CN113173905A - Coumaric acid in artemisia capillaris and pharmaceutical composition thereof as well as preparation method and application of coumaric acid - Google Patents
Coumaric acid in artemisia capillaris and pharmaceutical composition thereof as well as preparation method and application of coumaric acid Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 235000008658 Artemisia capillaris Nutrition 0.000 title description 10
- 241000092668 Artemisia capillaris Species 0.000 title description 10
- 239000002253 acid Substances 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 239000003814 drug Substances 0.000 claims abstract description 24
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- 206010019668 Hepatic fibrosis Diseases 0.000 claims abstract description 15
- 239000003937 drug carrier Substances 0.000 claims abstract description 9
- 229930101531 artemisinin Natural products 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 48
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- 238000011894 semi-preparative HPLC Methods 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
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- 238000000034 method Methods 0.000 claims description 11
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 11
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- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 14
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- 235000014899 silybin Nutrition 0.000 description 4
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
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- ROAYSRAUMPWBQX-UHFFFAOYSA-N ethanol;sulfuric acid Chemical compound CCO.OS(O)(=O)=O ROAYSRAUMPWBQX-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Abstract
The invention provides 14 novel coumaric compounds artemisinins A-N (1-14) shown in a structural formula (I) and a preparation method and application thereof, and a pharmaceutical composition containing the compounds artemisinins A-N (1-14) and application thereof, relating to the technical field of medicines. The compounds 1-14 of the invention have cytotoxic activity to human hepatic stellate cells (HSC-LX2), can form a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient, and can be used for preparing anti-hepatic fibrosis drugs.
Description
The technical field is as follows:
the invention belongs to the technical field of medicines. In particular to a coumaric compound artemisinins A-N (1-14) and a preparation method and application thereof, and a pharmaceutical composition containing the coumaric compound artemisinins A-N (1-14) and application thereof.
Background art:
liver fibrosis is a common pathological process of most liver diseases, i.e., under the action of various pathogenic factors, extracellular matrix (ECM) in the liver is excessively deposited, thereby affecting the physiological structure and function of the liver, and if the ECM is inhibited or reversed in time, the liver cirrhosis or liver cancer is accelerated, thus seriously affecting the living quality of human body. Currently, single control of etiology or liver protection by traditional Chinese medicines is the main way to treat hepatic fibrosis, and no chemosynthesis medicine aiming at hepatic fibrosis treatment exists clinically. Although development of anti-fibrosis drugs has progressed to some extent in recent years, some drug candidates have difficulty in achieving the intended therapeutic effect or side effects in clinical trials. The traditional Chinese medicine plays an important role in preventing and treating human diseases, and natural products separated from the traditional Chinese medicine provide abundant resources for searching new anti-hepatic fibrosis active ingredients or lead compounds due to the characteristics of various structures, various biological activities and the like. Artemisia capillaris (Artemisia capillaris) of Artemisia is recorded in ancient herbal books such as Shennong's herbal classic and Ben Cao gang mu: it is mainly indicated for wind-damp, cold-heat, pathogenic heat accumulation, yellow gallbladder, etc. At present, the active ingredients of artemisia capillaris for resisting hepatic fibrosis are not reported in the existing documents.
Artemisia capillaris (Artemisia capillaris) belongs to Artemisia of Compositae, is semi-shrub-shaped herbaceous plant, and produces Liaoning, Hebei, Shanxi (east and south), Shandong, Jiangsu, Anhui, Zhejiang, Jiangxi, Fujian, Taiwan, Henan (east and south), Hubei, Hunan, Guangdong, Guangxi, Sichuan and the like; it is grown in the low-altitude area, the wet sand land near the coast, the roadside and the low mountain slope area. The Chinese medicinal materials, named as "Yinchen", "herba Artemisiae Scopariae" or "herba Artemisiae Scopariae", are mainly used for treating rheumatism, cold and heat, pathogenic heat accumulation, and jaundice. In the previous work of the invention, the previous research finds that the artemisia capillaris ethanol extract has obvious HSC-LX2 cytotoxic activity (the inhibition rate is 68.7% when the concentration is 400 mu g/mL), and 14 new coumaric acids, namely artemicapillalasins A-N (1-14), are obtained through activity oriented separation. To date, the prior art has no reports of compounds 1-14, and no reports of compounds 1-14 and pharmaceutical compositions thereof as anti-hepatic fibrosis drugs.
