8Hz,1H,5-H),0.99(s,3H,18-C 3H),0.93(t,J＝7.4Hz,3H,c-C 3H),0.77(s,3H,19-C 3H),0.68(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ167.34(C-15),154.63(C-13),147.95(C-8),118.14(C-14),106.88(C-17),78.92(C-3),55.97(C-9),54.72(C-5),41.10(a-CH2),39.62(C-12),39.54(C-10),39.28(C-4),38.30(C-7),37.19(C-1),28.44(C-18),28.05(C-2),24.16(C-6),23.13(b-CH2),21.82(C-11),18.42(C-16),15.54(C-19),14.65(C-20),11.59(c-CH2).
yield: 75%, melting point: 194 ℃ to 196 ℃, mass spectrometry data: c23H39NO2[M+H]+Calculating the value: 362.3059, found: 362.3036.
example 6
(E) Preparation of-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-N- (prop-2-) yn-1-yl) pent-2-enamide (compound FB 9):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 8.26mg of propynylamine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, evaporating the dichloromethane phase by rotation to dryness, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.54(t,J＝5.9Hz,1H,NH),5.50(q,J＝1.3Hz,1H,14-H),4.85(t,J＝1.6Hz,1H,17-H),4.50(d,J＝1.7Hz,1H,17-H),4.08(dd,J＝5.2,2.6Hz,2H,NH-C 2H-C≡),3.25(dd,J＝11.8,4.4Hz,1H,3-H),2.40(ddd,J＝12.8,4.3,2.4Hz,1H,7-H),2.28-2.22(m,1H,12-H),2.22(t,J＝2.6Hz,1H,-C≡CH),2.15(d,J＝1.3Hz,3H,16-C 3H),1.92(tt,J＝15.9,7.8Hz,2H,7-H,12-H),1.80-1.44(m,7H,1-H,2-C 2H,6-H,9-H,11-C 2H),1.42-1.34(m,1H,6-H),1.15(td,J＝13.2,3.7Hz,1H,1-H),1.07(dd,J＝12.5,2.8Hz,1H,5-H),0.99(s,3H,18-C 3H),0.77(s,3H,19-C 3H),0.68(s,3H,20-C 3H).13C NMR(125CDCl3)δ166.62(C-15),156.69(C-13),147.89(C-8),117.10(C-14),106.91(C-17),80.02(-NH-C≡),78.90(C-3),71.54(-C≡CH),55.91(C-9),54.70(C-5),39.70(C-12),39.54(C-10),39.28(C-4),38.28(C-7),37.19(C-1),29.04(NH-CH2-C≡),28.43(C-18),28.04(C-2),24.15(C-6),21.78(C-11),18.58(C-16),15.54(C-19),14.65(C-20).
yield: 72%, melting point: 138 ℃ -140 ℃, mass spectrometry data: c23H35NO2[M+H]+Calculating the value: 358.2746, found: 358.2736.
example 7
(E) Preparation of-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-N-octylpent-2-enamide (compound FB 10):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 19.4mg of n-octylamine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.48(d,J＝1.8Hz,1H,14-H),5.43(t,J＝6.1Hz,1H,NH),4.84(t,J＝1.7Hz,1H,17-H),4.50(d,J＝1.9Hz,1H,17-H),3.29-3.20(m,3H,3-H,NHC 2H),2.38(ddd,J＝12.8,4.2,2.3Hz,1H,7-H),2.21(ddd,J＝14.0,9.9,4.0Hz,1H,12-H),2.12(s,3H,16-C 3H),1.97-1.83(m,2H,7-H,12-H),1.78-1.45(m,9H,1-H,2-CH2,6-H,9-H,11-CH2and C 2Hof octylamine moiety),1.37(dd,J＝12.9,4.2Hz,1H,6-H),1.32-1.20(m,10H,5×C 2Hof octylamine moiety),1.14(td,J＝13.3,3.7Hz,1H,1-H),1.06(dd,J＝12.5,2.7Hz,1H,5-H),0.98(s,3H,18-C 3H),0.89-0.83((t,J＝7.0Hz,3H,omega-C 3Hof octylamine moiety),0.75(s,3H,19-C 3H),0.67(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ167.24(C-15),154.49(C-13),147.93(C-8),118.17(C-14),106.86(C-17),78.86(C-3),55.94(C-9),54.70(C-5),39.61(C-12),39.52(C-10),39.40(NH-CH2-),39.26(C-4),38.28(C-7),37.17(C-1),31.92,29.88,29.42,29.34,28.42(C-18),28.03(C-2),27.15,24.14(C-6),22.76,21.80(C-11),18.39(C-16),15.54(C-19),14.64(C-20),14.21(omega-CH3of octylamine moiety).
