CN115505015A - Lignans compound and preparation method and application thereof - Google Patents
Lignans compound and preparation method and application thereof Download PDFInfo
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- CN115505015A CN115505015A CN202110690594.3A CN202110690594A CN115505015A CN 115505015 A CN115505015 A CN 115505015A CN 202110690594 A CN202110690594 A CN 202110690594A CN 115505015 A CN115505015 A CN 115505015A
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- ethanol
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- 229930013686 lignan Natural products 0.000 title claims abstract description 12
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- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 238000000034 method Methods 0.000 claims abstract description 15
- 235000003255 Carthamus tinctorius Nutrition 0.000 claims abstract description 10
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 165
- 238000010828 elution Methods 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
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- 241000720991 Illicium Species 0.000 claims description 11
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- 239000002904 solvent Substances 0.000 claims description 11
- 238000004440 column chromatography Methods 0.000 claims description 10
- DQFAAIWCCHDCLO-UHFFFAOYSA-N acetonitrile;formic acid;hydrate Chemical compound O.CC#N.OC=O DQFAAIWCCHDCLO-UHFFFAOYSA-N 0.000 claims description 9
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 9
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses a lignan compound which is a new chemical component found in Illicium verum leaves of safflower. The invention also carries out structural identification on the compound separated by the method through physicochemical properties and modern spectral means. The invention also utilizes an activity screening system such as an LPS (LPS) -induced RAW264.7 cell inflammation model and the like to carry out activity evaluation, and finds that the compound has a certain protection effect on a mouse macrophage system RAW264.7 and can obviously inhibit PGE (platelet-rich antigen) 2 Shows strong anti-inflammatory action.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a novel compound and a preparation method and application thereof.
Background
The Illicium sativum (Illicium dunnianum Tutcher) is a plant of Illicium genus (Illicium) of Magnoliaceae family (Magnolia). The illicium plants are evergreen trees or shrubs with aromatic odor, 34 varieties exist all over the world, 28 varieties exist in China, most varieties are distributed in east and south east of Asia, and few varieties are distributed in southeast and central south America of North America. The safflower anise is peculiar to China, is distributed in places such as Guangxi, fujian, guizhou, hunan and Guangdong, and is usually grown along the coasts of rivers, beside valley waters, in mountain forests, in wet hills or in rock seams at an elevation of 400-1000 m. The fruit shape is similar to that of the red fennel, the fruit is thin and small, and generally consists of 7-8 fruits, and a small number of 13 fruits have obvious diamond-shaped pointed ends and are slightly bent; the fruit stalks are fine but the fruit stalks are shorter, the seeds are smaller, and the fruit stalks are easy to distinguish. The medicine is bitter and pungent in taste and warm in nature, and has the effects of removing blood stasis, relieving swelling, dispelling wind, removing dampness and relieving pain, so roots and barks of the medicine are commonly used as medicines in folk, and the medicine is externally used for treating rheumatism bone pain, traumatic injury, contusion and fracture; toxic, the shikimic toxin and the new shikimic toxin separated from the root are convulsion components. Pharmacological experimental research shows that the alcohol extract of the aniseed leaves of the safflower has the functions of central analgesia and peripheral analgesia and has better analgesic and detumescence effects on various pains and acute soft tissue injuries.
The safflower aniseed is a special plant in China, is commonly used for treating rheumatic ostealgia, traumatic injury, contusion and fracture as a folk medicine, is not recorded by Chinese pharmacopoeia, but the safflower aniseed leaf is one of the medicinal ingredients of the Chinese patent medicine Jinhong tablet, the Jinhong tablet has the effects of soothing the liver and relieving depression, regulating qi and activating blood, and harmonizing the stomach and relieving pain, is mainly used for treating the liver-stomach disharmony syndrome of chronic superficial gastritis clinically, has definite curative effect and obvious effect, and the research on the chemical ingredients of the safflower aniseed leaf and the Jinhong tablet is very little at present, so that the chemical ingredients of the Jinhong tablet cannot be comprehensively clarified, the deep research on the pharmacodynamic substances and the action mechanism of the Jinhong tablet is limited, and the improvement of the quality control standard cannot be realized, so that the deep research on the active ingredients in the safflower leaf is carried out.
Disclosure of Invention
The invention aims to carry out more intensive research on active ingredients in Illicium verum leaves of safflower and discover the active ingredients.
