CN113880791B - Lignan compound, and preparation, application and product thereof - Google Patents
Lignan compound, and preparation, application and product thereof Download PDFInfo
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- CN113880791B CN113880791B CN202010625847.4A CN202010625847A CN113880791B CN 113880791 B CN113880791 B CN 113880791B CN 202010625847 A CN202010625847 A CN 202010625847A CN 113880791 B CN113880791 B CN 113880791B
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- arctigenin
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- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
The invention discloses a natural compound with an endothelin receptor A (ETA) inhibiting activity, and a preparation method and application thereof. The natural compound of the invention is named as double arctigenin (dificigenin), the structural formula of the natural compound is shown as formula I, and cell experiments prove that the double arctigenin has a certain ETA receptor inhibition activity and can be used for preparing one or more than two of treatment, prevention, inhibition or alleviation, which are activated by ETA receptorThe medicine for treating diseases regulated by sexual ligands has higher clinical application value and development prospect.
Description
Technical Field
The invention belongs to the technical field of traditional Chinese medicine and new medicine discovery, relates to the discovery and application of active molecules in natural products, and in particular relates to the discovery of natural compound arctigenin with ETA receptor inhibiting activity, and a preparation method and application thereof.
Background
Endothelin receptor type a (endothelin type A receptor, ETA) is one of the subtypes of endothelin receptors, plays an important role in physiological activities of the human body, and plays an important role in the occurrence and development of cardiovascular diseases such as pulmonary hypertension and atherosclerosis. The us FDA approved endothelin receptor antagonists bosentan (bosentan), an Beisen (ambrisentan) and Ma Tisen (macitentan) for the treatment of patients with clinical pulmonary arterial hypertension in 2001, 2007 and 2013, respectively. Recent researches show that the ETA receptor antagonist can be used for the treatment or auxiliary treatment of various diseases, for example, zhang et al find that the ETA receptor antagonist BQ123 can selectively improve tumor perfusion and enhance nano-administration efficiency of malignant glioma; hsu et al found that endothelin receptor inhibitors can reduce angiogenesis in liver cirrhosis rats; selective ETA receptor antagonists for the treatment of prostate cancer have entered clinical phase ii trials and the like. The discovery of ETA receptor antagonists is therefore of great importance. Currently, the literature reports that the ETA receptor antagonist molecules in natural products, such as Wang et al found aristolochic acid a as an antagonist of ETA and ETB receptors, hussain et al found phyllanthin (Phyllanthus niruri) and phyllanthin (nirtetralin) as selective antagonists of ETA receptors from phyllanthus niruri (Phyllanthus niruri), sakurawi et al found myristic acid A (myriceric acid A) as an antagonist of endothelin receptors from cerus, park et al found sargakul D as an antagonist of ETA and ETB receptors from marine organisms Sargassum siliquastrum, and these results showed the potential of finding endothelin receptor antagonists from natural compound molecules. ( Zhang, b., et al, pharmacological Research,2018,132:211-219; hsu, s. -j., et al European Journal of Clinical Investigation,2016,46 (6): 572-580; bagnato, A., et al, british Journal of Pharmacology,2011,163 (2): 220-233; wang, x., et al, int J Mol Sci,2016,17 (3): 389; hussain, R.A., et al Journal of Natural Products,1995,58 (10): 1515-1520; sakurawi, k., et al, chemical & Pharmaceutical Bulletin,1996,44 (2): 343-351; park, B.G., et al, bioorganic & Medicinal Chemistry,2017,25 (17): 4649-4655. )
Fructus Arctii is one of the common traditional Chinese medicines and is recorded in Ming Yi Bie Lu (miscellaneous records of famous physicians) of Chinese powder at the earliest time, and is called as the recipe for improving eyesight, tonifying middle energizer and eliminating wind injury, and has a history of nearly two thousand years. Summarized in the modern Chinese pharmacopoeia, burdock is pungent in nature, bitter in taste and cold in nature; enter the meridians and lung and stomach; has effects of dispelling pathogenic wind and heat, dispersing lung qi, promoting eruption, removing toxic substance, and relieving sore throat; can be used for treating wind-heat type common cold, cough with excessive phlegm, measles, rubella, and laryngopharynx swelling and pain. The modern research shows that the compounds in the burdock are mainly lignans, volatile oil, fatty acids, phenolic acids, terpenes and the like. Modern pharmacological researches have found that arctigenin has anticancer activity and the like, and can be used for preventing and treating diabetic nephropathy, resisting inflammation, resisting bacteria, resisting hypertension and the like.