yield: 85%, melting point: 113 ℃ -115 ℃, mass spectrometry data: c28H49NO2[M+H]+Calculating the value: 432.3842, found: 432.3832.
example 8
(E) Preparation of-N, N-dibenzyl-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-enamide (compound FB 11):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 29.6mg of dibenzylamine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ7.38-7.34(m,2H,Ph),7.34-7.29(m,3H,Ph),7.29-7.26(m,1H,Ph),7.26-7.22(m,2H,Ph),7.18-7.12(m,2H,Ph),5.88(s,1H,14-H),4.80(q,J＝1.5Hz,1H,17-H),4.66(d,J＝14.7Hz,1H,C 2HN),4.52(d,J＝14.8Hz,1H,C 2HN),4.47-4.42(m,3H,C 2HN&17-H),3.14(dd,J＝11.7,4.4Hz,1H,3-H),2.37-2.29(m,1H,7-H),2.21(ddd,J＝13.6,9.3,3.9Hz,1H,12-H),2.00(s,3H,16-C 3H),1.93(dt,J＝14.6,7.7Hz,1H,7-H),1.82(td,J＝13.0,5.1Hz,1H,12-H),1.72-1.41(m,7H,1-H,2-CH2,6-H,9-H,11-C 2H),1.33(dd,J＝12.9,4.2Hz,1H,6-H),1.06(td,J＝13.3,3.8Hz,1H,1-H),0.95-0.90(m,4H,5-H&18-C 3H),0.74(s,3H,19-C 3H),0.63(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ169.16(C-15),151.57(C-13),147.76(C-8),137.62(Ph-C),136.99(Ph-C),129.01(2×Ph-CH),128.70(2×PhCH),128.52(2×PhCH),127.73(PhC),127.47(PhC),126.95(2×PhCH),117.57(C-14),106.94(C-17),78.81(C-3),55.68(C-9),54.62(C-5),50.65(Ph-CH2N),47.39(C-12),39.45(C-10),39.21(C-4),38.66(Ph-CH2N),38.22(C-7),37.14(C-1),28.33(C-18),28.00(C-2),24.10(C-6),21.56(C-11),18.92(C-16),15.53(C-19),14.57(C-20).
yield: 80%, melting point: 178 ℃ -180 ℃, mass spectrometry data: c34H45NO2[M+H]+Calculating the value: 500.3529, found: 500.3512.
example 9
(E) Preparation of-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-N- (p-tolyl) pent-2-enamide (compound FB 12):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 16.1mg of p-toluidine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3and methanol-d4)δ7.41(d,J＝8.4Hz,2H,2×PhCH),7.08(d,J＝8.3Hz,2H,2×PhCH),5.81(s,1H,14-H),4.87(s,1H,17-H),4.56(s,1H,17-H),4.44(s,1H,NH),3.22-3.16(m,1H,3-H),2.44-2.36(m,1H,7-H),2.31(dd,J＝10.0,3.8Hz,1H,12-H),2.28(s,3H,Ph-C 3H),2.17(s,3H,16-C 3H),2.03-1.93(m,2H,7-H,12-H),1.83-1.51(m,7H,1-H,2-C 2H,6-H,9-H,11-C 2H),1.39(qd,J＝13.0,4.4Hz,1H,6-H),1.19(td,J＝12.6,5.1Hz,1H,1-H),1.10(dd,J＝12.5,2.8Hz,1H,5-H),0.97(s,3H,18-C 3H),0.75(s,3H,19-C 3H),0.71(s,3H,20-C 3H).13C NMR(125MHz,CDCl3and methanol-d4)δ167.45(C-15),157.21(C-13),148.82(C-8),137.01(PhC),134.21(PhC),129.90(2×PhCH),121.00(2×PhCH),119.19(C-14),107.13(C-17),79.13(C-3),56.77(C-9),55.61(C-5),40.60(C-12),40.14(C-10),39.89(C-4),38.97(C-7),38.03(C-1),28.72(C-18),28.23(C-2),24.89(C-6),22.60(C-11),20.97(Ph-CH3),18.77(C-16),15.97(C-19),14.95(C-20).