In view of the above, the present invention provides a lignan compound, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, prodrug molecule, or metabolite thereof, wherein the compound has the following structure, and the structure of the compound is shown in formula I below:
1 R 1 ＝OCH 3 ，R 2 ＝α-L-Rha-(1→2)-β-D-Xyl
2 R 1 ＝OH，R 2 ＝α-L-Rha-(1→2)-β-D-Xy1
3 R 1 ＝OH，R 2 ＝α-L-Rha-(1→2)-β-D-Fuc
4 R 1 ＝OCH 3 ，R 2 ＝β-D-Xyl-(1→2)-β-D-Glc
another object of the present invention is to provide a method for preparing the above compound, comprising:
a) Taking the aniseed leaves of the safflower, carrying out reflux extraction by 40-60% of ethanol, and removing the solvent to obtain a total extract;
b) Dissolving the total extract in water, separating by macroporous adsorption resin column chromatography, eluting with water, 25-35% ethanol, 45-55% ethanol and 90-100% ethanol in sequence, collecting eluates respectively, and concentrating under reduced pressure to obtain water eluate, 25-35% ethanol eluate, 45-55% ethanol eluate and 90-100% ethanol eluate; 4 column volumes per gradient elution (same below);
c) Taking the 45-55% ethanol elution part, separating by silica gel column chromatography, performing gradient elution and collection by using dichloromethane-methanol to obtain 15 fractions of 3A-3O, performing gradient elution on the fraction 3L by using ODS column chromatography methanol-water to obtain 5 fractions of 3L1-3L5, performing gradient elution on the fraction 3L4 by using polyamide column chromatography ethanol-water to obtain 6 fractions of 3L4A-3L4F, performing semi-preparative liquid chromatography on the 3L4A to obtain 8 fractions of a compound 2 and the fraction 3L4A2-3L4A9, performing semi-preparative liquid chromatography on the 3L4A 5to obtain a compound 3,3L4A7, and performing semi-preparative liquid chromatography on the compound 4,3L4A9 to obtain a compound 1.
Specifically, the Illicium palmatum leaves can be dried leaves of Illicium palmatum.
Further, the step a) includes: taking dry illicium griseum leaves, carrying out reflux extraction for 1-3 times by 3-5 times of 40-60% ethanol, each time for 1-3 hours, combining extracting solutions, and removing the solvent under reduced pressure to obtain the total extract.
Preferably, the step B) includes: sequentially eluting with water, 30% ethanol, 50% ethanol and 95% ethanol, respectively collecting eluates, and concentrating under reduced pressure until no ethanol smell exists to obtain water eluate, 30% ethanol eluate, 50% ethanol eluate and 95% ethanol eluate.
The dichloromethane-methanol gradient elution of the step C) is that gradient elution is carried out in a volume ratio of 100: 0to 0: 100; the methanol-water gradient elution is performed in a volume ratio of 15-30: 85-70 to 100:0; the ethanol-water gradient elution is carried out in a volume ratio of 5-15: 95-85 to 90-100: 10-0.
Preferably, said dichloromethane-methanol gradient elution of step C) is a gradient elution performed at a volume ratio of 100: 0to 0: 100; the methanol-water gradient elution is performed in a volume ratio of 30:70 to 100:0; the ethanol-water gradient elution is performed in a gradient from 10 to 90 to 95.
Specifically, said dichloromethane-methanol gradient of step C) is eluted at a rate of 100; 95; 90; 85; 80; 70; 60, mixing the raw materials in parts by weight; carrying out gradient elution at a volume ratio of 0; the methanol-water gradient eluted as a 30; 40, 60; 50; 70; performing gradient elution at a volume ratio of 100; the ethanol-water gradient eluted as a gradient of 10; 25, 75;40, 60; 50;70, preparing a mixture of; 95/5 volume ratio for gradient elution.
Specifically, the macroporous adsorption resin comprises one or more of D101 type macroporous adsorption resin, HP-20 type macroporous adsorption resin, HPD-100A type macroporous adsorption resin or HPD-300 type macroporous adsorption resin.
Further, the semi-preparative liquid chromatography conditions include:
compound 1: specification C 18 5 μm, 10X 250mm Phenomenex Gemini column; volume ratio of mobile phase: 18-28, wherein the detection wavelength is 240-260nm, and the flow rate is 2-4mL/min;
compound 2: specification C 18 5 μm, 10X 250mm Phenomenex Gemini column; volume ratio of mobile phase: 30-40, 0.05-0.5, the detection wavelength is 240-260nm, and the flow rate is 2-4mL/min;
compound 3: specification C 18 5 μm, 10X 250mm Phenomenex Gemini column; volume ratio of mobile phase: 17-27, 0.05-0.5, the detection wavelength is 240-260nm, and the flow rate is 2-4mL/min;
compound 4: specification C 18 5 μm, 10X 250mm Phenomenex Gemini column; volume ratio of mobile phase: 13-23, 77-87, wherein the detection wavelength is 240-260nm, and the flow rate is 2-4mL/min.
Preferably, said step a) is a 2-time reflux extraction with 50% ethanol for 2 hours each;
the mobile phases of compounds 1 to 4 were acetonitrile-water-formic acid at a volume ratio of 23.1, methanol-water-formic acid at 35.1, acetonitrile-water-formic acid at 22.
The invention further aims to provide the application of the compound or the pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, prodrug molecule and metabolite thereof in preparing anti-inflammatory drugs.
The invention also provides a medicament for treating inflammation, which comprises the lignan compound or pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, prodrug molecule and metabolite thereof.