The burdock has antihypertensive pharmacological activity, and the types of compounds contained in the burdock are similar to the structure of ETA receptor antagonists, but no report exists at present that the compounds in the burdock have ETA receptor activity.
Disclosure of Invention
The invention aims to provide a compound with endothelin receptor ETA inhibitory activity, and a preparation method and application thereof. Specifically, one of the purposes of the present invention is to provide a compound having an endothelin receptor ETA inhibitory activity, namely, arctigenin (difattin), the structural formula of which is shown as formula i. The second purpose of the invention is to provide a method for separating and preparing the arctigenin from the burdock. The invention further aims to provide an application of the double arctigenin, namely an application of the double arctigenin in inhibiting the ETA activity of an endothelin receptor obtained through a dynamic mass reset experiment, which provides a basis for subsequent drug development.
Chemical name 3,3'- [ (6, 6' -Dihydroxy-5,5'-dimethoxy [1,1' -biphen yl)]-3,3'-diyl)bis(methylene)]bis[dihydro-4-[(3,4-dimethoxyphenyl)methyl]-2(3H)-furanone]It is a white powder of formula C 42 H 46 O 12 Molecular weight 741.59.
The method for preparing the compound arctigenin specifically comprises the following steps:
(1) Soaking fructus Arctii in 50-100% ethanol water solution, heating, reflux extracting, collecting extractive solution, and concentrating to obtain extract;
(2) Subjecting the extract to SPE chromatographic column, gradient eluting with ethanol water solutions of different concentrations, collecting ethanol eluate with volume concentration of 50-90%, and concentrating to obtain concentrate;
(3) Separating and purifying the concentrate by two-dimensional liquid chromatography to obtain the compound arctigenin.
Wherein, the heating reflux extraction in the step (1) can be carried out for 1 to 5 times; during each extraction, the ratio of the addition amount of the ethanol aqueous solution to the mass of the burdock is (4-10) L:1kg; the extraction time is 0.5-5 hours each time. The SPE chromatographic column in the step (2) is a C18YE column; gradient elution was performed with 30% ethanol water, 80% ethanol water, 100% ethanol water, and 80% ethanol eluate was collected.
In step (3), the separation and purification are performed by using a two-dimensional reversed-phase X reversed-phase separation system, wherein the two-dimensional separation system comprises, but is not limited to, a C18HC X PTAS two-dimensional system.
The use of arctigenin is particularly indicated for the inhibition of ETA receptors on PC3 cell lines.
The application of the compound arctigenin provided by the invention comprises two aspects: (1) The application of the arctigenin and the derivatives thereof in preparing medicaments for treating, preventing, inhibiting or relieving one or more than two diseases regulated by ETA receptor active ligands, such as cardiovascular diseases including pulmonary hypertension, cardiac hypertrophy, coronary artery spasm and the like, and cancer diseases including prostate cancer, ovarian cancer and the like. (2) The use of arctigenin and its derivatives in preparing medicines for adjuvant treatment, adjuvant prevention, adjuvant inhibition or adjuvant alleviation of one or more than two diseases regulated by ETA receptor active ligand, such as cardiovascular diseases including pulmonary hypertension, myocardial hypertrophy, coronary artery spasm, etc., and cancer diseases such as prostatic cancer, ovarian cancer, etc.; auxiliary cancer nano-drug administration, etc.
The invention has the advantages that: the invention discovers the antagonistic activity of the endothelin receptor ETA of the arctigenin for the first time, and the better ETA receptor inhibitory activity can be used for preparing medicaments for treating, preventing, inhibiting or relieving one or more than two diseases regulated by ETA receptor active ligands, and has better development prospect.
Description of the drawings
Fig. 1 one-dimensional fraction of the target segment of burdock is prepared into a chromatogram and a grafting mode.
FIG. 2 two-dimensional separation of one-dimensional fraction F7 of Arctium lappa L.
FIG. 3 purification preparation chromatogram of crude bicdock aglycone.
FIG. 4 purity analysis chromatogram of arctigenin on PTAS column.