yield: 60%, melting point: 226 ℃ -228 ℃, mass spectrometry data: c27H39NO2[M+H]+Calculating the value: 410.3059, found: 410.3049.
example 10
(E) Preparation of-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-1- (piperidin-1-onyl) pent-2-en-1-one (compound FB 16):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 12.8mg of piperidine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, evaporating dichloromethane phase by rotation to dryness, separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.48(d,J＝1.8Hz,1H,14-H),5.43(t,J＝6.1Hz,1H,NH),4.84(t,J＝1.7Hz,1H,17-H),4.50(d,J＝1.9Hz,1H,17-H),3.29-3.20(m,3H,3-H,NHC 2H),2.38(ddd,J＝12.8,4.2,2.3Hz,1H,7-H),2.21(ddd,J＝14.0,9.9,4.0Hz,1H,12-H),2.12(s,3H,16-C 3H),1.97-1.83(m,2H,7-H,12-H),1.78-1.45(m,9H,1-H,2-CH2,6-H,9-H,11-CH2and C 2Hof octylamine moiety),1.37(dd,J＝12.9,4.2Hz,1H,6-H),1.32-1.20(m,10H,5×CH2of octylamine moiety),1.14(td,J＝13.3,3.7Hz,1H,1-H),1.06(dd,J＝12.5,2.7Hz,1H,5-H),0.98(s,3H,18-C 3H),0.89-0.83((t,J＝7.0Hz,3H,omega-C 3Hof octylamine moiety),0.75(s,3H,19-C 3H),0.67(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ167.24(C-15),154.49(C-13),147.93(C-8),118.17(C-14),106.86(C-17),78.86(C-3),55.94(C-9),54.70(C-5),39.61(C-12),39.52(C-10),39.40(NH-CH2-),39.26(C-4),38.28(C-7),37.17(C-1),31.92,29.88,29.42,29.34,28.42(C-18),28.03(C-2),27.15,24.14(C-6),22.76,21.80(C-11),18.39(C-16),15.54(C-19),14.64(C-20),14.21(omega-CH3of octylamine moiety).
yield: 68%, melting point: 167 ℃ -169 ℃, mass spectrometry data: c25H41NO2[M+H]+Calculating the value: 388.3216, found: 388.3208.
example 11
(E) Preparation of-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-1- (pyrrolidin-1-yl) pent-2-en-1-one (compound FB 17):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 10.7mg of pyrrolidine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.74(s,1H,14-H),4.86(s,1H,17-H),4.54(s,1H,17-H),3.50(t,J＝6.4Hz,1H,a-C 2H),3.42(d,J＝6.4Hz,1H,a-C 2H),3.25(dd,J＝11.8,4.3Hz,1H,3-H),2.44-2.37(m,1H,7-H),2.28-2.20(m,1H,12-H),2.05(s,3H,16-C 3H),1.95-1.91(m,4H,2×b-C 2H),1.87-1.83(m,2H,7-H,12-H),1.80-1.47(m,7H,1-H,2-C 2H,6-H,9-H,11-C 2H),1.43-1.33(m,2H,6-H),1.17(dd,J＝15.4,11.2Hz,1H,1-H),1.07(d,J＝12.7Hz,1H,5-H),0.99(s,3H,18-C 3H),0.77(s,3H,19-C 3H),0.68(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ166.65(C-15),152.78(C-13),147.95(C-8),117.69(C-14),106.89(C-17),78.90(C-3),55.90(C-9),54.76(C-5),47.04(a-CH2),45.47(a-CH2),39.52(C-12),39.43(C-10),39.27(C-4),38.32(C-7),37.18(C-1),28.44(C-18),28.06(C-2),26.33(b-CH2),24.55(b-CH2),24.16(C-6),21.84(C-11),18.62(C-16),15.54(C-19),14.66(C-20).
yield: 82%, melting point: 151 ℃ -153 ℃, mass spectrometry data: c24H39NO2[M+H]+Calculating the value: 374.3059, found: 374.3036.