Further, the medicine contains an effective amount of the lignan compound or pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, prodrug molecule and metabolite thereof, and one or more pharmaceutically acceptable carriers.
Specifically, the medicament can be any one of the dosage forms in pharmaceutics, including tablets, capsules, soft capsules, gels, oral preparations, suspensions, granules, patches, ointments, pills, powders, injections, infusion solutions, freeze-dried injections, intravenous emulsions, liposome injections, suppositories, sustained-release preparations or controlled-release preparations.
Further, the pharmaceutically acceptable carrier refers to a pharmaceutical carrier conventional in the pharmaceutical field, such as: diluents, excipients, and water, and the like, fillers such as starch, sucrose, lactose, microcrystalline cellulose, and the like; binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; humectants such as glycerol; disintegrating agents such as sodium carboxymethyl starch, hydroxypropyl cellulose, crosslinked carboxymethyl cellulose, agar, calcium carbonate and sodium bicarbonate; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol, sodium lauryl sulfate; adsorption carriers such as kaolin and bentonite; lubricants such as talc, calcium and magnesium stearate, micronized silica gel, polyethylene glycol, and the like. Other adjuvants such as flavoring agent, sweetener, etc. can also be added into the composition.
The lignan compound is a new chemical component found in Illicium palmatum leaves by researchers, and is found to stably exist in Illicium palmatum leaves of each batch. The inventors have obtained a good balance between physical and chemical properties modern spectroscopic methods (MS, MS, 1 H-NMR、 13 C-NMR, etc.), and carrying out structural identification on the compound obtained by the method, thereby confirming that the compound is four new compounds with the structure shown in the formula (I). The invention also utilizes an activity screening system such as an LPS (LPS) -induced RAW264.7 cell inflammation model and the like to carry out activity evaluation, and finds that the compound can be used for carrying out activity evaluation on mouse macrophageThe RAW264.7 has certain protection effect and can obviously inhibit PGE 2 The release of (2) shows a strong anti-inflammatory effect. Has good research and development prospect.
Drawings
FIG. 1 is a HR-ESI-Q-TOF-MS spectrum of Compound 1 of the present invention;
FIG. 2 is a UV spectrum of Compound 1 of the present invention;
FIG. 3 is an IR spectrum of Compound 1 of the present invention;
FIG. 4 shows Compound 1 of the present invention 1 H-NMR spectrum
FIG. 5 shows Compound 1 of the present invention 13 A C-NMR spectrum;
FIG. 6 is a DEPT-135 spectrum of Compound 1 of the present invention;
FIG. 7 is H of Compound 1 of the present invention 1 -H 1 A COSY spectrogram;
FIG. 8 is an HSQC spectrum of Compound 1 of the present invention;
FIG. 9 is an HMBC spectrum of compound 1 of the present invention;
FIG. 10 is a NOESY spectrum of Compound 1 of the present invention;
FIG. 11 is a CD map of Compound 1 of the present invention;
FIG. 12 is a HR-ESI-Q-TOF-MS spectrum of Compound 2 of the present invention;
FIG. 13 is a UV spectrum of Compound 2 of the present invention;
FIG. 14 is an IR spectrum of Compound 2 of the present invention;
FIG. 15 is a drawing of Compound 2 of the present invention 1 H-NMR spectrum
FIG. 16 shows Compound 2 of the present invention 13 A C-NMR spectrum;
FIG. 17 is a DEPT-135 spectrum of Compound 2 of the present invention;
FIG. 18 is H of Compound 2 of the present invention 1 -H 1 COSY spectrum;
FIG. 19 is an HSQC spectrum of Compound 2 of the present invention;
FIG. 20 is an HMBC spectrum of compound 2 of the present invention;
FIG. 21 is a NOESY spectrum of Compound 2 of the present invention;
FIG. 22 is a CD map of Compound 2 of the present invention;
FIG. 23 is a HR-ESI-Q-TOF-MS spectrum of Compound 3 of the present invention;
FIG. 24 is a UV spectrum of Compound 3 of the present invention;
FIG. 25 is an IR spectrum of Compound 3 of the present invention;
FIG. 26 is a drawing showing that Compound 3 of the present invention 1 H-NMR spectrum
FIG. 27 is a drawing of Compound 3 of the present invention 13 A C-NMR spectrum;
FIG. 28 is a DEPT-135 spectrum of Compound 3 of the present invention;
FIG. 29 shows H of Compound 3 of the present invention 1 -H 1 COSY spectrum;
FIG. 30 is an HSQC spectrum of Compound 3 of the present invention;
FIG. 31 is an HMBC spectrum of compound 3 of the present invention;
FIG. 32 is a NOESY spectrum of Compound 3 of the present invention;
FIG. 33 is a CD map of Compound 3 of the present invention;
FIG. 34 is a HR-ESI-Q-TOF-MS spectrum of Compound 4 of the present invention;
FIG. 35 is a UV spectrum of Compound 4 of the present invention;
FIG. 36 is an IR spectrum of Compound 4 of the present invention;
FIG. 37 shows Compound 4 of the present invention 1 H-NMR spectrum
FIG. 38 is a drawing of Compound 4 of the present invention 13 C-NMR spectrum;
FIG. 39 is a DEPT-135 spectrum of Compound 4 of the present invention;
FIG. 40 is H of Compound 4 of the present invention 1 -H 1 COSY spectrum;
FIG. 41 is a HSQC spectrum of Compound 4 of the present invention;
FIG. 42 is an HMBC spectrum of compound 4 of the present invention;
FIG. 43 is a NOESY spectrum of Compound 4 of the present invention;
FIG. 44 is a CD profile of Compound 4 of the present invention.