The invention content is as follows:
the invention aims to provide a novel coumaric acid with medicinal value, artemicapillasins A-N (1-14), a preparation method and application thereof, a pharmaceutical composition containing compounds 1-14 and application thereof.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
a coumaric compound artemicapillasins A-N (1-14) shown in a structural formula (I),
the invention also provides a preparation method of the coumaric acid compounds 1-14, which comprises the steps of crushing dried overground parts of artemisia capillaries, extracting twice with 90% ethanol for 3 days, merging ethanol extracting solutions, recovering ethanol extract under reduced pressure, dispersing the extract in water, extracting with ethyl acetate, concentrating to obtain an ethyl acetate extracting part, carrying out silica gel column chromatography on the ethyl acetate extracting part, and carrying out gradient elution by using acetone-petroleum ether (0:100,5:95,10:90,20:80,40:60 and 100:0) as an eluent to obtain six fractions Fr.A-Fr.F; subjecting fraction Fr.D to silica gel column chromatography (ethyl acetate-petroleum ether, 20:80,30:70 and 40:60) to obtain three fractions Fr.D1-Fr.D 3; subjecting the fraction Fr.D2 to MCI gel CHP 20P column chromatography (water-methanol, 50:50 and 0:100) to obtain four fractions Fr.D2-1-Fr.D2-4; subjecting Fr.D2-2 to silica gel column chromatography (ethyl acetate-petroleum ether, 20:80 and 30:70) to obtain three fractions Fr.D2-2-1-Fr.D2-2-3, subjecting Fr.D2-2-2 to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50), and subjecting to semi-preparative HPLC (water-acetonitrile, 60:40) to obtain compound 6; subjecting fraction Fr.D2-2-3 to silica gel column chromatography (ethyl acetate-chloroform, 20:80), subjecting to semi-preparative HPLC (water-acetonitrile, 67:33) to obtain compounds 4,8 and 10, subjecting fraction Fr.D2-3 to silica gel column chromatography (acetone-petroleum ether, 20:80 and 30:70) to obtain three fractions Fr.D2-3-3-3, subjecting fraction Fr.D2-3-2 to silica gel column chromatography (ethyl acetate-petroleum ether, 35:65 and 40:60) to obtain compound 2, subjecting fraction Fr.D2-3-3-1 to silica gel column chromatography (acetone-petroleum ether, 20:80 and 30:70) to obtain two fractions Fr.D2-3-3-1-Fr.D2-3-3-2, Fr.D2-3-3-1-Fr.D 2-3-3-1-LH-3-1, subjecting to silica gel column chromatography (chloroform-Sephadex-20 gel, 50:50), then obtaining a compound 7 by semi-preparative HPLC (water-acetonitrile, 50: 50); fraction Fr.D2-3-3-2 was subjected to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50), and then to silica gel column chromatography (ethyl acetate-chloroform, 10:90 and 20:80) to obtain compounds 9 and 11, fraction Fr.D-3 was subjected to silica gel column chromatography (ethyl acetate-petroleum ether, 15:85,40:60) to obtain three fractions Fr.D3-1-Fr.D3-3, fraction Fr.D3-1 was subjected to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50), and then to semi-preparative HPLC (water-acetonitrile, 55:45) to obtain compound 12, fraction Fr.D3-2 was subjected to silica gel column chromatography (chloroform-petroleum ether, 50:50), then to semi-preparative HPLC (water-acetonitrile, 55:45) to obtain compound 1,5,13,15, fraction D3-3, 20:80) followed by semi-preparative HPLC (water-acetonitrile, 47:53) gave compounds 3, 14.
