CN113754625B - Sesquiterpene coumarin compound and preparation method and application thereof - Google Patents

Sesquiterpene coumarin compound and preparation method and application thereof Download PDF

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CN113754625B
CN113754625B CN202010483912.4A CN202010483912A CN113754625B CN 113754625 B CN113754625 B CN 113754625B CN 202010483912 A CN202010483912 A CN 202010483912A CN 113754625 B CN113754625 B CN 113754625B
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sesquiterpene
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methanol
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CN113754625A (en
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李宁
周地
侯悦
陈刚
郭婷婷
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to the technical field of medicines, relates to a preparation method and application of a sesquiterpene coumarin compound, and particularly relates to a sesquiterpene coumarin compound structure, a preparation method and application of the sesquiterpene coumarin compound structure in the field of preparation of medicines for preventing and treating neurodegenerative diseases, wherein the compound has a structural general formula shown in the specification, wherein R is1–R7As described in the claims and specification.

Description

Sesquiterpene coumarin compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a sesquiterpene coumarin compound and a preparation method and application thereof.
Background
Resina Ferulae is resin of Ferula sinkiangensis (Ferula sinkiangensis K.M.Shen) or Ferula fukanensis (Ferula fukanensis K.M.Shen) belonging to Ferula (Umbelliferae) family. Ferula species have over 150 species in the world, mainly distributed in the southern mediterranean region of Europe and northern Africa, and also distributed in the Central Asia region of Iran, africa, soviet Union and Siberian regions, as well as in India, pakistan, etc. The Chinese asafetida is distributed mainly in Xinjiang area.
Ferula asafetida has the effects of removing food retention, eliminating mass, dissipating mass and killing parasites, and is used for treating food retention, blood stasis, abdominal mass and abdominal pain due to parasitic infestation. Clinically, the compound containing asafetida is mainly used for treating some gastrointestinal related diseases: such as asafetida pill, for treating meat stagnation; the asafetida and galangal pills are taken for a long time to treat middle-jiao cold accumulation, regurgitation and vomiting and diet reduction; the asafetida middle energizer regulating pill is used for treating cold attacking stabbing pain, heart and abdomen fullness, stomach cold vomiting and regurgitation, and umbilical and abdomen pinching pain. Modern pharmacological research shows that the asafetida has wide pharmacological activities of resisting tumor, resisting inflammation, etc. The compound has various chemical components such as coumarins, sesquiterpenes, sulfur-containing compounds and aromatics, wherein the sesquiterpene coumarins are characteristic components of the compound.
Disclosure of Invention
The invention aims to provide a series of sesquiterpene coumarin compounds, and a preparation method and medical application thereof.
The sesquiterpene coumarin compound provided by the invention and pharmaceutically acceptable salts and isomers thereof have the following structural general formula:
Figure BDA0002518235580000011
wherein, the first and the second end of the pipe are connected with each other,
R1is hydrogen, hydroxy, C1-C4 acyloxy, fragment A or fragment B;
R2is hydrogen or hydroxy;
R3is hydroxy, C1-C4 acyloxy or fragment B;
R4is hydrogen, C1-C4 alkyl or hydroxy;
R5is hydrogen, C1-C4 alkyl or hydroxy;
R6is hydrogen or hydroxy;
R7is hydrogen or hydroxy.
The invention preferably selects the sesquiterpene coumarin compound with the following structure and the pharmaceutically acceptable salt and isomer thereof,
wherein the content of the first and second substances,
R1is hydrogen, hydroxy, acetoxy, propionyloxy, fragment AOr fragment B;
R2is hydrogen or hydroxy;
R3is hydroxy, acetoxy, propionyloxy or fragment B;
R4is hydrogen, methyl or hydroxy;
R5is hydrogen, methyl or hydroxy;
R6is hydrogen or hydroxy;
R7is hydrogen or hydroxy.
The invention specifically discloses the following ten specific compounds:
Figure BDA0002518235580000021
the invention also provides a preparation method of the sesquiterpene coumarin compounds 1-10, which comprises the following steps:
(1) Extracting resina Ferulae with solvent such as methanol, ethanol, chloroform or dichloromethane, and recovering extractive solution to obtain crude extract;
(2) Separating the crude extract obtained in the step (1) by silica gel column chromatography, and performing gradient elution by using a petroleum ether-ethyl acetate mixed solvent, or a petroleum ether-acetone mixed solvent, or a dichloromethane-ethyl acetate mixed solvent, or a dichloromethane-acetone mixed solvent, or a chloroform-ethyl acetate mixed solvent, or a chloroform-acetone mixed solvent to obtain eluates with different polarities;
(3) Performing ODS column chromatography on the eluate with different polarities obtained in the step (2), and performing gradient elution by using a methanol-water mixed solvent or an acetonitrile-water mixed solvent as a mobile phase;
(4) And (4) further separating the methanol-water or acetonitrile-water eluate obtained in the step (3) by HPLC, and carrying out gradient elution by taking a methanol-water mixed solvent or acetonitrile-water mixed solvent as a mobile phase to obtain the sesquiterpene coumarin 1-10.
The invention provides a preparation method of 1-10 sesquiterpene coumarin compounds, wherein the extraction method in the step (1) is heating reflux extraction or heating ultrasonic extraction for 2-5 times. The volume concentration of the methanol used is 60% to 100%, preferably 80% to 90%. The volume concentration of the ethanol used is 60-100%, preferably 80-95%. The feed-liquid ratio is 1.
The preparation method of the sesquiterpene coumarin compounds 1-10 provided by the invention is characterized in that the volume ratio of the petroleum ether-ethyl acetate mixed solvent or the petroleum ether-acetone mixed solvent in the step (2) is (100); the volume ratio of the dichloromethane-ethyl acetate mixed solvent, the dichloromethane-acetone mixed solvent, the chloroform-ethyl acetate mixed solvent or the chloroform-acetone mixed solvent is 100.
According to the preparation method of the sesquiterpene coumarin compounds 1-10 provided by the invention, in the step (3), the volume ratio of the methanol-water mixed solvent is 50-100, preferably 60-90; the volume ratio of the acetonitrile-water mixed solvent is 30.
According to the preparation method of the sesquiterpene coumarin compounds 1-10 provided by the invention, in the step (4), the volume ratio of the methanol-water mixed solvent is (60-90); the volume ratio of the acetonitrile-water mixed solvent is 50.
The invention uses BV-2 cells in vitro as a model to carry out anti-inflammatory activity test, and evaluates the neuroinflammation inhibitory activity of the prepared sesquiterpene coumarin compounds 1-10. The results show that the sesquiterpene coumarins have remarkable anti-neuritis activity, and can be used for developing chemopreventive agents or therapeutic drugs for neuroinflammation.
The invention provides a method for preparing and identifying 10 sesquiterpene coumarins by taking ferula asafetida as a raw material for the first time, systematically evaluates the activity of the sesquiterpene coumarins in resisting neuritis and explains the application of the sesquiterpene coumarins in developing chemoprevention and treatment medicines related to neuroinflammation.
Detailed Description
The following examples further illustrate the invention but are not intended to limit it.
Example 1
(1) Reflux-extracting 1000g of resina Ferulae with 95% ethanol under heating for 3 times (10L), and recovering the crude extract under reduced pressure;
(2) Subjecting the crude 95% ethanol extract obtained in the step (1) to silica gel column chromatography, and performing gradient elution with a petroleum ether-ethyl acetate mixed solvent of 100, 10;
(3) The eluate of the petroleum ether-ethyl acetate mixed solvent 100 in the step (2) is separated by silica gel column chromatography, and is sequentially eluted with a petroleum ether-ethyl acetate mixed solvent 100;
(4) The petroleum ether obtained in the step (3): ethyl acetate 100-2 stream through ODS chromatography with a gradient of 50;
(5) The fraction of 80-90 parts of methanol-water obtained in the step (4) is prepared by HPLC-UV chromatography, the flow rate is 3mL/min, and the mobile phase is methanol: water =90, giving the sesquiterpene coumarin 3 (t)R=102 min) (yield 0.0003%), sesquiterpene coumarin 4 (t) R=80 min) (yield 0.0031%), sesquiterpene coumarin 5 (t)R=9 min) (yield 0.0010%), sesquiterpene coumarin 6 (t)R=24 min) (yield 0.0010%) to give sesquiterpene coumarin 7 (t)R=69 min) (yield 0.0016%), sesquiterpene coumarin 9 (t)R=13 min) (yield 0.0004%).
(6) And (3) separating the methanol-water 90 obtained in the step (4) by HPLC-UV chromatography at a flow rate of 3mL/min, wherein the mobile phase is methanol: water =82, giving the sesquiterpene coumarin 2 (t)R=23 min) (yield 0.0002%).