Detailed Description
The following will specifically describe the contents of the experimental examples.
It is specifically noted that similar alternatives and modifications will be apparent to those skilled in the art, which are also intended to be included within the present invention. It will be apparent to those skilled in the art that modifications or appropriate variations and combinations of the methods and applications described herein can be made to implement and use the present technology without departing from the spirit, scope, and content 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.
If the specific conditions are not indicated, the method is carried out according to the conventional conditions or the conditions suggested by manufacturers, and the used raw material medicines or auxiliary materials and the used reagents or instruments are the conventional products which can be obtained commercially.
EXAMPLE 1 preparation of the Compound of the invention
(1) Extracting dry leaves of Illicium verum L.with 40% ethanol under reflux for 2 times (2 hr each time), mixing extractive solutions, and removing solvent under reduced pressure to obtain total extract. Dissolving the total extract in water, separating by HP-20 macroporous adsorbent resin column chromatography, sequentially eluting with water, 25% ethanol, 45% ethanol, and 90% ethanol, eluting with 4 column volumes (the same below) for each gradient, collecting eluates, respectively, and concentrating under reduced pressure until no alcohol smell exists to obtain water eluate, 25% ethanol eluate, 45% ethanol eluate and 90% ethanol eluate;
(2) Taking the 45% ethanol elution fraction of step (1), separating by silica gel column chromatography, eluting with a dichloromethane-methanol gradient (95.
Wherein the semi-preparative liquid chromatography conditions described in step (2) aboveTo, semi-preparative column: phenomenex Gemini (C) 18 5 μm,10 × 250 mm), semi-preparative high performance liquid chromatography [ shimadzu, japan pump: LC-6AD (SHIMADZU, LIQUID CHROMATOGRAPH); a detector: SPD-20A (timing UV/VIS DETECTOR); a workstation: LC solution)]. The mobile phases of the compounds 1 to 4 are respectively in the volume ratio of: 18, acetonitrile-water-formic acid of 0.05, methanol-water-formic acid of 30.05, acetonitrile-water-formic acid of 17.
EXAMPLE 2 preparation of the Compound of the invention
(1) Taking dry leaves of Illicium verum leaves, extracting with 50% ethanol under reflux for 2 times, each for 2 hr, mixing extractive solutions, and removing solvent under reduced pressure to obtain total extract. Dissolving the total extract in water, separating by HP-20 macroporous adsorbent resin column chromatography, sequentially eluting with water, 30% ethanol, 50% ethanol, and 95% ethanol, collecting eluates, respectively, and concentrating under reduced pressure until no ethanol smell exists to obtain water eluate, 30% ethanol eluate, 50% ethanol eluate and 95% ethanol eluate;
(2) Taking the 50% ethanol elution site of step (1), separating by silica gel column chromatography, eluting with a dichloromethane-methanol gradient (100: fraction 3L4 was gradient eluted over polyamide column chromatography ethanol-water (10, 25, 50.
Wherein, the semi-preparative liquid chromatography conditions in the step (2) are as follows: phenomenex Gemini (C) 18 5 μm,10 × 250 mm), semi-preparative high performance liquid chromatograph [ shimadzu, japan pump: LC-6AD (SHIMADZU, LIQUID CHROMATOGRAPH); a detector: SPD-20A (timing UV/VIS DETECTOR); work byA station: LC solution)]. The mobile phases of the compounds 1 to 4 are respectively in volume ratio: 23, acetonitrile-water-formic acid of 0.1, methanol-water-formic acid of 35.1, acetonitrile-water-formic acid of 22.
EXAMPLE 3 preparation of the Compound of the invention
(1) Extracting dry leaves of Illicium verum with 60% ethanol under reflux for 2 times (2 hr each time), mixing extractive solutions, and removing solvent under reduced pressure to obtain total extract. Dissolving the total extract in water, separating by HP-20 macroporous adsorbent resin column chromatography, sequentially eluting with water, 35% ethanol, 55% ethanol, and 100% ethanol, collecting eluates, respectively, concentrating under reduced pressure until no ethanol smell exists to obtain water eluate, 35% ethanol eluate, 55% ethanol eluate, and 100% ethanol eluate;
(2) Taking the 55% ethanol elution fraction of step (1), separating by silica gel column chromatography, eluting with a dichloromethane-methanol gradient (90.