example 12
(E) Preparation of (E) -N- (4-chlorophenyl) -5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpentene-2-enamide (Compound FB 19):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 19.2mg of parachloroaniline, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ7.47(d,J＝8.2Hz,2H,2×PhCH),7.24(s,2H,2×PhCH),7.07(s,1H,NH),5.62(s,1H,14-H),4.86(s,1H,17-H),4.51(s,1H,17-H),3.24(dd,J＝11.8,4.3Hz,1H,3-H),2.40(dt,J＝13.6,3.3Hz,1H,7-H),2.32-2.24(m,1H,12-H),2.19(s,3H,16-C 3H),1.98-1.92(m,2H,7-H,12-H),1.80-1.48(m,7H,1-H,2-C 2H,6-H,9-H,11-C 2H),1.38(qd,J＝12.9,4.3Hz,1H,6-H),1.15(td,J＝13.2,2.8Hz,1H,1-H),1.07(dd,J＝12.6,2.8Hz,1H,5-H),0.98(s,3H,18-C 3H),0.76(s,3H,19-C 3H),0.68(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ165.07(C-15),158.54(C-13),147.91(C-8),137.01(PhC-NH),129.11(4×PhCH),121.01(PhC-Cl),117.77(C-14),106.94(C-17),78.90(C-3),55.96(C-9),54.75(C-5),39.97(C-12),39.58(C-10),39.30(C-4),38.31(C-7),37.24(C-1),28.44(C-18),28.06(C-2),24.16(C-6),21.85(C-11),18.74(C-16),15.55(C-19),14.67(C-20).
yield: 88%, melting point: 202 ℃ -204 ℃, mass spectrometry data: c26H36ClNO2[M+H]+Calculating the value: 430.2513, found:430.2493。
example 13
(E) Preparation of-N-ethyl-5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methylpent-2-enamide (compound FB 21):
dissolving 32mg of silvestris acid in 5ml of dichloromethane, adding 19ml of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 12mg of ethylamine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.48(s,1H,14-H),5.37(s,1H,NH),4.85(s,1H,17-H),4.50(s,1H,17-H),3.36-3.27(m,2H,NHC 2H),3.25(dd,J＝11.7,4.3Hz,1H,3-H),2.39(dt,J＝12.4,3.4Hz,1H,7-H),2.22(ddd,J＝14.0,10.0,4.1Hz,1H,12-H),2.13(s,3H,16-C 3H),1.99-1.83(m,2H,7-H,12-H),1.81-1.44(m,7H,1-H,2-C 2H,6-H,9-H,11-C 2H),1.37(td,J＝12.9,4.2Hz,,1H,6-H),1.19-1.10(m,4H,1-H and NHCH2C 3H),1.07(dd,J＝12.4,2.5Hz,1H,5-H),0.98(s,3H,18-C 3H),0.76(s,3H,19-C 3H),0.68(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ167.26(C-15),154.70(C-13),147.94(C-8),118.08(C-14),106.87(C-17),78.90(C-3),55.93(C-9),54.70(C-5),39.61(C-12),39.52(C-10),39.27(C-4),38.28(C-7),37.18(C-1),34.19(NHCH2CH3),28.42(C-18),28.03(C-2),24.14(C-6),21.81(C-11),18.40(C-16),15.54(C-19),15.08(NHCH2CH3),14.64(C-20).
yield: 77%, melting point: 192 ℃ -194 ℃, mass spectrometry data: c22H37NO2[M+H]+Calculating the value: 348.2903, found: 348.2880.
example 14
(E) Preparation of-5- ([1R,4aS,6R,8aS ] - -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -N, 3-dimethylpent-2-enamide (compound FB 22):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 10mg of methylamine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, rotatably evaporating dichloromethane phase to dryness, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.49(s,1H,14-H),5.45(s,1H,NH),4.84(s,1H,17-H),4.50(s,1H,14-H),3.24(dd,J＝11.8,4.3Hz,1H,3-H),2.82(d,J＝4.9Hz,3H,NHC 3H),2.39(dt,J＝12.7,3.1Hz,1H,7-H),2.24-2.17(m,1H,12-H),2.13(s,3H,16-C 3H),1.98-1.85(m,2H,7-H,12-H),1.79-1.45(m,7H,1-H,2-C 2H,6-H,9-H,11-C 2H),1.37(qd,J＝13.0,4.3Hz,1H,6-H),1.14(td,J＝13.4,3.8Hz,1H,1-H),1.06(dd,J＝12.6,2.8Hz,1H,5-H),0.98(s,3H,18-C 3H),0.76(s,3H,19-C 3H),0.67(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ168.02(C-15),154.72(C-13),147.93(C-8),117.92(C-14),106.85(C-17),78.87(C-3),55.87(C-9),54.70(C-5),39.56(C-12),39.26(C-10),38.74(C-4),38.28(C-7),37.17(C-1),28.42(C-18),28.02(C-2),26.11(-NHCH3),24.14(C-6),21.77(C-11),18.37(C-18),15.53(C-19),14.63(C-20).