FIG. 5 effect of one-dimensional fraction of Arctium lappa on ETA receptor on a label-free cell-integrated pharmacological platform.
FIG. 6 effect of two-dimensional fractions of arctium fruit on ETA receptor on label-free cell-integrated pharmacology platform.
FIG. 7 effect of compounds in Arctium lappa on ETA receptor on label-free cell-integrated pharmacology platform.
Detailed Description
The present invention will be described with reference to the following specific examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and biological materials, unless otherwise specified, are commercially available.
Example 1 extraction of Arctium lappa medicinal material
Weighing 5kg of burdock seeds (not crushed), placing into a 100L extraction tank, and heating and extracting for three times. For the first time, 50L of 70% ethanol is used for soaking for 48 hours, steam is heated to 80 ℃, discharging is carried out after 2 hours are kept, and solid-liquid separation is carried out, so as to obtain 32.5kg of extracting solution. And adding 40L of 70% ethanol solution in volume fraction into the solid residue for the second time, heating to 80 ℃ by steam, maintaining for 2 hours, discharging, and performing solid-liquid separation to obtain 30.1kg of extract. Thirdly, adding 30L of 70% ethanol solution in volume fraction into the solid residues, heating to 80 ℃ by steam, maintaining for 2 hours, discharging, and carrying out solid-liquid separation to obtain 30.15kg of extract. Combining the three extracting solutions to obtain 92.7L total extracting sample solution. 10mL of the sample solution was sampled, the solid content of the sample was found to be 7.08mg/mL, and the mass obtained by the co-extraction was calculated to be 656g. The extract was concentrated using a 20L rotary steaming apparatus (Shanghai kanqun, new RE-1010) and finally rotary steamed at 55℃to 16.15kg, about 16L.
And standing the concentrated solution for 48 hours, and carrying out solid-liquid separation to obtain a precipitate sample. The precipitate was redissolved with 80% ethanol by volume fraction (sample concentration about 150 mg/mL), membrane-coated (0.45 μm) to clarify the solution, and then sectioned with a C18 YE-packed SPE column (30 μm,50 x 250 mm), rinsed with 30% ethanol, eluted with 80% ethanol and 100% ethanol, respectively, at a loading of 2% (loading sample to packing mass ratio). All the precipitated samples were concentrated by rotary evaporation at 55℃to give about 25L of the target section (80% ethanol eluted fraction) samples, which were dried by a freeze-dryer to give 79g of the total samples.
Example 2 one-dimensional separation preparation of Arctium lappa medicinal material
One-dimensional preparation conditions: instrument: hanbang preparative chromatograph, sample (prepared from example 1): dissolving fructus Arctii sample in ethanol-acetonitrile in a solvent of water (20:20:60, v:v:v), concentration 50mg/mL, column: C18HC (10 μm, 50X 240 mm), mobile phase: A20% acetonitrile/water (v/v) B20% acetonitrile/ethanol (v/v), mobile phase gradient: 0-2min, A/B:100/0 (v/v); 2-10min, 75/25 of A/B; 10-40min, 75/25-37/63 of A/B; 40-60min, A/B:12/88, flow rate: 50mL/min, column temperature: room temperature, detection wavelength: 254nm, sample injection amount: 90mL (A pump loading, time-2 min).
The preparation chromatogram and the fraction extraction mode are shown in figure 1 according to the preparation conditions. Comprehensively considering the peak-out condition of the chromatographic spectrum and the number of collected fractions, collecting 8 fractions according to the peak collection, and respectively naming F1-F8 according to the peak-out sequence. The mass of the prepared sample is about 65g, 15 needles are prepared in total, the loading amount is 1.6%, and the loading volume is 90mL. The 8 fractions were concentrated by rotary evaporation at 55℃and lyophilized.
Example 3 two-dimensional separation preparation of fraction F7
Two-dimensional preparation conditions of F7: instrument: hanbang preparative chromatograph, sample (prepared in example 2): fructus Arctii F7 (50 mg/mL, solvent 60% acetonitrile water, v: v) was dissolved, column chromatography: PTAS (7-epoxytetrazole) (50X 250mm,7 μm), mobile phase: a: acetonitrile, D: pure water, mobile phase gradient: 0-10min, A/D,40/60 (v/v); 10-30min, A/D,40/60-60/40;30-40min, A/D,60/40-90/10;40-45min, A/D,90/10, flow rate: 80mL/min, column temperature: room temperature, detection wavelength: UV dual wavelength (254 nm and 280 nm), sample volume: 7mL.