Wherein, the semi-preparative liquid chromatography conditions in the step (2) are as follows: phenomenex Gemini (C) 18 5 μm,10 × 250 mm), semi-preparative high performance liquid chromatography [ shimadzu, japan pump: LC-6AD (SHIMADZU, LIQUID CHROMATOGRAPH); a detector: SPD-20A (timing UV/VIS DETECTOR); a workstation: LC solution)]. The mobile phases of the compounds 1 to 4 are respectively in volume ratio: 28, 72, 0.5, 40, 0.5, 27, 73, 77.
EXAMPLE 4 structural characterization of the Compounds of the invention
As shown in FIGS. 1 to 11, of Compound 1 1 H-NMR(400MHz,in CD 3 OD) spectrum showing a group of 1,2, 4-trisubstituted benzene ring hydrogen signals [ delta ] H 6.96(1H,d,J＝1.8Hz,H-2),6.83(1H,dd,J＝8.2,1.8Hz,H-6),6.75(1H,d,J＝8.2Hz,H-5)]1,2,3, 5-tetra-substituted benzene ring hydrogen signal [ delta ] H 6.73(2H,brs,H-2′,6′)](ii) a 1 continuous oxygen methine hydrogen signal [ delta ] H 5.57(1H,d,J＝5.8Hz,H-7)](ii) a2 continuous oxygen methylene hydrogen signals [ delta ] H 3.92(2H,m,H-9)，3.57(2H,t,J＝6.5Hz,H-9′)](ii) a 1 methine hydrogen signal [ delta ] H 3.62(1H,m,H-8)](ii) a2 methylene hydrogen signals [ delta ] H 2.62(2H,t,J＝7.7Hz,H-7′)，1.82(2H,m,H-8′)](ii) a2 methoxy hydrogen signals [ delta ] H 3.85(3H,s,5′-OCH 3 ),3.83(3H,s,3-OCH 3 )](ii) a2 sugar end group hydrogen signals [ delta ] H 5.18(1H,d,J＝1.3Hz,H-1″′)，4.35(1H,d,J＝6.9Hz,H-1″)]And several sugar domain methine and methylene hydrogen signals.
13 C-NMR(100MHz,in CD 3 OD) gives a total of 31 carbon signals, divided by 11 glycosyl carbon signals (delta) C 103.6,102.3,79.2,78.9,74.0,72.3,72.2,71.5,69.9,66.9, 17.9), the remaining carbon signals including 7 quaternary carbon signals (delta C 149.0,147.5,147.4145.2,136.9,134.8, 129.0), 7 methine carbon signals (. Delta.) ( C 119.7,118.0,116.1,114.2,110.8,89.8, 53.1), 4 methylene carbon signals (. Delta.) C 72.6,62.2,35.8, 32.9), and 2 methoxy carbon signals (. Delta.)) C 56.8,56.4)。
In that 1 H- 1 In the H COSY spectrum, two methines and one methylene H-7/H-8/H are observed 2 The obvious COSY correlation exists between 9 and the combination of HMBC correlation H-7/C-2,6,9 infers that the structure contains a C 6 -C 3 A structural unit, a structural unit and a structural unit,similarly, another H-7'/H-8'/H can be observed 2 9' obvious COSY correlation, another C was deduced by combining the HMBC correlations H-7'/C-1',2',6',8',9' and H-8'/C-7',9 6 -C 3 And (3) fragment. Furthermore, methine H-7 (. Delta.) H 5.57 With a benzene ring C-4' (delta) C 147.5 ); methylene H-9 (. Delta.) H 3.92 With a benzene ring C-3' (delta) C 129.0 And benzene ring H-2' (delta) H 6.73 With methine C-8 (. Delta.) C 53.1 Respectively, there is a clear HMBC correlation, so the two C's are combined 6 -C 3 The fragments are connected to form a benzofuran-type lignan skeleton. Finally, CH was observed in HMBC spectra 3 O-(δ H 3.85)/C-5′(δ C 145.2),CH 3 O-(δ H 3.83)/C-3(δ C 149.0 Remote correlation of) determines the substitution position of two methoxy groups; the 1D nuclear magnetic spectrum of the compound shows that the structure contains 2 molecular sugar residues, and the sugar hydrolysis derivatization experiment is carried out on the compound, the result shows that two sugar residues contained in the 1 are D-type xylose and L-type rhamnose respectively, and a sugar end group proton signal [ delta ] H 4.35(1H,d,J＝6.9Hz,H-1″),5.18(1H,d,J＝1.3Hz,H-1″′)]Suggesting that xylose and rhamnose are respectively in beta, alpha configuration [34,35] . Wherein the chemical shift (delta) H 4.35 Sugar end groups H-1' and C-9 (. Delta.) C 72.6 Remote association of the sugar group with the C-9 position, the sugar end group H-1' (delta) H 5.18 Delta. With C-2' (delta.) C 79.2 Remote correlation of xylose suggests that it is linked to the C-2 "position of xylose.