yield: 75%, melting point: 134 ℃ -136 ℃, mass spectrometry data: c21H35NO2[M+H]+Calculating the value: 334.2746found, measurement: 334.2728.
example 15
(E) Preparation of 5- ([1R,4aS,6R,8aS ] -6-hydroxy-5, 5,8 a-trimethyl-2-methylenedecahydronaphthalen-1-yl) -3-methyl-1- (4-methylpiperazin-1-yl) pent-2-en-1-one (compound FB 23):
dissolving 32mg of silvestris acid in 5mL of dichloromethane, adding 19mL of diisopropylethylamine and 47mg of condensing agent HATU, finally adding 15mg of N-methylpiperazine, uniformly mixing, stirring at room temperature for 2h, adding water after the reaction is completed to stop the reaction, then extracting with dichloromethane, carrying out rotary evaporation on the dichloromethane phase, and separating and purifying to obtain the target compound.
The nuclear magnetic data are as follows:1H NMR(500MHz,CDCl3)δ5.71(s,1H,14-H),4.86(s,1H,17-H),4.52(s,1H,17-H),3.73-3.64(m,2H,a-C 2H),3.53-3.48(m,2H,a-C 2H),3.24(dd,J＝11.6,4.4Hz,1H,3-H),2.44-2.34(m,5H,7-H and 2×b-C 2H),2.31(s,3H,c-C 3H),2.23(ddd,J＝13.8,9.8,3.7Hz,1H,12-H),1.94(td,J＝16.5,14.5,6.4Hz,2H,7-H,12-H),1.86(s,3H,16-CH3),1.82-1.46(m,7H,1-H,2-CH2,6-H,9-H,11-CH2),1.43-1.33(m,2H,6-H),1.15(td,J＝13.1,3.8Hz,1H,1-H),1.06(dd,J＝12.5,2.8Hz,1H,5-H),0.99(s,3H,18-C 3H),0.77(s,3H,19-C 3H),0.69(s,3H,20-C 3H).13C NMR(125MHz,CDCl3)δ167.50(C-15),149.53(C-13),147.90(C-8),117.48(C-14),106.93(C-17),78.91(C-3),56.04(C-9),55.49(b-CH2),54.91(b-CH2),54.81(C-5),46.23(a-CH2),46.18(C-12),41.22(a-CH2),39.54(C-10),39.28(C-4),38.53(c-CH3),38.31(C-7),37.22(C-1),28.46(C-18),28.04(C-2),24.13(C-6),21.69(C-11),18.79(C-16),15.55(C-19),14.65(C-20).
yield: 80%, melting point: 140 ℃ -142 ℃, mass spectrometry data: c25H42N2O2[M+H]+Calculating the value: 403.3325, found: 403.3301.
the anacardic acid and 15 synthesized derivatives are used for the research of the bacteriostatic activity and the anti-tumor activity.
1. Experimental procedure for bacteriostatic activity
(1) Strain activation and dilution
Taking the thawed escherichia coli liquid, placing the escherichia coli liquid in 10mL of LB liquid culture medium sterilized and cooled by high-pressure steam, and shaking the liquid at the constant temperature of 37 ℃ for 24 hours to obtain a bacterial suspension. A certain amount of the bacterial suspension was taken out, and the OD value at 600nm was measured, and the bacterial suspension was diluted with LB medium to OD 0.8, and the bacterial concentration was about 1X 108 cfu/mL. The resulting bacteria were then prepared at a concentration of about 6X 106cfu/mL for use.