(7) And (3) separating the methanol-water 90 obtained in the step (4) by HPLC-UV chromatography at a flow rate of 3mL/min, wherein the mobile phase is methanol: water =79, giving sesquiterpene coumarin 1 (t)R=44 min) (yield 0.0003%), sesquiterpene coumarin 10 (t)R=39 min) (yield 0.0012%).
(8) Separating the methanol-water 60-30 fractions obtained in the step (4) by HPLC RID-10A chromatographyPreparation, flow rate is 3mL/min, mobile phase is methanol: water =70, giving sesquiterpene coumarin 8 (t)R=24 min) (yield 0.0005%).
The structures of the compounds 1 to 10 were identified based on their physicochemical properties and spectral data.
The structural identification data of sesquiterpene coumarin 1 are as follows:
Yellow oil (MeOH), HRESIMS gave the excimer peak m/z 449.2307[ M ] +Na]+:(calcd.449.2304 for C26H34O5Na) and is presumed to be C26H34O5The unsaturation degree was 10.1H NMR(600MHz,CDCl3) The characteristic hydrogen signal of 7-O-substituted coumarin parent nucleus is given by a low field region in the spectrum: 7.63 (1H, d, J =9.4Hz, H-4), 7.37 (1H, d, J =8.5Hz, H-5), 6.86 (1H, dd, J =8.5,2.2Hz, H-6), 6.83 (1H, d, J =2.2Hz, H-8) and deltaH6.25 (1H, d, J =9.4Hz, H-3); the high field region gives 5 methyl hydrogen signals: deltaH2.04 (3H, s, me-2 "), 1.79 (3H, s, me-11 '), 1.68 (3H, s, me-15'), 1.66 (3H, s, me-14 ') and 0.97 (3H, d, J =6.9Hz, me-12'). In addition, an olefinic hydrogen signal is also observed in the hydrogen spectrum: delta. For the preparation of a coatingH5.49 (1H, t, J =6.5Hz, H-2'); two sets of vicinal oxymethylene signals: deltaH4.60 (2H, d, J =6.5Hz, H-1 ') and 4.06 (2H, m, H-10').13C NMR(150MHz,CDCl3) The spectrum gives a total of 26 signals, except for 9 characteristic carbon signals of 7-O-substituted coumarin parent nucleus: deltaC162.3 (C-7), 161.5 (C-2), 156.0 (C-9), 143.6 (C-4), 128.8 (C-5), 113.4 (C-6), 113.1 (C-3), 112.6 (C-10) and 101.7 (C-8); one set of acetyl carbon signals: deltaC171.4 (C-1 '), 21.2 (C-2'), still present 15 carbon signals, which are sesquiterpene backbone carbon signals, comprising two sets of alkene carbon signals: deltaC143.2 (C-3 '), 118.0 (C-2'), and δC134.9 (C-6 '), 126.2 (C-13'); 2 vicinal oxygen carbon signals: delta. For the preparation of a coating C65.6 (C-1 '), 65.0 (C-10'). The compound is supposed to be sesquiterpene coumarin by combining the hydrogen spectrum data and the carbon spectrum data. Since 1 coumarin unit (7 unsaturations), 1 carbonyl group and two olefin bonds in the structure of the compound constitute 10 unsaturations of the compound, the sesquiterpene part of the compound is presumed to be a chain structure. Root of herbaceous plantsAll hydrogen carbon data were assigned by HSQC (tables 1 and 2).
1H-1H COSY shows that the compound has 3 spin coupling systems which are respectively H2-1′/H-2′,H2-4′/H2-5', and H3-12′/H-7′/H2-8′/H2-9′/H210' indicating the presence of three fragments C-1'/C-2', C-4'/C-5', and C-7' (C- '12 ')/C-8 '/C-9'/C-10 '. In HMBC spectrum, δH 4.60(H2-1') and δC118.0 (C-2 '), 143.2 (C-3'), related, δH5.49 (H-2') and deltaC143.2 (C-3 '), 40.2 (C-4 '), 17.0 (C-11 '), deltaH 2.08(Ha-5') and 2.02 (H)b-5') and δC143.2 (C-3 '), 134.9 (C-6'), 35.6 (C-7 '), 126.2 (C-13'), deltaH 1.34(H2-8') and δC134.9 (C-6') correlation, δH 1.66(H3-14') and 1.68 (H)3-15') and δC126.2 (C-13 '), 134.9 (C-6'). And (3) integrating the HMBC related signals to establish a planar structure of the sesquiterpene unit. Further, δH 4.06(H2-10') and δC171.4 (C-1 ') indicates that the acetyl group is attached at the C-10' position. Delta. For the preparation of a coating H 4.60(H2-1') and δC162.3 (C-7) remote correlation, which indicates that the sesquiterpene fragment is connected to the C-7 position of the coumarin parent nucleus. NOESY spectrum of H314 'is related to H-7', suggesting that Me-14 'is ipsilateral to H-7'; h3-15' and Ha,b5 'correlation, suggesting Me-15' with Ha,b-5' on the same side. The absolute configuration of compound 1 was determined by comparing the measured electron circular dichroism spectra (ECD) and calculating ECD data. The compound is a novel compound which is not reported through literature search and is named as (7R) -ferusingensine A.
The structural identification data of sesquiterpene coumarin 2 are as follows:
yellow oil (MeOH), HRESIMS gave the excimer peak m/z 407.2200. M + Na]+:(calcd.407.2198for C24H32O4Na) and the molecular formula thereof is presumed to be C24H32O4. Its hydrogen spectrumThe carbon spectrum data are similar to that of compound 1, except that the substituent on C-10' is different, and the data are combined to speculate that-OAc of compound 1 may be replaced by-OH.1H NMR(600MHz,CDCl3) In the spectrum, the characteristic proton signals of 5 7-O-substituted coumarin parent nuclei are given by a low field region: deltaH7.64 (1H, d, J =9.5Hz, H-4), 7.37 (1H, d, J =8.6Hz, H-5), 6.86 (1H, dd, J =8.6,2.4Hz, H-6), 6.83 (1H, d, J =2.4Hz, H-8), 6.25 (1H, d, J =9.5Hz, H-3); the high field region provides 4 methyl hydrogen signals: deltaH1.79 (3H, s, me-11 '), 1.68 (3H, s, me-15'), 1.66 (3H, s, me-14 ') and 0.97 (3H, d, J =6.9Hz, me-12'). In addition, there is a double bond hydrogen signal in the hydrogen spectrum: delta H5.49 (1H, t, J=6.5Hz, H-2'); two sets of vicinal oxymethylene signals: delta. For the preparation of a coatingH4.60 (2H, d, J =6.5Hz, H-1') and deltaH 3.61(2H,t,J＝6.6Hz,H-10')。13C NMR(150MHz,CDCl3) The spectrum has 24 signals in total, and the low field region gives 9 characteristic carbon signals of 7-O-substituted coumarin parent nucleus: delta. For the preparation of a coatingC162.3 (C-7), 161.5 (C-2), 156.0 (C-9), 143.6 (C-4), 128.8 (C-5), 113.4 (C-6), 113.1 (C-3), 112.6 (C-10) and 101.7 (C-8), the remaining 15 carbon signals being sesquiterpene backbone carbon signals comprising two sets of double bond carbon signals: delta. For the preparation of a coatingC143.3 (C-3 '), 118.0 (C-2') and deltaC135.1 (C-6 '), 125.9 (C-13'); 2 vicinal oxygen carbon signals: deltaC65.7 (C-1 '), 63.5 (C-10'). All hydrogen carbon data were assigned according to HSQC (tables 1 and 2).
In HMBC spectra, deltaH 4.60(H2-1') and δC118.0 (C-2 '), 143.3 (C-3'), related, δH5.49 (H-2') and deltaC143.3 (C-3 '), 40.2 (C-4 '), 17.0 (C-11 '), deltaH 2.08(Ha-5') and 2.02 (H)b-5') and δC143.3 (C-3 '), 135.1 (C-6'), 35.7 (C-7 '), 125.9 (C-13'), deltaH 1.34(H2-8') and δC135.1 (C-6') correlation, δH 1.66(H3-14') and 1.68 (H)3-15') and δC125.9 (C-13 '), 135.1 (C-6'). And (4) integrating the HMBC related signals to determine the planar structure of the sesquiterpene part. By deltaH 4.60(H2-1') and δC162.3 (C-7) remote correlation, determinationThe sesquiterpene fragment is connected with the C-7 phase of the coumarin parent nucleus through an ether bond. The absolute configuration of compound 2 was determined by comparing the measured ECD and calculated ECD data. The compound is a novel compound which is not reported by the literature search and is named as (7R) -ferusingensine B.