NOESY patterns showed correlation peaks H-7/H-9, H-8/H-2 and H-8/H-6, combined coupling constant J 7,8 Determination of 7,8-position as trans form at 5.8Hz [36,37] The CD map shows a negative Cotton effect at 226nm (-1.75), and positive Cotton effects at 242nm (+ 5.26) and 291nm (+ 3.35), indicating that the absolute configuration at the 7,8 position is 7S,8R [37,38] . Combining the above data, all hydrocarbon signals for compound 1 were assigned (table 1). The derivative is identified as a new benzofuran lignan which is named as illicium lignan G and has the following structure:
Yellow amorphous powder, [ alpha ]]25 D -23.8 (c 0.55, meOH), HR-ESI-MS gave m/z 647.2333[ 2 ], [ M + Na ]] + (calculated value: 647.2316), determining the molecular formula as C 30 H 40 O 14 The unsaturation is 11.
High resolution data for compounds 2 and 1 differ by one CH 2 According to the comparison of nuclear magnetic data of the two compounds, the methylation degree of the compound 2 is different from that of the compound 1, only one methoxylhydrogen signal can be seen in the hydrogen spectrum of the compound 2, and only one group of remote related signals shown by a HMBC (high molecular weight binding chain C) spectrum is combined, namely CH 3 O-(δ H 3.83)/C-3(δ C 148.9 Compound 2 was confirmed to be methylated only at the C-3 position. Determining the trans relative configuration of two glycosyl groups of beta-D xylose and alpha-L rhamnose by the same method as 1, wherein the trans relative configuration of H-7 and H-8 is related by NOESY of H-7/H-9 and H-8/H-2, H-8/H-6 and the coupling constant of 7,8 (J) 7,8 =5.6 Hz), the CD profile showed a negative Cotton effect at 226nm (-0.87) and a positive Cotton effect at 239nm (+ 1.02) and 293nm (+ 1.71), indicating an absolute configuration at position 7,8 of 7s,8r. As shown in particular in fig. 12-22.
By integrating NMR nuclear magnetic information, all hydrocarbon signals of compound 2 (Table 1) were assigned and identified as a novel benzofuran lignan, named illiumignan H, with the following structure:
TABLE 1 preparation of Compounds 1-2 1 H and 13 C NMR data
Measured at 400MHz for 1 H and 100MHz for 13 C in CD 3 OD
Multiplets andor overlapped signals arereportedwithoutdesignating multiplicity
Brown amorphous powder, [ alpha ]]25D-18 (c 0.55, meOH), HR-ESI-MS gave in cation mode the excimer peak m/z 661.2477 2 [ 2 ] M + Na + [ alpha ]] + (calculated value: 661.2472) and determination of molecular formula C 31 H 42 O 14 The unsaturation degree was 11.
The nuclear magnetic data of the compounds 3 and 2 are compared to find that the aglycones of the compounds are consistent, the difference is that the glycosyl groups connected to the C-9 position are different, the 3 is subjected to a glycohydrolysis derivatization experiment, and the result shows that the two glycosyl groups contained in the 3 are respectively D-fucose and L-rhamnose, and are combined with a terminal sugar proton signal [ delta ] H 5.18(1H,brs,H-1″′)，4.33(1H,d,J＝7.6Hz,H-1″)]Determination of the respective alpha, beta configuration of rhamnose and fucose [39] . In the HMBC spectrum, the sugar end group H-1 ' is remotely related to C-2 ', and the rhamnosyl is determined to be connected with the C-2 ' position of fucose; the sugar end group H-1' is related to the long range of C-9, and the fucosyl group is determined to be connected with the C-9 position.
NOESY correlation of H-7/H-9, H-8/H-2 and H-8/H-6, binding coupling constant J 7,8 5.5Hz, the relative configuration of 7,8 positions of aglycone is consistent with 2, and the aglycone is trans. The Cotton effect of CD profiles at 225nm (-0.86), 241nm (+ 1.15) and 292nm (+ 1.97) was also consistent with 2, indicating an absolute configuration at position 7,8 of 7S,8R. As shown in particular in fig. 23-33. Thus, compound 3 was identified as a novel benzofuran-type lignan (table 2), designated illiumilignan I, and having the following structure:
Brown amorphous powder, [ alpha ]]25D-14.75 ° (c 0.4, meOH), HR-ESI-MS gave peak excimer ion m/z 677.2423[ m + Na ] in positive ion mode] + (calculated value: 677.2421), the molecular formula is determined to be C 31 H 42 O 15 The unsaturation degree was 11.