The invention also provides application of the coumaric acid compounds 1-14 in preparing anti-hepatic fibrosis medicines.
In addition, the present invention provides a pharmaceutical composition comprising at least one of coumaric compounds 1-14 and a pharmaceutically acceptable carrier or excipient.
The invention also provides application of the pharmaceutical composition in preparing anti-hepatic fibrosis drugs.
The series of coumaric acid compounds artemicapillasins A-N (1-14) provided by the invention have obvious cytotoxic effect on HSC-LX2 cells, and can be used for preparing anti-hepatic fibrosis drugs.
The method for applying the compound in the preparation of the anti-hepatic fibrosis medicine is not particularly limited, and the method well known in the field can be selected.
When at least one of the compounds 1 to 14 is used for preparing the anti-hepatic fibrosis drug, the compounds 1 to 14 are preferably used directly or in the form of a pharmaceutical composition.
The pharmaceutical compositions of the present invention comprise at least one of compounds 1-14 and a pharmaceutically acceptable carrier or excipient. In the present invention, the pharmaceutically acceptable carrier or excipient is preferably a solid, semi-solid or liquid diluent, filler and pharmaceutical product adjuvant. The pharmaceutically acceptable carrier or excipient is not particularly limited in the present invention, and may be selected from pharmaceutically acceptable carriers and/or excipients which are well known in the art, are non-toxic and inert to humans and animals.
The preparation method of the pharmaceutical composition is not particularly limited, at least one of the compounds 1 to 14 can be directly mixed with a pharmaceutically acceptable carrier or excipient, the mixing process is not particularly limited, and the pharmaceutical composition can be obtained by selecting the process well known in the art.
The method for applying the pharmaceutical composition in the preparation of the anti-hepatic fibrosis medicine is not particularly limited, and the method well known in the field can be selected.
In the invention, when the compound or the pharmaceutical composition is used for preparing an anti-hepatic fibrosis drug, the content of the compound or the pharmaceutical composition in the drug is preferably 0.1-99%; in the pharmaceutical composition, the content of at least one of the compounds 1-14 in the pharmaceutical composition is preferably 0.5-90%. The pharmaceutical composition of the present invention is preferably used in the form of a dose per unit body weight. In the present invention, the prepared drug can be administered preferably by both injection (intravenous injection, intramuscular injection) and oral administration.
Description of the drawings:
FIG. 1 is a schematic structural view of artemicapillasins A-N (1-14) which are coumaric compounds of the present invention.
The specific implementation mode is as follows:
for better understanding of the essence of the present invention, the test examples and examples of the present invention are described below in conjunction with the drawings to further illustrate the coumaric compounds of the present invention, arteminapasins a-N (1-14), and the preparation method, structural identification, and pharmacological effects thereof, but the present invention is not limited thereto.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
preparation of Compounds 1-14:
drying aerial parts of herba Artemisiae Scopariae, pulverizing, cold extracting with 90% ethanol twice each for 3 days, mixing ethanol extractive solutions, recovering ethanol extract under reduced pressure, dispersing the extract in water, extracting with ethyl acetate, concentrating to obtain ethyl acetate extract, performing silica gel column chromatography on the ethyl acetate extract, and gradient eluting with acetone-petroleum ether (0:100,5:95,10:90,20:80,40:60 and 100:0) as eluent to obtain six fractions Fr.A-Fr.F; subjecting fraction Fr.D to silica gel column chromatography (ethyl acetate-petroleum ether, 20:80,30:70 and 40:60) to obtain three fractions Fr.D1-Fr.D 3; subjecting the fraction Fr.D2 to MCI gel CHP 20P column