The structural identification data of sesquiterpene coumarin 3 are as follows:
yellow oil (MeOH), HRESIMS gave the excimer peak m/z 573.3553[ m ] +Na]+:(calcd.573.3556for C35H50O5Na) and is presumed to be C35H50O5. The hydrogen spectrum and carbon spectrum data are similar to those of the compound 1, and the difference is that the substituent on C-10' is different.1H NMR(600MHz,CDCl3) In the spectrum, the low field region indicates 5 characteristic proton signals of the 7-O-substituted coumarin parent nucleus: delta. For the preparation of a coatingH7.64 (1H, d, J =9.4Hz, H-4), 7.36 (1H, d, J =8.5Hz, H-5), 6.86 (1H, dd, J =8.5,2.2Hz, H-6), 6.83 (1H, d, J =2.2Hz, H-8) and 6.25 (1H, d, J =9.4Hz, H-3); the high field region provides 5 methyl hydrogen signals deltaH1.79 (3H, s, me-11 '), 1.68 (3H, s, me-15'), 1.66 (3H, s, me-14 '), 0.97 (3H, d, J =6.8Hz, me-12') and 0.87 (3H, t, J =6.8Hz, me-10 "). In addition, the hydrogen spectrum also has a double bond hydrogen signal deltaH5.49 (1H, t, J =6.5Hz, H-2'), two sets of continuous oxygen methylene signals deltaH4.60 (2H, d, J =6.5Hz, H-1 ') and 4.05 (2H, t, J =6.7Hz, H-10').13C NMR(150MHz,CDCl3) The spectrum gives 35 signals in total, and the low field region gives 9 characteristic carbon signals of 7-O-substituted coumarin parent nucleus: delta. For the preparation of a coatingC162.3 (C-7), 161.4 (C-2), 156.1 (C-9), 143.6 (C-4), 128.8 (C-5), 113.4 (C-6), 113.2 (C-3), 112.6 (C-10) and 101.7 (C-8). The remaining 26 carbon signals, compared with the compound 1 carbon spectrum data, are presumed to be sesquiterpene unit carbon signals, including two groups of double-bond carbon signals: delta. For the preparation of a coating C143.2 (C-3 '), 118.1 (C-2'), and deltaC135.0 (C-6 '), 126.1 (C-13'); 2 oxygen linked carbon signals: delta. For the preparation of a coatingC65.7 (C-1 '), 64.8 (C-10'). The remaining 11 carbon signals are those of the substituent at the C-10' position. All hydrogen carbon data were assigned according to HSQC (tables 1 and 2).
1H-1In the H COSY spectrum, C-10' position extraction is givenGeneration-based spin-coupled systems: h-2 '/H-3' (H-11 ')/H-4'/H-5 '-based on the presence of a marker gene in the tissue H-6'/H-7 '/H-8'/H-9 '/H-10'. In HMBC spectrum, δH 0.70(Ha-11 ") and-0.15 (H)b-11 ") and δC34.2 (C-2 '), 11.7 (C-3'), 15.7 (C-4 '), 29.0 (C-5') signals correlate suggesting the presence of a cyclopropane fragment. In addition, delta is made ofH0.87 (H-10') and deltaC22.8 (C-9 '), 32.0 (C-8'), relative, deltaH1.30 (H-7') and deltaC32.0 (C-8') related, deltaH 1.37(Ha-6 ") and 1.26 (H)b-6 ") and δC29.4 (C-7') related, deltaH 1.36(Ha-5 ") and 1.16 (H)b-5 ") and δC11.7 (C-3 '), 15.7 (C-4 '), 30.0 (C-6 '), and deltaH 2.35(Ha-2 ") and 2.24 (H)b-2 ") and δC174.0 (C-1 '), 11.7 (C-3'), 15.7 (C-4 '), define the planar configuration of the substituent at the C-10' position. According to1High field region signal delta in H NMR spectrumH 0.79(1H,m,H-4”),0.70(1H,dt,J＝8.4,4.7Hz,Ha-11”),-0.15(1H,q,J＝4.7Hz,Hb11 ") determining the relative configuration of the cyclopropane; the absolute configuration of compound 3 was determined by comparing the measured ECD and calculated ECD data. The literature search showed that the compound is a novel compound which is not reported and is named as (7 ' S, 3' R,4 ' R) -ferusingensine C.
The structural identification data of sesquiterpene coumarin 4 are as follows:
yellow oil (MeOH), HRESIMS gave the excimer peak m/z 559.3396[ m ] +Na +]+:(calcd.559.3399for C34H48O5Na) and is presumed to be C34H48O5The hydrogen and carbon spectra data are similar to compound 1, except that the substituent at the C-10' position is different.1H NMR(600MHz,CDCl3) In the spectrum, the low field region gives 5 characteristic proton signals of the 7-O-substituted coumarin parent nucleus: delta. For the preparation of a coatingH7.63 (1H, d, J =9.5Hz, H-4), 7.36 (1H, d, J =8.6Hz, H-5), 6.86 (1H, dd, J =8.6,2.2Hz, H-6), 6.82 (1H, d, J =2.2Hz, H-8) and 6.24 (1H, d, J =9.5Hz, H-3); the high field region provides 5 methyl proton signals: deltaH 1.79(3H,s,Me-11'),1.68(3H,s,Me-15'),1.65(3H, s, me-14 '), 0.96 (3H, d, J =6.8Hz, me-12') and 0.87 (3H, t, J =6.6Hz, me-10 "). In addition, there are 3 double bond hydrogen signals in the hydrogen spectrum: deltaH5.49 (1H, t, J =6.5Hz, H-2 '), 5.40 (1H, m, H-5 ') and 5.31 (1H, m, H-4 '); two groups of vicinal oxymethylene hydrogen signals: deltaH4.59 (2H, d, J =6.5Hz, H-1 ') and 4.02 (2H, t, J =6.7Hz, H-10').13C NMR(150MHz,CDCl3) The spectrum gives 34 signals in total, and the low field region gives 9 7-O-substituted coumarin parent nucleus characteristic carbon signals: deltaC162.3 (C-7), 161.4 (C-2), 156.0 (C-9), 143.6 (C-4), 128.8 (C-5), 113.3 (C-6), 113.1 (C-3), 112.6 (C-10), 101.7 (C-8). By comparison with compound 1 carbon spectrum data, the 15 carbon signal is presumed to be a sesquiterpene unit carbon signal, which includes two groups of double bond carbon signals: delta C143.2 (C-3 '), 118.1 (C-2') and deltaC135.0 (C-6 '), 126.1 (C-13'); 2 vicinal oxygen carbon signals: delta. For the preparation of a coatingC65.6 (C-1 '), 64.8 (C-10'). The remaining 10 carbon signals are those of the C-10' substituent and comprise a set of double bond carbon signals: delta. For the preparation of a coatingC131.7 (C-5 '), 127.5 (C-4'). All hydrogen carbon data were assigned according to HSQC (tables 1 and 2).
1H-1In H COSY spectrum ,provide a spin coupled system H-3 "/H-4"/H-5 "/H-6"/H-7 "/H-8"/H-9 "/H-10" with substituents at the C-10 'position , suggesting the presence of enoate fragments. Combining signals in HMBC spectra, deltaH 2.35(Ha-2 ") and 2.27 (H)b-2 ") and δC173.5 (C-1 '), 22.7 (C-3'), relative, deltaH2.33 (H-3') and deltaC127.5 (C-4 '), 131.7 (C-5'), relative, deltaH2.04 (H-6') and deltaC127.5 (C-4 '), 131.7 (C-5'), 29.4 (C-7 '), 31.6 (C-8'), and deltaH0.87 (H-10') and deltaC23.0 (C-9 '), 31.6 (C-8 '), define the planar structure of the 4-decenoate substituent at the C-10' position. By comparing the measured ECD and calculated ECD data, the absolute configuration of compound 4 was determined. The compound is a novel compound which is not reported through literature search and is named as (7R) -ferusingensine D.