The prepared chromatograms and the fraction extraction modes obtained according to the experimental conditions are shown in figure 2. According to the distribution of chromatographic peaks, 10 fractions are collected and collected according to peaks, and F7-1 to F7-10 are respectively named according to the sequence of the peaks. The prepared sample is about 4g, 10 needles are prepared, the loading amount is about 0.12%, and the loading volume is 7mL. The 10 fractions were concentrated by rotary evaporation at 55℃and lyophilized.
EXAMPLE 4 purification of Biburdock aglycone
The purification preparation conditions of the double arctigenin are as follows: instrument: waters Alliance high performance liquid chromatograph, sample (prepared from example 3): crude double arctigenin sample (arctium lappa fraction F7-7) (35 mg/mL, solvent CH) 2 Cl 2 ) Dissolving, chromatographic column: NH (NH) 2 Column (10X 250mm,10 μm), mobile phase: a methanol, B dichloromethane, mobile phase gradient: 0-5min, A/B,2/98 (v/v); 5-35min, A/B,2/98-35/65;35-45min, A/B,95/5, flow rate: 3mL/min, column temperature: 25 ℃, detection wavelength: UV dual wavelength (254 nM and 280 nM), sample injection volume: 100 mu L。
According to the above experimental conditions, a preparative chromatogram as shown in FIG. 3 was obtained. A total of 10 needles were prepared at a loading volume of 100. Mu.L (loading 0.125%) and fractions were withdrawn over a period of 18-19.7 min. The obtained sample is dried by rotary evaporation and is white powder, the weight is weighed to obtain 28mg, and the sample recovery rate is 80%. Chromatographic purity analysis was performed on PTAS column (fig. 4) to give a sample with a purity of 95%.
Example 5 identification of Biburdock aglycone
High resolution mass spectrometry of the compound double arctigenin was detected in positive/negative ion mode using quadrupole time-of-flight mass spectrometry (Agilent 6540UHD Accurate Q-TOF) with electrospray ion source. The mass spectrometry conditions employed were as follows: the spray air pressure is 35psi, the drying air flow rate is 8L/min, the capillary voltage is 3500V, the collision energy is 25eV, the cracking energy is 75V, and the primary mass spectrum mass scanning range is 100-1000m/z. The nuclear magnetic resonance spectrum of the compound is measured by using a Bruker AV II I-600 type nuclear magnetic resonance spectrometer, and the reagent is MeOD.
The compound is double arctigenin which is obtained by ultraviolet spectrum, high resolution mass spectrum and nuclear magnetic spectrum data analysis and literature investigation. Qualitative information of the compound bisarctigenin obtained by the experiment is as follows.
The compound Biburdock aglycone (difectin), white powder, UVmax (MeCN/H2O) 230,282nM, HR-ESI-MS:741.5895[ M-H ] - (computed for C42H46O 12); 13C-NMR (150 MHz, meOD): delta 128.94 (C-1), 111.60 (C-2), 148.99 (C-3), 147.66 (C-4), 111.20 (C-5), 120.62 (C-6), 37.44 (C-7), 40.80 (C-8), 71.56 (C-9), 131.43 (C-1 '), 112.15 (C-2 '), 148.10 (C-3 '), 142.07 (C-4 '), 124.30 (C-5 '), 125.42 (C-6 '), 33.98 (C-7 '), 46.41 (C-8 '), 180.13 (C-9 '), 55.15 (C-10), 55.01 (C-11), 54.88 (C-12); 1H NMR (600 MHz, meOD): delta 6.73 (dd, J=5.2, 3.4Hz,2H, H-5,H-6 '), 6.63 (d, J=1.9 Hz,1H, H-2 '), 6.58-6.55 (m, 2H, H-2, H-6), 4.19-4.14 (m, 1H, H-9), 3.90 (t, J=8.2 Hz,1H, H-9), 3.84 (s, 3H, H-10), 3.73 (s, 3H, H-11), 3.60 (s, 3H, H-12), 2.93-2.84 (m, 2H, H-7 '), 2.67 (dd, J=13.4, 6.6Hz,1H, H-8 '), 2.62-2.57 (m, 2H, H-7) 2.53 (m.1H, H-8 ').