chromatography (water-methanol, 50:50 and 0:100) to obtain four fractions Fr.D2-1-Fr.D2-4; subjecting Fr.D2-2 to silica gel column chromatography (ethyl acetate-petroleum ether, 20:80 and 30:70) to obtain three fractions Fr.D2-2-1-Fr.D2-2-3, subjecting Fr.D2-2-2 to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50), and subjecting to semi-preparative HPLC (water-acetonitrile, 60:40) to obtain compound 6; subjecting fraction Fr.D2-2-3 to silica gel column chromatography (ethyl acetate-chloroform, 20:80), subjecting to semi-preparative HPLC (water-acetonitrile, 67:33) to obtain compounds 4,8 and 10, subjecting fraction Fr.D2-3 to silica gel column chromatography (acetone-petroleum ether, 20:80 and 30:70) to obtain three fractions Fr.D2-3-3-3, subjecting fraction Fr.D2-3-2 to silica gel column chromatography (ethyl acetate-petroleum ether, 35:65 and 40:60) to obtain compound 2, subjecting fraction Fr.D2-3-3-1 to silica gel column chromatography (acetone-petroleum ether, 20:80 and 30:70) to obtain two fractions Fr.D2-3-3-1-Fr.D2-3-3-2, Fr.D2-3-3-1-Fr.D 2-3-3-1-LH-3-1, subjecting to silica gel column chromatography (chloroform-Sephadex-20 gel, 50:50), then obtaining a compound 7 by semi-preparative HPLC (water-acetonitrile, 50: 50); fraction Fr.D2-3-3-2 was subjected to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50) and then to silica gel column chromatography (ethyl acetate-chloroform, 10:90 and 20:80) to obtain compound 9, and fraction Fr.D-3 was subjected to silica gel column chromatography (ethyl acetate-petroleum ether, 15:85,40:60) to obtain three fractions Fr.D3-1-Fr.D3-3. fraction Fr.D3-1 was subjected to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50) and then to semi-preparative HPLC (water-acetonitrile, 55:45) to obtain compound 12. fraction Fr.D3-2 was subjected to silica gel column chromatography (chloroform-petroleum ether, 50:50) and then to semi-preparative HPLC (water-acetonitrile, 55:45) to obtain compound 1, Fr 5,13,15. fraction Fr.D3-3-3, 20:80) followed by semi-preparative HPLC (water-acetonitrile, 47:53) gave compounds 3, 14.
Structural data for compounds 1-14:
specific optical rotations were measured by an Autopol VI polarimeter (Rudolph Research Analytical, Hackettstown, USA); the infrared spectrum was measured by an ATR attenuated Total reflectance-Diamond Crystal (ATR ITX-DIAMOND) method using a NICOLET iS10 type infrared spectrometer (Thermo Fisher Scientific, Madison, USA);the ultraviolet spectrum was measured by a UV-2401PC type ultraviolet spectrometer (Shimadzu, Kyoto, Japan); ECD spectra were determined by an Applied Photophysics circular dichroism (Applied Photophysics, Surrey, UK); nuclear magnetic resonance spectroscopy was measured using an Avance III 600(Bruker, Bremerhaven, Germany) superconducting nuclear magnetic resonance instrument using TMS (tetramethylsilane) as internal standard; high resolution mass spectra were determined using Shimadzu LC-MS-IT-TOF (Shimadzu, Kyoto, Japan), Agilent UPLC/Q-TOF and G6230 mass spectrometer (Agilent Technologies, Santa Clara, USA); the thin layer chromatography silica gel plate HSGF254 is purchased from Yangtze river friend silica gel development Co, Ltd; column chromatography silica gel (200-300 mesh) is produced by Haixiang chemical industry Co., Ltd in Linyi city; column chromatography Sephadex LH-20 is available from GE Healthcare Bio-Sciences AB; the high performance liquid chromatograph is purchased from Shimadzu corporation, the model of the controller is CBM-20A, the model of the pump is LC-20AR, the model of the detector is SPD-M20A, the model of the column oven is AT-350, and the model of the chromatographic column is Agilent-Eclipse XDB-C18(5 mu M,9.4 multiplied by 250 mm); chromatographically pure acetonitrile was purchased from Mirrida and the deionized channel water was purified by the MingCheTM-D24 UV Merk Millipore system; the medium-pressure liquid phase (Dr Flash-II) is a product of Shanghai Lisui company, and the MCI column of Mitsubishi company, the model of which is CHP-20P (75-150 mu m); analytically pure methanol and acetonitrile were purchased from Tianjin Damao chemical reagent factory; developer of 10% H2SO4-EtOH solution.