The structural identification data of sesquiterpene coumarin 5 are as follows:
yellow oil (MeOH), HRESIMS gave a quasi-oil Molecular ion peak m/z 405.2045 2M + Na]+:(calcd.405.2042 for C24H30O4Na) and is presumed to be C24H30O4Contains 10 unsaturations.1H NMR(600MHz,CDCl3) In the spectrum, the low field region shows 5 proton signals characteristic of the 7-O-substituted coumarin parent nucleus: delta. For the preparation of a coatingH7.63 (1H, d, J =9.5Hz, H-4), 7.36 (1H, d, J =8.6Hz, H-5), 6.85 (1H, dd, J =8.6,2.3Hz, H-6), 6.82 (1H, d, J =2.3Hz, H-8) and 6.24 (1H, d, J =9.5Hz, H-3); the high field region gives 4 sets of methyl proton signals: delta. For the preparation of a coatingH1.76 (3H, s, me-13 '), 1.60 (3H, s, me-14'), 1.08 (3H, d, J =6.9Hz, me-15 ') and 1.08 (3H, d, J =6.9Hz, me-12'). In addition, there are 2 double bond proton signals in the hydrogen spectrum: deltaH5.46 (1H, t, J =6.5Hz, H-2 ') and 5.09 (1H, t, J =6.9Hz, H-6'); and group 1 oxymethylene proton signals: deltaH 4.60(2H,d,J＝6.5Hz,H-1′)。13C NMR(150MHz,CDCl3) The spectrum shows 24 carbon signals, the low field region gives 9 7-O-substituted coumarin parent carbon signals: deltaC162.3 (C-7), 161.5 (C-2), 156.0 (C-9), 143.6 (C-4), 128.8 (C-5), 113.4 (C-6), 113.1 (C-3), 112.6 (C-10), 101.7 (C-8). The remaining 15 carbon signals are those of sesquiterpene units, comprising 2 sets of double bond carbon signals: deltaC142.3 (C-3 '), 118.7 (C-2') and deltaC134.6 (C-7 '), 124.1 (C-6'); 1 carbonyl carbon signal: deltaC214.6 (C-10'); 1 oxygen carbon signal: delta. For the preparation of a coatingC65.6 (C-1'). All hydrogen carbon data were assigned according to HSQC (tables 1 and 2).
1H-1H COSY spectrum, giving 4 coupling systems for sesquiterpene fragments: h-1'/H-2', H-4'/H-5'/H-6', H-8'/H-9', and H-13'/H-11'/H-14'. In HMBC spectrum, δH 2.09(H2-4') and δC118.7 (C-2 '), 142.3 (C-3'), 26.3 (C-5 '), 124.1 (C-6'), deltaH 2.22(H2-8') and δC124.1 (C-6 '), 134.6 (C-7'), 39.2 (C-9 '), 214.6 (C-10'), related, δH 1.08(H3-12') and 1.08 (H)3-15') and δC41.0 (C-11 '), 214.6 (C-10'), and the planar structure of sesquiterpene fragments was determined. Delta. For the preparation of a coatingH 4.60(H2-1') and δC162.3 (C-7) related, suggesting that the sesquiterpene unit is connected with the C-7 position of the coumarin parent nucleus through an ether bond. The natural product is found by literature search and is named as ferusingensine E.
The structural identification data of sesquiterpene coumarin 6 are as follows:
white needle crystal (MeOH), HRESIMS gave the excimer peak m/z 463.2459[ M ] +Na +]+:(calcd.463.2460for C27H36O5Na) and the molecular formula thereof is presumed to be C27H36O5This suggests that there are 10 unsaturations in the structure.1H NMR(600MHz,CDCl3) 5 proton signals in the spectrum that characterize the 7-O-substituted coumarin nucleus: deltaH7.63 (1H, d, J =9.4Hz, H-4), 7.34 (1H, d, J =8.6Hz, H-5), 6.81 (1H, dd, J =8.6,2.3Hz, H-6), 6.75 (1H, d, J =2.3Hz, H-8) and 6.23 (1H, d, J =9.4Hz, H-3); group 2 continuous oxygen methylene proton signal: delta H 4.06(2H,m,H-3′),3.88(1H,d,J＝8.3Hz,Ha11') and 3.69 (1H, d, J=8.3Hzb-11'). The high field region gives 5 methyl proton signals: delta. For the preparation of a coatingH1.62 (3H, s, me-14 '), 1.45 (3H, d, J =1.7Hz, me-13 '), 1.16 (1H, t, J =7.6Hz, me-3 '), 1.12 (3H, s, me-15 ') and 0.91 (3H, d, J =7.0Hz, me-12 ').13C NMR(150MHz,CDCl3) The spectrum shows 27 carbon signals, 9 are characteristic carbon signals delta of 7-O-substituted coumarin parent nucleusC163.1 (C-7), 161.5 (C-2), 156.1 (C-9), 143.7 (C-4), 128.7 (C-5), 113.3 (C-6), 112.9 (C-3), 112.4 (C-10), 101.3 (C-8). 15 carbon signals for sesquiterpene units, including 1 set of double bond carbon signals: delta. For the preparation of a coatingC130.3 (C-5 '), 125.4 (C-4'); 2 oxygen linked carbon signals: delta. For the preparation of a coatingC71.8 (C-11 '), 65.0 (C-3'). 3 are propionyl signals: deltaC174.8 (C-1 "), 27.8 (C-2") and 9.4 (C-3 "). Since the coumarin nucleus, 1 carbonyl group and 1 double bond together provide 9 unsaturations, the sesquiterpene moiety of the compound is presumed to be a single ring structure. All hydrogen-carbon data were then assigned according to HSQC (tables 1 and 3).
In HMBC spectra, deltaH 1.45(H3-13') and 1.62 (H)3-14') and δC125.4 (C-4 '), 130.3 (C-5'), related to deltaC65.0 (C-3') is irrelevant, suggesting cleavage of the A-ring of the sesquiterpene unit. DeltaH 0.91(H3-12') and δC32.2 (C-7 '), 35.0 (C-8 '), 40.9 (C-9 '), indicating that Me-12' is attached at the C-8' position; delta. For the preparation of a coating H 1.12(H3-15') and δC35.0 (C-8 '), 40.9 (C-9'), 43.1 (C-10 '), 71.8 (C-11'), relative, suggesting that Me-15 'is attached at the C-9' position; delta. For the preparation of a coatingH 1.16(H3-3 ") and δC27.8 (C-2 '), 174.8 (C-1'), deltaH4.06 (H-3') and deltaC174.8 (C-1 ') indicates that propionyl is connected at the C-3' position. Further, δH 3.88(Ha-11') and 3.69 (H)b11') and δC163.1 The remote correlation of (C-7) suggests that the sesquiterpene fragment is linked to the C-7 position of the coumarin parent nucleus via an ether bond.
In NOESY spectrum, H3-12' and Hb11 'related, H-10' with Ha11' correlation, H3-15' and H2-1 'correlation, suggesting Me-12' and Ha,b-11' is β -oriented, H-1' and Me-15' are α -oriented, and the relative configuration of the chiral centers is presumed to be 8. By comparing the actually measured ECD and the calculated ECD data, it was confirmed that the absolute configuration of Compound 6 was 8' S,9' S,10' S. A novel compound was found to be reported in the literature and was named (8 ' S,9' S,10' S) -propionyl fekrynol.
The structural identification data of sesquiterpene coumarin 7 are as follows:
yellow oil (MeOH), HRESIMS gave the excimer peak m/z 559.3387[ 2 ] M + Na]+:(calcd.559.3399 for C34H48O5Na) and the molecular formula thereof is presumed to be C34H48O5The hydrogen and carbon spectra data are similar to compound 6, except that the substituent at the C-3' position is different. By comparing the 1D NMR spectrum data of the compound 7 and the compound 4 (see tables 1 to 3), it was found that the hydrogen spectrum carbon spectrum data of the substituent at the C-3 'position of the compound 7 was the same as that of the substituent at the C-10' position of the compound 4.1H NMR(600MHz,CDCl3) In the spectra, the low field region shows 5 proton signals characteristic of the 7-O-substituted coumarin nucleus: delta. For the preparation of a coatingH7.62(1H,d,J＝9.5Hz,H-4),7.34(1H,d,J＝8.6Hz,H-5),6.81(1H,dd,J＝8.6,2.2Hz,H-6), 6.75 (1H, d, J =2.2Hz, H-8) and 6.22 (1H, d, J =9.5Hz, H-3); group 1 alkene hydrogen signals: delta. For the preparation of a coatingH5.42 (1H, m, H-5') and deltaH5.34 (1H, m, H-4'); group 2 continuous oxygen methylene proton signal: delta. For the preparation of a coatingH 4.06(2H,m,H-3′),3.88(1H,d,J＝8.3Hz,Ha11') and 3.69 (1H, d, J =8.3Hzb-11'). The high field region gives 5 methyl proton signals: delta. For the preparation of a coatingH1.62 (3H, s, me-14 '), 1.45 (3H, d, J =1.5Hz, me-13 '), 1.11 (3H, s, me-15 '), 0.90 (3H, d, J =7.0Hz, me-12 '), and 0.88 (1H, t, J =7.1Hz, me-10 ').13C NMR(150MHz,CDCl3) The spectrum shows 34 carbon signals, 9 are characteristic carbon signals delta of 7-O-substituted coumarin parent nucleusC163.1 (C-7), 161.4 (C-2), 156.1 (C-9), 143.6 (C-4), 128.7 (C-5), 113.3 (C-6), 112.9 (C-3), 112.4 (C-10), 101.3 (C-8). 15 are carbon signals of sesquiterpene units, comprising a 1-group double-bond carbon signal: deltaC130.3 (C-5 '), 125.3 (C-4'); 2 vicinal oxygen carbon signals: deltaC71.9 (C-11 '), 65.1 (C-3'). 10 are decenoate fragments: contains 1 set of double bond carbon signals: deltaC131.7 (C-5 "), 127.5 (C-4"). All hydrogen carbon data were assigned according to HSQC (tables 1 and 3).