Scraping staphylococcus aureus lawn on the nutrient medium sterilized and cooled by high-pressure steam, adding a proper amount of normal saline, and standing and culturing at constant temperature of 37 ℃ for 24 hours to obtain the bacterial liquid. The OD value of a certain bacterial liquid under 450nm is measured, and the bacterial liquid is diluted to OD 0.8 by sterilized normal saline, and the bacterial concentration is about 1 × 108 cfu/mL. The resulting bacteria were then prepared at a concentration of about 6X 106cfu/mL for use.
(2) Bacteriostatic ring
The LB culture medium and the nutrition culture medium are sterilized by high pressure steam, cooled to 40-50 ℃, shaken up and rapidly subpackaged in a culture dish, and cooled and solidified on a super clean bench.
Sterilized round filter paper sheets (r 3mm, d 6mm) were attached to the corresponding medium surface, and 4.5. mu.L of each sample (concentration: 100. mu.M) of sterile solution was pipetted onto the filter paper sheets, using DMSO as a blank and kanamycin at the same concentration as a positive control. After being cultured in a constant temperature incubator at 37 ℃ for 24 hours, the radius of the inhibition zone is observed and measured. All the steps are operated in a sterile environment, and each group is divided into three groups, and the average value is obtained in parallel.
(3) Measurement index
And (3) measuring the diameter of the inhibition zone: the diameter d of the zone of inhibition was measured using a ruler in a cross-hatch method and expressed in mm, and the mean values were determined for each set of three replicates, the results of which are given in table 1.
TABLE 1 inhibitory Activity of the Compound (FB-FB23) against Escherichia coli and Staphylococcus aureus
Figure BDA0001981814360000181
Figure BDA0001981814360000191
2. Experimental procedure for antitumor Activity
(1) Cells in log phase were collected, cell suspension concentration was adjusted, 100. mu.L was added to each well, and the test cells were plated to 1000-10000 wells, (the marginal wells were filled with sterile PBS).
(2)5％CO2Incubation at 37 ℃ until cell monolayer is confluent at the bottom of well (96-well flat bottom plate), and addition of drug in concentration gradient, as a ruleThe cells can be applied after adhering to the wall, or two hours or half a day, and are usually spread in the afternoon of the previous day and applied in the morning of the next day. Typically 5-7 gradients, 10. mu.L per well, 3-5 multiple wells.
(3)5％CO2Incubation was carried out at 37 ℃ for 72 hours and observed under an inverted microscope.
(4) mu.L of MTT solution (5mg/ml, i.e., 0.5% MTT) was added to each well and incubation was continued for 4 h. If the drug reacts with MTT, the culture medium can be discarded after centrifugation, and the MTT-containing culture medium can be added after 2-3 times of washing with PBS carefully.
(5) Add 100. mu.L of triple liquid into each well, put 5% CO2The culture was incubated at 37 ℃ overnight to dissolve the crystals sufficiently. The absorbance of each well was measured at OD 570nm in an ELISA detector.
(6) And setting a zero setting hole (culture medium, MTT and dimethyl sulfoxide) and a control hole (cells, a drug dissolving medium with the same concentration, a culture solution, MTT and dimethyl sulfoxide).
IC of each compound on non-small cell lung cancer A549, breast cancer MCF-7, prostatic cancer PC-3 and cervical cancer Hela, and normal human liver cell HL-770250As shown in table 2.
TABLE 2 results of antitumor Activity of Compound (FB-FB23)
Figure BDA0001981814360000192
Figure BDA0001981814360000201
The invention takes the silvestris acid as a substrate, and reacts with various amines under the action of a condensing agent to obtain a series of silvestris acid amide derivatives, and the compounds are structurally identified by physicochemical properties and a plurality of spectrum methods. In the screening of antibacterial activity, the inhibition effect of the meadowsweet acid and the 15 synthesized derivatives on gram-positive bacteria, i.e., Staphylococcus aureus (Staphylococcus aureus) and Escherichia coli (Escherichia coli), was examined by using kanamycin as a positive control. In the screening of anticancer activity, camptothecin is used as a positive control, and the inhibition effect on non-small cell lung cancer A549, breast cancer MCF-7, prostatic cancer PC-3, cervical cancer Hela and normal human liver cells is determined by adopting an MTT method.
The bacteriostatic result shows that: most compounds show bacteriostatic activity, and the bacteriostatic activity on staphylococcus aureus is more obvious. FB1, FB4, FB7, FB9, FB10, FB11, FB23 (the inhibition zone is greater than 8mm) have obvious antibacterial activity to Escherichia coli. FB1, FB2, FB7, FB9, FB12, FB16, FB17, FB21, FB22 (the inhibition zone is >8mm) have obvious antibacterial activity on staphylococcus aureus.