Artemicapillasin A(1)
The molecular formula is as follows: c18H20O5
Molecular weight: 316
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.09, methanol)
HRESIMS (-) M/z Experimental value 315.1252[ M-H]–Calculated value 315.1238[ M-H]–。
IR vmax:3520-2658,1717,1692,1624,1604,1492,1441,1198,776cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 1 and 3.
Artemicapillasin B(2)
The molecular formula is as follows: c19H20O5
Molecular weight: 328
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.09, methanol)
HRESIMS (-) M/z Experimental value 329.1370[ M-H]–Calculated value 329.1384[ M-H]–。
IR vmax:3520-2601,1698,1604,1493,1438,1379,1296,1247,773cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 1 and 3.
Artemicapillasin C(3)
The molecular formula is as follows: c15H16O4
Molecular weight: 260
The characteristics are as follows: white amorphous powder
HRESIMS (-) M/z Experimental value 259.0956[ M-H]–Calculated value 259.0976[ M-H]–。
IR vmax:3520-2426,3392,1640,1543,1434,1384,1271,1228,1154cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 1 and 3.
Artemicapillasin D(4)
The molecular formula is as follows: c15H16O5
Molecular weight: 276
The characteristics are as follows: white amorphous powder
HRESIMS (-) M/z Experimental value 275.0916[ M-H]–Calculated value 275.0925[ M-H]–。
IR vmax:3520-2610,3430,1681,1638,1607,1464,1383,1312,1229,764cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 1 and 3.
Artemicapillasin E(5)
The molecular formula is as follows: c19H24O5
Molecular weight: 332
The characteristics are as follows: white amorphous powder
HRESIMS (-) M/z Experimental value 331.1541[ M-H]–Calculated value 331.1551[ M-H]–。
IR vmax:3520-2577,3392,1682,1600,1477,1345,1260,1191,773cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 1 and 3.
Artemicapillasin F(6)
The molecular formula is as follows: c19H22O3
Molecular weight: 298
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.09, methanol)
HRESIMS (+) M/z Experimental value 299.1636[ M + H]+Calculated value 299.1642[ M + H]+。
IR vmax:3500-2500,1688,1628,1475,1438,1308,1278,1205,1144,757cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 1 and 3.
Artemicapillasin G(7)
The molecular formula is as follows: c19H22O4
Molecular weight: 314
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.09, methanol)
HRESIMS (+) M/z Experimental value 315.1577[ M + H]+Calculated value 315.1591[ M + H]+。
IR vmax:3500-2854,3379,1684,1632,1598,1477,1438,1276,1194,1156,759cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 1 and 3.
Artemicapillasin H(8)
The molecular formula is as follows: c19H24O4
Molecular weight: 316
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.09, methanol)
HRESIMS (+) M/z Experimental value 317.1742[ M + H]+Calculated value 317.1747[ M + H]+。
IR vmax:3500-2630,3421,1682,1628,1601,1478,1434,1270,1174,1155,778cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 2 and 3.
Artemicapillasin I(9)
The molecular formula is as follows: c17H20O5
Molecular weight: 304
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.04, methanol)
HRESIMS (+) M/z Experimental value 305.1372[ M + H]+Calculated value 305.1384[ M + H]+。
IR vmax:3500-2500,3427,1688,1633,1604,1475,1435,1271,1213,1100,777cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 2 and 3.
Artemicapillasin J(10)
The molecular formula is as follows: c19H24O4
Molecular weight: 316
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.09, methanol)
HRESIMS (+) M/z Experimental value 317.1729[ M + H]+Calculated value 317.1747[ M + H]+。
IR vmax:3500-2500,3401,1686,1631,1602,1474,1436,1265,1223,1136,777cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 2 and 3.