In HMBC spectrum, δH4.06 (H-3') and deltaC173.5 (C-1 ') associated, suggesting that the decenoate fragment is linked at the C-3' position of the sesquiterpene unit. Delta. For the preparation of a coating H 3.88(Ha11') and 3.69 (H)b11') and δC163.1 The remote correlation of (C-7) suggests that the sesquiterpene fragment is linked to the C-7 position of the coumarin nucleus via an ether linkage. NOESY spectrum of H3-12' and Hb11 'related, H-8' with H3-15' correlation, H3-15' and Ha,b-1 'correlation, suggesting Me-12' and Ha,b11' is in the beta-orientation, Ha,b-1' and Me-15' are in α -orientation, the relative configuration of the chiral centers is presumed to be 8' S,9' S,10' S. By comparing the actually measured ECD and the calculated ECD data, it was confirmed that the absolute configuration of Compound 7 was 8' S,9' S,10' S. New compound reported as an undiscovered document through retrieval and named as (8 ' S,9' S,10' S) -ferusingensine F.
The structural identification data of sesquiterpene coumarin 8 are as follows:
yellow oil (MeOH), HRESIMS gives the peak of excimer ion m/z 419.1832[ 2 ], [ M ] +Na ]]+:(calcd.419.1834 for C24H28O5Na) and the molecular formula thereof is presumed to be C24H28O5Indicating that there are 11 unsaturations in the structure.1H NMR(600MHz,CDCl3) In the spectrum, the low field region shows 5 proton signals characteristic of the 7-O-substituted coumarin parent nucleus: deltaH7.64 (1H, d, J =9.5Hz, H-4), 7.35 (1H, d, J =8.6Hz, H-5), 6.84 (1H, dd, J =8.6,2.3Hz, H-6), 6.81 (1H, d, J =2.3Hz, H-8) and 6.25 (1H, d, J =9.5Hz, H-3); 3 double bond hydrogen signals: deltaH6.64 (1H, d, J =10.2Hz, H-1 '), 5.82 (1H, d, J =10.2Hz, H-2 ') and 5.51 (1H, t, J =6.6Hz, H-9 '); group 1 continuous oxygen methylene proton signal: delta. For the preparation of a coating H4.60 (2H, m, H-11'). The high field region gives 4 methyl proton signals: delta. For the preparation of a coatingH1.80 (3H, s, me-12 '), 1.37 (3H, s, me-15'), 1.18 (3H, s, me-13 '), and 1.04 (3H, s, me-14').13C NMR(150MHz,CDCl3) The spectrum shows 24 carbon signals, 9 are characteristic carbon signals delta of 7-O-substituted coumarin parent nucleusC162.1 (C-7), 161.4 (C-2), 156.0 (C-9), 143.6 (C-4), 128.9 (C-5), 113.4 (C-6), 113.2 (C-3), 112.7 (C-10), 101.7 (C-8); the remaining 15 are carbon signals of sesquiterpene units, containing 2 sets of double bond carbon signals: delta. For the preparation of a coatingC154.8 (C-1 '), 125.1 (C-2'), and. DeltaC142.9 (C-8 '), 119.3 (C-9'); 1 carbonyl carbon signal: deltaC204.2 (C-3'); 2 vicinal oxygen carbon signals: deltaC72.1 (C-10 '), 65.4 (C-11'). Since 10 unsaturations are provided by the coumarin parent nucleus (7 unsaturations), 1 carbonyl group and 2 double bonds, the compound sesquiterpene moiety is presumed to be a monocyclic structure. All hydrogen-carbon data were then assigned according to HSQC (tables 1 and 3).
In HMBC spectra, deltaH6.64 (H-1') and deltaC204.2 (C-3') correlation,. Delta.H5.82 (H-2') and deltaC46.2 (C-4') is related, suggesting the presence of an α, β -unsaturated ketone fragment; deltaH 1.18(H313') and 1.04 (H)3-14') and δC204.2 (C-3 '), 46.2 (C-4'), 53.2 (C-5 '), relative, suggesting that Me-13', me-14 'is attached at the C-4' position; deltaH 1.37(H3-15') and δ C154.8 (C-1 '), 72.1 (C-10 '), 53.2 (C-5 ') phasesOff, and deltaC65.4 (C-11 ') is irrelevant, suggesting that Me-15' is linked at the C-10' position, and the B ring of the sesquiterpene unit is cleaved; delta. For the preparation of a coatingH 1.80(H3-12') and δC40.5 (C-7 '), 142.9 (C-8 '), 119.3 (C-9 '), indicating that Me-12' is attached at the C-8' position; delta. For the preparation of a coatingH 4.60(H211') and δC142.9 (C-8 '), 119.3 (C-9') are related, suggesting that another double bond is located at C-8'/C-9'. Further, δH 4.60(H211') and deltaC162.1 The remote correlation of (C-7) suggests that the sesquiterpene fragment is linked to the C-7 position of the coumarin parent nucleus via an ether bond.
NOESY spectrum of H3-14' and H3-15', H-5' related, H26 'and H-1', H3-13' correlation, suggesting that Me-14', me-15' and H-5' are in the α -orientation, me-13' and-OH are in the β -orientation, assuming a relative configuration of chiral centers of 5's,10' r. By comparing the actually measured and calculated ECD data, it was determined that the absolute configuration of Compound 8 was 5'S,10' R. A novel compound which is searched to be reported in a non-literature is named as (5 'S,10' R) -ferusingensine G.
The structural identification data of sesquiterpene coumarin 9 are as follows:
yellow oil (MeOH), HRESIMS gave the excimer peak m/z 383.2216M + H]+:(calcd.383.2222for C24H31O4) The molecular formula is presumed to be C24H30O4This suggests that there are 10 unsaturations in the structure. 1H NMR(600MHz,CDCl3) In the spectra, the low field region shows 5 proton signals characteristic of the 7-O-substituted coumarin nucleus: delta. For the preparation of a coatingH7.61 (1H, d, J =9.4Hz, H-4), 7.32 (1H, d, J =8.6Hz, H-5), 6.83 (1H, dd, J =8.6,2.3Hz, H-6), 6.75 (1H, d, J =2.3Hz, H-8) and 6.22 (1H, d, J =9.4Hz, H-3); 1 double bond hydrogen signal: delta. For the preparation of a coatingH5.43 (1H, t, J=3.8Hz, H-6'); group 2. Continuous oxymethylene hydrogen signals: delta. For the preparation of a coatingH 3.66(1H,dt,J＝12.5,3.2Hz,Ha-3′),3.32(1H,m,Hb-3′),3.81(1H,d,J＝8.3Hz,Ha11') and 3.76 (1H, d, J =8.3Hzb-11'); the high field region gives 4 methyl proton signals: deltaH 1.31(3H,s,Me-14′),1.19(3H,s,Me-15′),0.98(3H,J＝7.9Hz,Me-12′) And 0.97 (3H, s, me-13').13C NMR(150MHz,CDCl3) The spectrum shows 24 carbon signals, 9 are characteristic carbon signals delta of 7-O-substituted coumarin parent nucleusC163.0 (C-7), 161.5 (C-2), 156.1 (C-9), 143.6 (C-4), 128.7 (C-5), 113.5 (C-6), 112.9 (C-3), 112.4 (C-10), 100.9 (C-8); 15 are carbon signals of sesquiterpene units, comprising a 1-group double-bond carbon signal: deltaC148.7 (C-5 '), 120.3 (C-6'); 3 continuous oxygen carbon signal deltaC78.0 (C-4 '), 71.6 (C-11'), 64.3 (C-3 '), binding hydrogen profiles suggest that C-4' is 1 vicinal quaternary carbon signal in sesquiterpene fragments, except for C-3 'and C-11'. Since the coumarin parent nucleus and 1 double bond together provide 8 unsaturations, the structure has the remaining 2 unsaturations, and the sesquiterpene part of the compound is supposed to be a bicyclic structure. All hydrogen carbon data were assigned according to HSQC (tables 1 and 3).