The nuclear magnetic data of the compound 4 and the nuclear magnetic data of the compound 1 are compared to find that the aglycone is consistent and the glycosyl groups connected to the C-9 position are different, and the same method is adopted to determine that the two glycosyl groups contained in the compound 4 are respectively beta-D type xylosyl and beta-D type glucosyl [40] . In the HMBC spectra, the glucose end group H-1' (delta) H 4.43 C-2' (delta.) of xylose C 83.0 Remote correlation of glucose group with C-2' position of xylose; xylose end group H-1' (delta H 4.48 With aglycone C-9 (. Delta.) C 71.9 Remote correlation of xylosyl groups to the C-9 position.
NOESY correlation by H-7/H-9, H-8/H-2 and H-8/H-6 and coupling constant value J of 7,8 bits 7,8 =6.8Hz determined that the relative configuration at positions 7,8 of compound 4 and 1 was trans, and the Cotton effect at 226nm (-1.32), 241nm (+ 1.84) and 293nm (+ 1.17) of the CD profile was consistent with 1, indicating that the absolute configuration at position 7,8 was also 7s,8r. As shown in particular in fig. 34-44. Compound 4 was identified as illimiclignan J (table 2) and has the following structure:
TABLE 2 preparation of Compounds 1-2 1 H and 13 C NMR data
Measuredat400 MHz for 1 H and 100MHz for 13 C in CD 3 OD
Multiplets andor overlapped signals arereportedwithoutdesignating multiplicity
EXAMPLE 5 in vitro anti-PGE of Compounds of the invention 2 Experiment of the invention
1. Material
1.1 pharmaceutical compounds 1-4;
1.2 cell model mouse macrophage cell line RAW264.7, which is from Chinese medicine academy of sciences; the culture conditions are as follows: DMEM +10% Fetal Bovine Serum (FBS), 37 ℃,5% CO 2 。
2. Principles and methods
2.1 principle of the experiment
Lipopolysaccharide (LPS) of gram-negative outer membrane (Sigma, USA, 114M 4009) is one of the most main pathogenic molecules mediating infectious inflammatory lesions, and many diseases are closely related to LPS-induced persistent subclinical inflammation. LPS is widely used to induce inflammation in animals and in cellular experiments.
Macrophages play a crucial role in the inflammatory response, and after stimulation, macrophages produce large amounts of inflammatory factors and mediators, such as: TNF-alpha, IL-1 beta, IL-6, NO and PGE 2 And the like. Activation of these inflammatory factors and mediators is a key process of inflammation, and their inhibition is often used as an important index for evaluating the anti-inflammatory activity of drugs.
2.2 drug Pair secretion of PGE 2 Inhibition test of
The method comprises the following steps:
(1) Preparing a liquid medicine: the compound of the present invention was dissolved in 10% FBS DMEM medium to prepare a stock solution of 2 mg/ml.
(2) The experimental method comprises the following steps: digesting the cells with 0.25% pancreatin (containing 0.02% EDTA), adjusting the cell density to 1X 10% in DMEM medium containing 10% FBS 5 Each/ml, inoculated evenly into a 24-well plate, each well 400. Mu.l, plated and put into an incubator for 24 hours.
Blank control group (N group): add 495 ul serum-free DMEM medium to each well;
vehicle/solvent control (RM): 495 mul serum-free DMEM medium containing one thousandth of DMSO was added to each well;
model group (group M): add 495. Mu.l of LPS 100. Mu.g/ml per well;
administration sample group: 495 mul of culture medium containing different concentrations of medicaments is added into each well;
simultaneously provided with 6 composite holesAfter the medicine is added, putting CO into the 24-hole plate 2 The cell culture chamber was incubated for 1 hour. After 1 hour, 5. Mu.l of LPS (final concentration: 1. Mu.g/ml) of 100. Mu.g/ml was added to each well except for the blank control and the solvent control, 5. Mu.l of serum-free DMEM medium was added to each well of the solvent control and the blank control, and after the addition of the reagents, the 24-well plate was placed in CO 2 The cell incubator was continued for 18 hours.
After 18 hours, cell culture fluid is collected, and PGE in cell supernatant is detected by ELISA method according to the kit instructions 2 The content of (b).
PGE 2 Inhibition ratio (%) = (model group PGE) 2 Average content of-sample group PGE 2 Average content of (3)/(model group PGE) 2 Average content of-solvent group PGE 2 Average content) x 100%.
3. Results of the experiment
3.1 drug sample on mouse macrophage line RAW264.7 cell supernatant PGE 2 Influence of (2)
The result shows that the drug sample can obviously inhibit LPS to induce mouse macrophage RAW264.7 PGE 2 Shows strong anti-inflammatory action. Data results are shown in table 3.
TABLE 3 concentrations of Compounds 1-4 PGE supernatant of mouse macrophage cell line RAW264.7 2 Influence of (A)
n＝6)
The invention adopts Graphadprism 7.00 analysis software, and compounds 1-4 in the invention inhibit LPS in vitro to induce mouse macrophage RAW264.7 to secrete inflammatory mediator PGE through a linear regression analysis method 2 Average IC of 50 15.51. Mu.M, 10.47. Mu.M, 18.89. Mu.M and 14.61. Mu.M, respectively.