Artemicapillasin K(11)
The molecular formula is as follows: c19H24O5
Molecular weight: 332
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.10, methanol)
HRESIMS (+) M/z Experimental value 333.1681[ M + H]+Calculated value 333.1697[ M + H]+。
IR vmax:3500-2500,3421,1685,1631,1602,1475,1436,1266,1222,1136,778cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 2 and 3.
Artemicapillasin L(12)
The molecular formula is as follows: c19H24O4
Molecular weight: 316
The characteristics are as follows: white amorphous powder
And (3) optical rotation:
(c 0.07, methanol)
HRESIMS (-) M/z Experimental value 315.1583[ M-H]–Calculated value 315.1602[ M-H]–。
IR vmax:3500-2852,3428,1631,1604,1553,1475,1438,1260,1220,1135,1064cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 2 and 3.
Artemicapillasin M(13)
The molecular formula is as follows: c19H22O4
Molecular weight: 314
The characteristics are as follows: white amorphous powder
HRESIMS (+) M/z Experimental value 315.1572[ M + H]+Calculated value 315.1591[ M + H]+。
IR vmax:3500-2543,1680,1625,1608,1487,1462,1280,1208,1101,1062cm-1。
1H NMR and13the C NMR (DEPT) data are shown in tables 2 and 3.
Artemicapillasin N(14)
The molecular formula is as follows: c18H18O4
Molecular weight: 298
The characteristics are as follows: white amorphous powder
HRESIMS (-) M/z Experimental value 297.1126[ M-H]–Calculated value 297.1132[ M-H]–。
IR vmax:3500-2500,1684,1637,1605,1561,1275,1138,757cm-1。
1H NMR and13c NMR (DEPT) numberSee tables 2 and 3.
Example 2:
cytotoxic Activity of Compounds 1-14 against HSC-LX 2.
1. Materials and methods
1.1 materials
Human hepatic stellate cell line LX2 (HSC-LX2) was purchased from Jiening Biotech, Inc., Shanghai; RPMI-1640 medium and fetal bovine serum were purchased from Gibco BRL (NY, USA); MTT was purchased from cantonese seiko biotechnology limited.
1.2 instruments
Flex Station 3 desktop multifunctional microplate reader (Bio-RAD 680, USA); analytical balance (AG135, Metler Toledo, china); incubator (DHP-9082, Shanghai).
1.3 Experimental procedures
MTT method was used to determine the toxic activity of the samples against HSC-LX2 cells. HSC-LX2 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Cells grown in log phase at 1X 104The density of each well is inoculated in a 96-well plate, after 24 hours, the maintenance solution is replaced by a culture medium containing test samples with different concentrations, a cell control group only added with the maintenance solution is arranged, and silybin is used as a positive drug control. After 48h of incubation, the culture broth was discarded and 100. mu.L of MTT solution (1 mg/mL) was added; placing in a constant temperature box at 37 ℃ for incubation for 4h, discarding MTT solution and adding 100 mu L DMSO to dissolve alpha crystal; finally, the absorbance value of each well was measured at 490nm with a microplate reader. The calculation formula of the HSC-LX2 cell inhibition rate is inhibition rate (%) ═ A(blank)–A(sample)]/A(blank)X 100%. Its half Inhibitory Concentration (IC) is50) Calculated using Graphpad Prism 5 software.
2. Results
All the compounds isolated were evaluated for their cytotoxic activity of HSC-LX2 in vitro (Table 4). All compounds had cytotoxic activity at the tested concentration of 400. mu.M, with compounds 1-8 and 10-14 inhibiting HSC-LX2 cells by more than 50%. Dose-effect relationship studies indicate IC's for Compounds 1 and 250The values were 122.1 and 24.5. mu.M, in comparison with the positive drug Silibinin (IC)50162.3. mu.M) was more excellent.
TABLE 4 data on the cytotoxic activity of HSC-LX2 in vitro for Compounds 1-14 of the present invention
Silybin was used as the positive control(IC50＝162.3±2.8μM).