In HMBC spectrum, δH 1.31(H3-14') and 0.97 (H)3-13') and δC78.0 (C-4') is related to deltaC64.3 (C-3') is irrelevant, but deltaH 3.66(Hα-3') and δH 3.32(Hβ-3') and δC78.0 (C-4 ') is related, indicating that C-3'/C-4 'are linked by an ether linkage, while Me-13', me-14 'are linked at the C-4' position; delta. For the preparation of a coatingH 1.19(H3-15') and δC30.8 (C-8 '), 38.7 (C-9'), 41.2 (C-10 '), 71.6 (C-11'), indicating that Me-15 'is attached at the C-9' position; delta. For the preparation of a coatingH 0.98(H3-12') and δC33.0 (C-7 '), 30.8 (C-8 '), 48.7 (C-9 '), indicating that Me-12' is attached at the C-8' position; deltaH 3.81(Ha-11') and 3.76 (H)b11') and deltaC163.0 The remote correlation of (C-7) suggests that the sesquiterpene fragment is linked to the C-7 position of the coumarin parent nucleus via an ether bond.
In NOESY spectrum, H3-12' and Hb11 'related, H-10' with Ha-11′,H3-12' correlation with H315' is related to H-8', suggesting Me-12', H211', H-10' is in the beta-orientation, H-8', me-15' is in the alpha-orientation; h-10' and H3-13 'correlation, suggesting Me-13' is β -oriented, me-14 'is α -oriented, and the relative configuration of the chiral centers is presumed to be 8's,9's,10' r. By comparing measured valuesECD and calculation of ECD data confirmed that the absolute configuration of Compound 9 was 8' S,9' S,10' R. A novel compound is searched and reported in an unpublished literature and is named as (8 ' S,9' S,10' R) -ferringensine H.
The structural identification data of sesquiterpene coumarin 10 are as follows:
white amorphous powder (MeOH), HRESIMS gave the excimer ion peak m/z 449.2301[ m ] +Na ]]+:(calcd.449.2226 for C26H34O5Na) and is presumed to be C26H34O5This suggests that there are 10 unsaturations in the structure.1H NMR(600MHz,CDCl3) In the spectrum, the low field region shows 5 proton signals characteristic of the 7-O-substituted coumarin parent nucleus: delta. For the preparation of a coatingH7.62 (1H, d, J =9.4Hz, H-4), 7.35 (1H, d, J =8.6Hz, H-5), 6.83 (1H, dd, J =8.6,2.3Hz, H-6), 6.79 (1H, d, J =2.3Hz, H-8) and 6.23 (1H, d, J =9.4Hz, H-3); group 1 continuous oxygen methylene proton signal: 3.72 (1H,d,J=8.7Hz,Ha-11') and 3.65 (1H, d, J =8.7Hzb-11'); 1 continuous oxygen methine hydrogen signal: deltaH4.67 (1H, td, J =11.1,5.1Hz, H-3'); the high field region gives 5 methyl proton signals: deltaH2.04 (3H, s, me-2 ') 1.06 (3H, s, me-15 '), 0.94 (3H, d, J =7.1Hz, me-12 '), 0.91 (3H, s, me-14 ') and 0.80 (3H, d, J =6.6Hz, me-13 ').13C NMR(150MHz,CDCl3) The spectrum shows 26 carbon signals, 9 are 7-O-substituted coumarin parent nucleus characteristic carbon signals deltaC162.6 (C-7), 161.4 (C-2), 156.0 (C-9), 143.5 (C-4), 128.8 (C-5), 113.1 (C-6), 113.1 (C-3), 112.6 (C-10), 101.6 (C-8). 15 carbon signals for sesquiterpene units, including 2 vicinal carbon signals: deltaC76.1 (C-11 '), 74.7 (C-3'). The 2 carbon signal is an acetyl signal: delta C171.1 (C-1 "), 21.5 (C-2"). Since the coumarin parent nucleus and 1 carbonyl group provide 8 unsaturations, the sesquiterpene moiety of the compound is suggested to be a bicyclic structure. All hydrogen carbon data were assigned according to HSQC (tables 1 and 3).
In HMBC spectrum, δH 0.80(H3-13') and δC74.7 (C-3 '), 49.9 (C-4 '), 38.3 (C-5 '), indicating that Me-13' is attached at the C-4' position; delta. For the preparation of a coatingH 0.91(H3-14') and δC 49.9(C-4′) 38.3 (C-5 '), 32.5 (C-6 '), 44.5 (C-10 '), indicating that Me-14' is attached at the C-5' position; deltaC 0.94(H3-12') and δC25.3 (C-7 '), 35.5 (C-8 '), 39.2 (C-9 '), indicating that Me-12' is attached at the C-8' position; delta. For the preparation of a coatingH 1.12(H3-15') and δC35.5 (C-8 '), 39.2 (C-9'), 44.5 (C-10 '), 76.1 (C-11'), relative, suggesting that Me-15 'is attached at the C-9' position; deltaH 2.04(H3-2 ") and 4.67 (H-3') and deltaC171.1 (C-1 ') associated, indicating that the acetyl group is attached at the C-3' position. Further, δH 3.72(Ha11') and 3.65 (H)b11') and deltaC162.6 The remote correlation of (C-7) suggests that the sesquiterpene fragment is linked to the C-7 position of the coumarin parent nucleus via an ether bond.
In NOESY spectrum, H3-14 'and H-3', Hβ-7′,H315' related, H-10' with H-4', Ha,b-11′,H3-12' correlation, suggesting that Me-13', me-14', me-15' and H-3' are in β -orientation, H-10' and Me-12' are in α -orientation, and the relative configuration of the chiral centers is presumed to be 3' r,4' r,5's,8' r,9' r,10' r. By comparing the actually measured ECD and the calculated ECD data, it was confirmed that the absolute configuration of Compound 10 was 3'R,4' R,5'S,8' R,9'R,10' R. A novel compound reported to be an unpublished literature was named (3 'R,4' R,5'S,8' R,9'R,10' R) -kamolol acetate.
The NMR data of sesquiterpene coumarins 1-10 are shown in Table 1-3.
TABLE 1 carbon spectra data for compounds 1-10 (150MHz, CDCl3)
Figure BDA0002518235580000131
TABLE 2 Hydrogen spectral data (600MHz, CDCl) for Compounds 1-53)
Figure BDA0002518235580000141
a Overlapped resonances.
Hydrogen of compounds 6-10 of Table 3Spectral data (600MHz, CDCl)3)
Figure BDA0002518235580000151
a Overlapped resonances.
Example 2
(1) Extracting 1500g of resina Ferulae with 95% ethanol under reflux for 3 times (30L), and recovering the crude extract under reduced pressure;
(2) Subjecting the crude 95% ethanol extract obtained in the step (1) to silica gel column chromatography, and performing gradient elution with a chloroform-acetone mixed solvent 100, 10;
(3) In the step (2), the eluate of the chloroform-acetone mixed solvent 100;
(4) The petroleum ether-ethyl acetate 100-1 stream obtained in the above step (3) is subjected to ODS chromatography, and eluted with a mixed solvent gradient of 50;
(5) The fraction of 80-90 parts of methanol-water obtained in the step (4) is prepared by HPLC RID-10A chromatography, the flow rate is 3.5mL/min, and the mobile phase is methanol: water =90, giving the sesquiterpene coumarin 3 (t)R=90 min) (yield 0.0003%), sesquiterpene coumarin 4 (t) R=68 min) (yield 0.0033%), sesquiterpene coumarin 5 (t)R=6 min) (yield 0.0009%), sesquiterpene coumarin 6 (t)R=18 min) (yield 0.0010%), sesquiterpene coumarin 7 (t)R=53 min) (yield 0.0015%), sesquiterpene coumarin 9 (t)R=15 min) (yield 0.0004%).
(6) The methanol-water 90 obtained in the step (4) is prepared by HPLC RID-10A chromatographic separation at the flow rate of 3mL/min and the mobile phase is methanol: water =80, giving sesquiterpene coumarin 2 (t)R=28 min) (yield 0.0002%).
(7) The methanol-water 80 obtained in the step (4) flows through HPLC RID-10A chromatographic separation preparation, the flow rate is 3.5mL/min, and the mobile phase is methanol: water =80, giving the sesquiterpene coumarin 1 (t)R=34 min) (yield 0.0003%), sesquiterpene coumarin 10 (t)R=30 min) (yield 0.0013%).
(8) The fraction of methanol-water 65-80 obtained in the step (4) is prepared by HPLC-UV chromatography, the flow rate is 3mL/min, and the mobile phase is methanol: water =70, giving sesquiterpene coumarin 8 (t)R=26 min) (yield 0.0005%).
The structural identification of sesquiterpene coumarins 1-10 is shown in example 1.