4. Conclusion
The compound of the invention induces mouse macrophage RAW264.7 to secrete inflammatory medium PGE by LPS 2 Has remarkable inhibiting effect, strong anti-inflammatory effect, and can treat PGE with the increase of drug concentration 2 Increased inhibition of secretion, IC of Compounds 1 to 4 50 15.51. Mu.M, 10.47. Mu.M, 18.89. Mu.M and 14.61. Mu.M, respectively.
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 (10)
1. A lignan compound or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, prodrug molecule and metabolite thereof, wherein the structure of the compound is shown as formula I:
2. a process for preparing a compound of claim 1, comprising:
a) Taking the aniseed leaves of the safflower, carrying out reflux extraction by 40-60% of ethanol, and removing the solvent to obtain a total extract;
b) Dissolving the total extract in water, separating by macroporous adsorption resin column chromatography, eluting with water, 25-35% ethanol, 45-55% ethanol and 90-100% ethanol in sequence, collecting eluates respectively, and concentrating under reduced pressure to obtain water eluate, 25-35% ethanol eluate, 45-55% ethanol eluate and 90-100% ethanol eluate;
c) Taking the 45-55% ethanol elution part, separating by silica gel column chromatography, performing gradient elution and collection by using dichloromethane-methanol to obtain 15 fractions of 3A-3O, performing gradient elution on fraction 3L by using ODS column chromatography methanol-water to obtain 5 fractions of 3L1-3L5, performing gradient elution on fraction 3L4 by using polyamide column chromatography ethanol-water to obtain 6 fractions of 3L4A-3L4F, performing semi-preparative liquid chromatography on 3L4A to obtain 8 fractions of compound 2 and fraction 3L4A2-3L4A9, performing semi-preparative liquid chromatography on 3L4A 5to obtain compound 3,3L4A7, and performing semi-preparative liquid chromatography on compound 4,3L4A9 to obtain compound 1.
3. The method of claim 2, wherein the step a) comprises:
taking dry illicium griffithii leaves, carrying out reflux extraction for 1-3 times by 3-5 times of 40-60% ethanol for 1-3 hours each time, combining extracting solutions, and removing the solvent under reduced pressure to obtain the total extract.
4. The method of manufacturing according to claim 2, wherein the step B) includes: sequentially eluting with water, 30% ethanol, 50% ethanol and 95% ethanol, respectively collecting eluates, and concentrating under reduced pressure until no ethanol smell exists to obtain water eluate, 30% ethanol eluate, 50% ethanol eluate and 95% ethanol eluate.
5. The process according to claim 2, wherein the dichloromethane-methanol gradient elution of step C) is a gradient elution performed at a volume ratio of 100; the methanol-water gradient elution is performed by gradient elution at a volume ratio of 30; the ethanol-water gradient elution is performed by gradient elution at a volume ratio of 10.
6. The preparation method of claim 2, wherein the macroporous adsorbent resin comprises one or more of D101 type macroporous adsorbent resin, HP-20 type macroporous adsorbent resin, HPD-100A type macroporous adsorbent resin, or HPD-300 type macroporous adsorbent resin.
7. The method of claim 2, wherein the semi-preparative liquid chromatography conditions include:
specification C 18 5 μm, 10X 250mm Phenomenex Gemini column; the mobile phase volume ratios for preparing compounds 1 to 4 were respectively: 18-28, 0.05-0.5 of acetonitrile-water-formic acid30-40, methanol-water-formic acid of 0.05-0.5, acetonitrile-water-formic acid of 17-27-0.05-83, acetonitrile-water-formic acid of 13-23-77-0.5;
8. the method according to claim 7, wherein the step A) is a reflux extraction with 50% ethanol for 2 times, each for 2 hours;
preparation of compounds 1 to 4 mobile phase volume ratios of 23.1 acetonitrile-water-formic acid, 35.1 methanol-water-formic acid, 22.
9. Use of the lignan-type compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, prodrug molecule, or metabolite thereof for the manufacture of an anti-inflammatory agent.
10. A medicament comprising the lignan-type compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, prodrug molecule, metabolite thereof.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669617A (en) * | 2016-03-04 | 2016-06-15 | 江苏康缘药业股份有限公司 | Lignin compound as well as preparation method and application thereof |
| CN112409310A (en) * | 2020-12-18 | 2021-02-26 | 许昌学院 | Compound with LSD1 inhibitory activity, preparation method and application |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669617A (en) * | 2016-03-04 | 2016-06-15 | 江苏康缘药业股份有限公司 | Lignin compound as well as preparation method and application thereof |
| CN112409310A (en) * | 2020-12-18 | 2021-02-26 | 许昌学院 | Compound with LSD1 inhibitory activity, preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| FANG LI等: ""New Phenylpropanoid Glycosides from Illicium majus and Their Radical Scavenging Activities"", CHEM. BIODIVERSITY, vol. 18, pages 1 - 9 * |
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