3. Conclusion
The results of the experiment show that IC of the compounds 1 and 250The values were 122.1 and 24.5. mu.M, in comparison with the positive drug Silibinin (IC)50162.3 μ M) is more excellent; compounds 3-14 also exhibited varying degrees of cytotoxic activity. The results show that the compounds 1-14 in the artemisia capillaris can be used as medicines for treating liver fibrosis related diseases.
Formulation examples:
in the following formulation examples, conventional reagents were selected and formulation preparation was carried out according to conventional methods, and this example merely shows that at least one of the compounds 1 to 14 according to the present invention can be prepared into various formulations, and specific reagents and procedures are not particularly limited:
1. at least one of the compounds 1-14 prepared in example 1 is dissolved in DMSO, and then water for injection is added according to a conventional method, fine filtration, encapsulation and sterilization are carried out to prepare injection, and the concentration of the injection is 0.5-5 mg/mL.
2. Dissolving at least one of the compounds 1-14 prepared in example 1 in DMSO, dissolving in sterile water for injection, stirring to dissolve, filtering with sterile suction filter funnel, sterile fine filtering, packaging in ampoule, freeze drying at low temperature, and sealing by aseptic melting to obtain powder for injection.
3. At least one of the compounds 1 to 14 prepared in example 1 was added to an excipient in a mass ratio of 9:1 to the excipient, and made into powder.
4. At least one of the compounds 1 to 14 prepared in example 1 was added with an excipient in a mass ratio of 5:1 to the excipient, and granulated and tabletted.
5. At least one of the compounds 1 to 14 prepared in example 1 was prepared into an oral liquid according to a conventional method for preparing an oral liquid.
6. At least one of the compounds 1 to 14 prepared in example 1 is added with an excipient according to the mass ratio of 5:1 to the excipient, and then the mixture is prepared into capsules.
7. At least one of the compounds 1 to 14 prepared in example 1 is added with an excipient according to the mass ratio of 5:1 to the excipient, and granules are prepared.
From the above embodiments, the invention provides a compound in artemisia capillaris and a preparation method and application thereof, and a pharmaceutical composition and application thereof. The 14 novel coumaric acid compounds provided by the invention have cytotoxic activities with different degrees on human hepatic stellate cell HSC-LX2, can form a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient, and can be used for preparing anti-hepatic fibrosis drugs.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (5)
1. A coumaric compound artemicapillasins A-N (1-14) shown in a structural formula (I),
2. a process for the preparation of the coumaric compounds of formula (I) a-N (1-14) according to claim 1, characterized in that it comprises the following steps: drying aerial parts of herba Artemisiae Scopariae, pulverizing, cold extracting with 90% ethanol twice each for 3 days, mixing ethanol extractive solutions, recovering ethanol extract under reduced pressure, dispersing the extract in water, extracting with ethyl acetate, concentrating to obtain ethyl acetate extract, performing silica gel column chromatography on the ethyl acetate extract, and gradient eluting with acetone-petroleum ether (0:100,5:95,10:90,20:80,40:60 and 100:0) as eluent to obtain six fractions Fr.A-Fr.F; subjecting fraction Fr.D to silica gel column chromatography (ethyl acetate-petroleum ether, 20:80,30:70 and 40:60) to obtain three fractions Fr.D1-Fr.D 3; subjecting the fraction Fr.D2 to MCI gel CHP 20P column chromatography (water-methanol, 50:50 and 0:100) to obtain four fractions Fr.D2-1-Fr.D2-4; subjecting Fr.D2-2 to silica gel column chromatography (ethyl acetate-petroleum ether, 20:80 and 30:70) to