Example 3
(1) Heating and ultrasonically extracting 2000g of resina Ferulae with dichloromethane for 4 times (the dosage is 30L), and recovering the crude extract of the extractive solution under reduced pressure;
(2) Performing silica gel column chromatography on the dichloromethane crude extract obtained in the step (1), and performing gradient elution by using a petroleum ether-acetone mixed solvent 100, 1, 10;
(3) The eluate of the petroleum ether-acetone mixed solvent 100 in the step (2) is subjected to silica gel column chromatography, and is sequentially eluted with a petroleum ether-ethyl acetate mixed solvent 100;
(4) The petroleum ether-ethyl acetate 100-2 stream obtained in the above step (3) is subjected to ODS chromatography, and eluted with an acetonitrile-water mixed solvent gradient of 40;
(5) The acetonitrile-water 80-90 fractions obtained in the step (4) are prepared by HPLC-UV chromatography, the flow rate is 4mL/min, and the mobile phase is methanol: water =90, giving the sesquiterpene coumarin 3 (t)R=91 min) (yield 0.0003%), sesquiterpene coumarin 4 (t)R=67 min) (yield 0.0031%), sesquiterpene coumarin 5 (t)R=5 min) (yield 0.0008%), sesquiterpene coumarin 6 (t)R=15 min) (yield 0.0008%), sesquiterpene coumarin 7 (t)R=49 min) (yield 0.0013%), sesquiterpene coumarin 9 (t)R=8 min) (yield 0.0003%).
(6) 30-8 of acetonitrile-water obtained in the step (4) 0: water =80, giving the sesquiterpene coumarin 1 (t)R=36 min) (yield 0.0002%), sesquiterpene coumarin 2 (t)R=23 min) (yield 0.0002%), sesquiterpene coumarin 10 (t)R=30 min) (yield 0.0011%).
(7) The acetonitrile-water 40-60 fraction obtained in the step (4) is prepared by HPLC RID-10A chromatographic separation, the flow rate is 3.5mL/min, and the mobile phase is methanol: water =70, yielding sesquiterpene coumarin 8 (t)R=20 min) (yield 0.0004%).
The structural identification of sesquiterpene coumarins 1-10 is shown in example 1.
Example 4
(1) Extracting 500g of resina Ferulae with chloroform under reflux for 3 times (10L), and recovering the crude extract under reduced pressure;
(2) Subjecting the chloroform crude extract obtained in the step (1) to silica gel column chromatography, and performing gradient elution by using a dichloromethane-ethyl acetate mixed solvent 100;
(3) In the step (2), the eluate of the dichloromethane-ethyl acetate mixed solvent 100;
(4) Subjecting the petroleum ether-ethyl acetate 100 obtained in the step (3) to ODS chromatography, and eluting with a mixed solvent gradient of 50;
(5) The fraction of 80-90 parts of methanol-water obtained in the step (4) is prepared by HPLC RID-10A chromatography, the flow rate is 3.5mL/min, and the mobile phase is methanol: water =90, giving the sesquiterpene coumarin 3 (t)R=97 min) (yield 0.0003%), sesquiterpene coumarin 4 (t)R=74 min) (yield 0.0027%), sesquiterpene coumarin 5 (t)R=4 min) (yield 0.0009%), sesquiterpene coumarin 6 (t)R=19 min) (yield 0.0009%), sesquiterpene coumarin 7 (t)R=53 min) (yield 0.0015%), sesquiterpene coumarin 9 (t)R=9 min) (yield 0.0004%).
(6) The methanol-water 90 obtained in the step (4) is prepared by HPLC RID-10A chromatographic separation at a flow rate of 4mL/min and a mobile phase of methanol: water =80, giving the sesquiterpene coumarin 1 (t)R=34 min) (yield 0.0003%), sesquiterpene coumarin 2 (t)R=18 min) (yield 0.0003%), sesquiterpene coumarin 10 (t)R=27min (yield 0.0012%).
(7) And (3) separating the methanol-water 80 obtained in the step (4) by HPLC-UV chromatography at a flow rate of 3.5mL/min, wherein the mobile phase is methanol: water =70, giving sesquiterpene coumarin 8 (t) R=19 min) (yield 0.0005%).
The structural identification of sesquiterpene coumarins 1-10 is shown in example 1.
Example 5
(1) Heating and reflux-extracting 2500g of resina Ferulae with 90% methanol for 4 times (25L), and recovering the crude extract under reduced pressure;
(2) Subjecting the 90% methanol crude extract obtained in the step (1) to silica gel column chromatography, and performing gradient elution with a chloroform-ethyl acetate mixed solvent 100, 10;
(3) In the step (2), the eluate of the chloroform-ethyl acetate mixed solvent 100;
(4) The petroleum ether-acetone 100-2 stream obtained in the above step (3) is subjected to ODS chromatography, and eluted with a mixed solvent gradient of 50;
(5) The methanol-water 80-90 fraction obtained in the step (4) is prepared by HPLC RID-10A chromatographic separation, the flow rate is 4mL/min, and the mobile phase is acetonitrile: water =80, giving the sesquiterpene coumarin 3 (t)R=93 min) (yield 0.0003%), sesquiterpene coumarin 4 (t)R=70 min) (yield 0.0030%), sesquiterpene coumarin 5 (t) R=4 min) (yield 0.0009%), sesquiterpene coumarin 6 (t)R=16 min) (yield 0.0008%), sesquiTerpene coumarin 7 (t)R=57 min) (yield 0.0016%), sesquiterpene coumarin 9 (t)R=8 min) (yield 0.0005%).
(6) The methanol-water 90 obtained in the step (4) is prepared by HPLC RID-10A chromatography separation, the flow rate is 3mL/min, and the mobile phase is acetonitrile: water =70, giving sesquiterpene coumarin 2 (t)R=20 min) (yield 0.0002%).
(7) The methanol-water fraction of 80-90 obtained in the step (4) is prepared by HPLC RID-10A chromatographic separation, the flow rate is 3.5mL/min, and the mobile phase is acetonitrile: water =65, giving the sesquiterpene coumarin 1 (t)R=38 min) (yield 0.0003%), sesquiterpene coumarin 10 (t)R=30 min) (yield 0.0011%).
(8) And (3) separating the methanol-water fraction of 70-80 obtained in the step (4) by HPLC RID-10A chromatography, wherein the flow rate is 4mL/min, and the mobile phase is acetonitrile: water =55, to give sesquiterpene coumarin 8 (t)R=16 min) (yield 0.0005%).
The structural identification of sesquiterpene coumarins 1-10 is shown in example 1.
Example 6
(1) Extracting 1000g resina Ferulae with 90% ethanol under reflux for 4 times (15L), and recovering the crude extract under reduced pressure;
(2) Subjecting the 90% ethanol crude extract obtained in the step (1) to silica gel column chromatography, and performing gradient elution by using a dichloromethane-acetone mixed solvent 100, 10;
(3) The eluate in the dichloromethane-acetone mixed solvent 100 to 100 in the step (2) is separated by silica gel column chromatography, and is sequentially eluted by a petroleum ether-ethyl acetate mixed solvent 100, 5, 100, 8, 10;
(4) Subjecting the petroleum ether-ethyl acetate 100 obtained in the step (3) to ODS chromatography, and eluting with a mixed solvent gradient of 50;
(5) The methanol-water 80-90 fraction obtained in the step (4) is prepared by HPLC-UV chromatography, the flow rate is 3mL/min, and the mobile phase isIs methanol: water =90, giving the sesquiterpene coumarin 3 (t)R=105 min) (yield 0.0002%), sesquiterpene coumarin 4 (t)R=83 min) (yield 0.0031%), sesquiterpene coumarin 5 (t)R=11 min) (yield 0.0009%), sesquiterpene coumarin 6 (t)R=27 min) (yield 0.0008%), sesquiterpene coumarin 7 (t)R=71 min) (yield 0.0013%), sesquiterpene coumarin 9 (t)R=15 min) (yield 0.0003%).
(6) The fraction of 80-90 parts of methanol-water obtained in the step (4) is prepared by HPLC-UV chromatography, the flow rate is 3mL/min, and the mobile phase is methanol: water =80, giving the sesquiterpene coumarin 1 (t)R=43 min) (yield 0.0003%), sesquiterpene coumarin 2 (t)R=25 min) (yield 0.0002%), sesquiterpene coumarin 10 (t)R=37 min) (yield 0.0011%).
(7) And (3) separating the methanol-water 70 obtained in the step (4) by HPLC-UV chromatography at a flow rate of 3mL/min, wherein the mobile phase is methanol: water =70, giving sesquiterpene coumarin 8 (t)R=25 min) (yield 0.0004%).
The structural identification of sesquiterpene coumarins 1-10 is shown in example 1.