The antitumor results show that most compounds show obvious antitumor activity, the FB4 and FB7 have good effects, and the IC of the compounds is used for treating 4 different human cancer cell lines including non-small cell lung cancer A549, breast cancer MCF-7, prostate cancer PC-3 and cervical cancer Hela50Both are about 10. mu.M, wherein the IC of compound FB5 on Hela cells50It was 7.39. mu.M. FB19 IC of Hela against 3 different cancer cell lines, non-small cell lung carcinoma A549, breast carcinoma MCF-7, and cervical carcinoma50All have a concentration of about 10 μ M and have a toxicity of more than 100 μ M to human normal liver cell HL-7702, and FB22 has IC values for 3 different cancer cell lines, namely non-small cell lung cancer A549, breast cancer MCF-7 and prostate cancer PC-350They were all about 10. mu.M.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (5)

1. The silvestris acid derivative is characterized by having a structural formula as follows:
Figure 438987DEST_PATH_IMAGE001
。
2. the method for preparing silvestris acid derivative according to claim 1, wherein the method for preparing the silvestris acid derivative comprises the following steps:
(1) dissolving the meadowrue acid powder in dichloromethane, then sequentially adding diisopropylethylamine, a condensing agent and primary amine or secondary amine, stirring at room temperature, after complete conversion, quenching reaction with water, extracting, and evaporating to dryness;
(2) separating and purifying the substance obtained by evaporating to dryness in the step (1) by silica gel column chromatography, or dissolving by using methanol, and separating and purifying by using a semi-preparative liquid phase to obtain a target product.
3. The method for preparing sillagonic acid derivative according to claim 2, wherein in step (1): the condensing agent is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
4. The method for preparing sillagonic acid derivative according to claim 2, wherein in step (1): the primary amine or the secondary amine is one of diethylamine, 4-methylpiperidine, 4- (1-piperidyl) piperidine, 4-dimethylaminopiperidine, N-propylamine, propynylamine, N-octylamine, dibenzylamine, p-toluidine, piperidine, pyrrolidine, p-chloroaniline, ethylamine, methylamine and N-methylpiperazine.
5. Use of the silvestris acid derivative according to claim 1 for preparing bacteriostatic drugs and antitumor drugs.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001048841A (en) * 1999-08-02 2001-02-20 Toagosei Co Ltd Hydronaphthalene derivative and its amide compound
EP1975612A1 (en) * 2007-03-29 2008-10-01 Deutsches Institut für Ernährungsforschung Potsdam -Rehbrücke-Stiftung des öffentlichen Rechts- Vertreten durch den Stiftungsvorstand Agonists of bitter taste receptors and uses thereof
WO2013151161A1 (en) * 2012-04-06 2013-10-10 学校法人東京理科大学 Novel compound, method for producing same and antitumor agent
CN103585196A (en) * 2013-10-31 2014-02-19 济南星懿医药技术有限公司 Application of silvery aleuritopteris herb extract in preparation of anticancer drugs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001048841A (en) * 1999-08-02 2001-02-20 Toagosei Co Ltd Hydronaphthalene derivative and its amide compound
EP1975612A1 (en) * 2007-03-29 2008-10-01 Deutsches Institut für Ernährungsforschung Potsdam -Rehbrücke-Stiftung des öffentlichen Rechts- Vertreten durch den Stiftungsvorstand Agonists of bitter taste receptors and uses thereof
WO2013151161A1 (en) * 2012-04-06 2013-10-10 学校法人東京理科大学 Novel compound, method for producing same and antitumor agent
CN103585196A (en) * 2013-10-31 2014-02-19 济南星懿医药技术有限公司 Application of silvery aleuritopteris herb extract in preparation of anticancer drugs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Copalic acid analogs down-regulate androgen receptor and inhibit small chaperone protein;Bin Su等;《Bioorganic & Medicinal Chemistry Letters》;20171231;第27卷;第2292-2295页 *
Engineering of Streptomyces platensis MA7339 for Overproduction of Platencin and Congeners;Ben Shen等;《Org. Lett.》;20101231;第12卷(第8期);第1744-1747页 *

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