obtain three fractions Fr.D2-2-1-Fr.D2-2-3, subjecting Fr.D2-2-2 to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50), and subjecting to semi-preparative HPLC (water-acetonitrile, 60:40) to obtain compound 6; fraction Fr.D2-2-3 was subjected to silica gel column chromatography (ethyl acetate-chloroform, 20:80) and then to semi-preparative HPLC (water-acetonitrile, 67:33) to give compounds 4,8 and 10; subjecting fraction Fr.D2-3 to silica gel column chromatography (acetone-petroleum ether, 20:80 and 30:70) to obtain three fractions Fr.D2-3-1-Fr.D2-3-3 and fraction Fr.D2-3-2 to silica gel column chromatography (ethyl acetate-petroleum ether, 35:65 and 40:60) to obtain compound 2; subjecting fraction Fr.D2-3-3-1 to silica gel column chromatography (acetone-petroleum ether, 20:80 and 30:70) to obtain two fractions Fr.D2-3-3-1-Fr.D2-3-3-2, subjecting fraction Fr.D2-3-3-1 to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50), and subjecting to semi-preparative HPLC (water-acetonitrile, 50:50) to obtain compound 7; subjecting fraction Fr.D2-3-3-2 to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50), and silica gel column chromatography (ethyl acetate-chloroform, 10:90 and 20:80) to obtain compounds 9 and 11; subjecting fraction Fr.D-3 to silica gel column chromatography (ethyl acetate-petroleum ether, 15:85,40:60) to obtain three fractions Fr.D3-1-Fr.D3-3, subjecting fraction Fr.D3-1 to Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50), and subjecting to semi-preparative HPLC (water-acetonitrile, 55:45) to obtain compound 12; subjecting fraction Fr.D3-2 to silica gel column chromatography (chloroform-petroleum ether, 50:50), and subjecting to semi-preparative HPLC (water-acetonitrile, 55:45) to obtain compounds 1,5,13, and 15; fraction Fr.D3-3 was subjected to silica gel column chromatography (ethyl acetate-chloroform, 20:80) and then to semi-preparative HPLC (water-acetonitrile, 47:53) to give compounds 3, 14.
3. Use of a coumaric compound of formula (I) as defined in claim 1, artemicapillasins a-N (1-14) for the preparation of an anti-hepatic fibrosis medicament.
4. A pharmaceutical composition comprising at least one of the coumaric compounds artemisinins a-N (1-14) of formula (I) according to claim 1 and a pharmaceutically acceptable carrier or excipient.
5. Use of the pharmaceutical composition of claim 4 for the preparation of an anti-liver fibrosis medicament.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008000081A (en) * | 2006-06-23 | 2008-01-10 | Api Co Ltd | New cinnamic acid derivative, method for producing the same and fermented product of propolis |
| JP2010150161A (en) * | 2008-12-24 | 2010-07-08 | Chube Univ | Inhibitor of lowering of adiponectin expression and application thereof |
| CN110917184A (en) * | 2019-12-16 | 2020-03-27 | 中国科学院昆明植物研究所 | Application of coumaric compounds, pharmaceutical composition and application thereof |
| CN111635380A (en) * | 2020-06-17 | 2020-09-08 | 中国科学院昆明植物研究所 | Sesquiterpene in mugwort, pharmaceutical composition thereof, preparation method and application thereof |
-
2021
- 2021-04-28 CN CN202110467896.4A patent/CN113173905A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008000081A (en) * | 2006-06-23 | 2008-01-10 | Api Co Ltd | New cinnamic acid derivative, method for producing the same and fermented product of propolis |
| JP2010150161A (en) * | 2008-12-24 | 2010-07-08 | Chube Univ | Inhibitor of lowering of adiponectin expression and application thereof |
| CN110917184A (en) * | 2019-12-16 | 2020-03-27 | 中国科学院昆明植物研究所 | Application of coumaric compounds, pharmaceutical composition and application thereof |
| CN111635380A (en) * | 2020-06-17 | 2020-09-08 | 中国科学院昆明植物研究所 | Sesquiterpene in mugwort, pharmaceutical composition thereof, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 孙远南;冯健;: "茵陈蒿的化学成分与药理作用研究进展", 中国现代医生, no. 21, pages 18 - 20 * |
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Application publication date: 20210727 |