EXAMPLE 7 anti-neuritic Activity test of the New sesquiterpene coumarins 1-10 prepared in examples 1-6
(1) The experimental principle is as follows:
chronic neuroinflammation mediated by excessive microglial activation plays a key role in the development and progression of neurodegenerative diseases. Under resting state, microglia can eliminate metabolic products in brain and maintain brain tissue homeostasis. When the central nervous system is damaged (e.g., inflammation), microglia are activated and over-activated, producing large amounts of inflammatory factors that damage neurons. Meanwhile, the inflammatory factors further activate microglia, so that a malignant cycle is formed in the brain, and finally, the neurodegenerative disease is generated and further deepened. Therefore, inhibition of activation of neuroinflammation mediated by activation of microglial activity is an effective strategy for prevention and treatment of neurodegenerative diseases. According to the invention, the anti-inflammatory activity of the new sesquiterpene coumarins 1-10 is evaluated by constructing a screening model for abnormal activation of BV2 microglia activated by in vitro LPS and taking NO released by activated microglia as an index.
(2) The experimental method comprises the following steps:
(1) culture of mouse microglial cell line BV-2
All glassware and metal instruments (culture bottles, pipettes, solution bottles, etc.) used in cell culture and model building were autoclaved at 121 ℃ for 30min to completely remove the contaminated LPS. A cell culture medium containing 10% fetal bovine serum was prepared on the basis of DMEM medium. The microglia count is about 2.0X 105cells/mL at a concentration of 5% CO2And subculturing in a culture bottle at 37 ℃, wherein the adherent cells account for about 70-80% of the bottom area of the culture bottle by the third day, digesting the adherent cells by pancreatin, and subculturing to another culture bottle. BV2 after frozen and thawed in an ultra-low temperature refrigerator at minus 80 ℃ is taken as the first generation, and BV2 cells of 3 rd to 8 th generations are selected for experiments.
(2) Method for preparing medicine
Test compounds were all solid and dissolved in DMSO. The stock solution was prepared at a concentration of 100mM and stored at-20 ℃. It was diluted with DMDM medium at the time of use to 100. Mu.M, 30. Mu.M, 10. Mu.M and 1. Mu.M in this order. The final concentration of DMSO is less than 1 ‰.
(3) Griess method for detecting inhibition effect of compound on LPS (LPS) activated microglia
Taking BV2 microglia in logarithmic growth phase, adjusting cell density to 2.0 × 10 by using fresh DMDM culture medium containing 10% fetal calf serum 5cells/mL, seeded in 96-well plates, 100. Mu.L/well, at 37 ℃ 5%2The incubator of (2) for cultivation. After the cells are cultured for 24 hours in an adherent way, the cells are replaced by serum-free fresh culture solution and are simultaneously treated by adding drugs. Each compound was administered at a dose of 100. Mu.M, 30. Mu.M, 10. Mu.M, 1. Mu.M in combination with LPS. Meanwhile, a blank control is set. The final concentration of LPS in each administration group was 100ng/mL. Continuously culturing for 24h after adding medicine into cells, collecting supernatant, and detecting NO in the supernatant by Griess colorimetric method2 -And (4) content.
(4) MTT method for detecting influence of compound on survival rate of microglia cells
Taking BV2 microglia cultured in logarithmic growth phase, adjusting cell density to 2.0 × 10 by using fresh DMDM culture medium containing 10% fetal calf serum5cells/mL, seeded in 96-well plates, 100. Mu.L/well at 37 ℃ C. 5% CO2Culturing in the incubator. After the cells are cultured for 24 hours adherent, the cells are changed into fresh culture solution, and meanwhile, the cells are treated by adding medicine. Each compound was administered at a dose of 100. Mu.M, 30. Mu.M, 10. Mu.M, 1. Mu.M in combination with LPS. Blank control was also set. The final concentration of LPS in each administration group was 100ng/mL. After the addition of the drug, the cells were cultured for 24 hours, then MTT solution, 10. Mu.L/well was added to the cell fluid, the cells were incubated with 0.25mg/mL MTT at 37 ℃ for 3 hours, the culture fluid was aspirated, and then 150. Mu.L DMSO solution was added to determine the OD value of the optical density. And (3) processing data, namely processing the data by using corresponding software of a microplate reader, calculating an average value of OD values of 3 holes of each sample, and calculating the Cell viability (CV%) by using the average value according to the following formula.
Cell survival% = average value of sample group OD value/average value of blank group OD value × 100%
(5) Statistical method
All data were examined and analyzed using the SPSS statistical software package. Results are expressed as mean ± standard error, and the global differences were evaluated, and the means between groups was analyzed by One-Way ANOVA analysis for homogeneity of variance and by Dunnett's test analysis for comparison between groups. The multiple sample homogeneity of variance test uses a Leven test, when p is greater than 0.05, the variances are uniform, dunnett's double-sided T test is used for testing the difference of the mean values among the groups, when p is less than 0.05, the variances are not uniform, dunnett T3 test is used for testing the difference of the mean values among the groups.
⑥IC50Is calculated by a computer
Calculating IC by nonlinear regression fitting of parameters such as each dosage and inhibition rate50。
(3) The experimental results are as follows: see Table 4
TABLE 4 sesquiterpene coumarins 1-10 Experimental results for inhibiting microglial cell activation
Figure BDA0002518235580000211
Significance:*P<0.05,**P<0.01,***P<0.001 compared to LPS-induced group;###P<0.001 compared to the control group.
As a result, the new sesquiterpene coumarin compounds 1 (30. Mu.M, 100. Mu.M), 3 (100. Mu.M), 4 (100. Mu.M), 5 (100. Mu.M), 6 (30. Mu.M, 100. Mu.M), 7 (10. Mu.M, 30. Mu.M, 100. Mu.M), 8 (1. Mu.M, 10. Mu.M, 30. Mu.M, 100. Mu.M), 9 (30. Mu.M, 100. Mu.M) and 10 (100. Mu.M) prepared in examples 1 to 6 were able to significantly inhibit the release of LPS-induced over-activated BV2 microglia NO.

Claims (5)

1. The sesquiterpene coumarin compound and the pharmaceutically acceptable salt thereof are as follows:
Figure QLYQS_1
。
2. the preparation method of the sesquiterpene coumarin compound and the pharmaceutically acceptable salt thereof is characterized by comprising the following steps:
(1) Extracting the asafetida with a methanol or ethanol solvent, and recovering an extracting solution to obtain a crude extract, wherein the volume concentration of the methanol or the ethanol is 60-100%;
(2) Separating the crude extract obtained in the step (1) by silica gel column chromatography, and performing gradient elution by using a petroleum ether-ethyl acetate mixed solvent, or a petroleum ether-acetone mixed solvent, or a dichloromethane-ethyl acetate mixed solvent, or a dichloromethane-acetone mixed solvent, or a chloroform-ethyl acetate mixed solvent, or a chloroform-acetone mixed solvent to obtain eluates with different polarities;
(3) Performing ODS column chromatography on the eluate with different polarities obtained in the step (2), and performing gradient elution by using a methanol-water mixed solvent or an acetonitrile-water mixed solvent as a mobile phase;
(4) Further separating the methanol-water or acetonitrile-water eluate obtained in the step (3) by HPLC, and carrying out gradient elution by using a methanol-water mixed solvent or acetonitrile-water mixed solvent as a mobile phase to obtain sesquiterpene coumarins 1-10;
The volume ratio of the petroleum ether-ethyl acetate mixed solvent or the petroleum ether-acetone mixed solvent in the step (2) is (100); the volume ratio of a dichloromethane-ethyl acetate mixed solvent, or a dichloromethane-acetone mixed solvent, or a chloroform-ethyl acetate mixed solvent, or a chloroform-acetone mixed solvent is (100);
in the step (3), the volume ratio of the methanol-water mixed solvent is 50 to 100, and the volume ratio of the acetonitrile-water mixed solvent is 30;
the volume ratio of the methanol-water mixed solvent in the step (4) is 60 to 90, and the volume ratio of the acetonitrile-water mixed solvent is 50 to 80;
Figure QLYQS_2
。
3. the process for the preparation of sesquiterpene coumarins and pharmaceutically acceptable salts thereof according to claim 2, wherein: the extraction method in the step (1) is heating reflux extraction or heating ultrasonic extraction for 2 to 5 times, wherein the ratio of the feed to the liquid is 1 to 5 to 30 g/mL.
4. A pharmaceutical composition comprising the sesquiterpene coumarin compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, diluent or carrier.
5. The use of the sesquiterpene coumarins of claim 1 and pharmaceutically acceptable salts thereof or the pharmaceutical composition of claim 4 in the preparation of a medicament for the prevention or treatment of neurodegenerative disorders.
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