EXAMPLE 6 Effect of one-dimensional fraction of Arctium lappa on ETA receptor on a label-free cell-integrated pharmacological platform
The activity of 8 one-dimensional fractions at ETA receptors was determined using a label-free cell-integrated pharmacological technology platform. The test mode is as follows:
prostate cancer cells PC3 (purchased from the cell bank of the national academy of sciences' typical culture collection Committee) endogenously expressing ETA receptor were cultured in cell microplates and after 24h, one-dimensional fractions of burdock were added at a final concentration of 25. Mu.g/mL or 50. Mu.g/mL, with F5, F7 and F8 fractions of 25. Mu.g/mL and F1, F2, F3, F4 and F6 fractions of 50. Mu.g/mL, 10. Mu.L per well, and treated for 60min. A baseline was established on an Epic instrument (second generation of Corning Co., USA) system, endothelin-1 (10. Mu.L) was added at a final concentration of 10nM per well, and cellular DMR response signals were monitored for 60min to obtain the signal effect of one-dimensional fractions of arctium on the agonist endothelin-1.
The resulting signal response was converted to data output using Imager Beta v3.7 software, and the output data was processed using Microsoft Excel 2010 and GraphPad Prism 6 software to give a signal impact profile of arctium fruit one-dimensional fraction on endothelin-1 on PC3 cell line (fig. 5).
As a result of the experiment, F1 (50. Mu.g/mL), F2 (50. Mu.g/mL), F7 (25. Mu.g/mL) and F8 (25. Mu.g/mL) were found to exhibit inhibitory activity against ETA receptor probe molecules, and the inhibition ratio was more than 50%.
Example 7 Effect of two-dimensional fraction of Arctium lappa on ETA receptor on a label-free cell-integrated pharmacological platform
The activity of 10 two-dimensional fractions at ETA receptors was determined using a label-free cell-integrated pharmacological technology platform.
The test mode is as follows:
after culturing prostate cancer cells PC3 endogenously expressing ETA receptor in cell microwell plates for 24h, burdock two-dimensional fraction with final concentration of 50 μg/mL was added into microwells, and treated for 60min at 10 μl per well. A baseline is established on an Epic instrument system, endothelin-1 (10 mu L) with a final concentration of 10nM is added into each hole, and cell response signals are monitored for 60min to obtain the signal influence of the arctium lappa two-dimensional fraction on the agonist endothelin-1.
The resulting signal response was converted to data output using Imager Beta v3.7 software, and the output data was processed using Microsoft Excel 2010 and GraphPad Prism 6 software to give a signal impact profile of arctium fruit two-dimensional fraction on endothelin-1 on PC3 cell line (fig. 6).
Experimental results show that F7-1, F7-2, F7-3 and F7-7 all show inhibition on the ET-1 signal of the agonist, wherein F7-2 has the strongest inhibition on the ET-1 signal and inhibits the signal to 16% of the original signal intensity; secondly, F7-1 can inhibit the signal of ET-1 to 40%; then F7-3 and F7-7, the signal of ET-1 can be suppressed to 55%. The other fractions F7-4, F7-5, F7-6, F7-8, F7-9 and F7-10 did not show inhibition of ET-1 signal. In summary, F7-1, F7-2, F7-3 and F7-7 are ETA receptor active.
EXAMPLE 8 antagonism of 8 Compounds such as Biarctigenin on a Label-free cell-integrated pharmacology platform on ETA receptor
The activity of 8 compounds at ETA receptors was determined using a label-free cell-integrated pharmacological technology platform, with eight compounds being arctigenin, arctigenin (1 #), isosarctigenol C (2 #), arctigenol C (3 #), arctigenin D (4 #), arctigenin E (5 #), arctigenin (6 #) and 4, 5-O-dicaffeoylquinic acid (7 #), respectively. The test mode is as follows:
after culturing prostate cancer cells PC3 endogenously expressing ETA receptors in cell microwell plates for 24h, arctigenin or other seven compounds at a final concentration of 67 μm were added at 10 μl per well for 60min. A baseline was established on the Epic instrument system, endothelin-1 (10. Mu.L) was added at a final concentration of 10nM per well, and the cellular response signal was monitored for 60min to obtain the signal effect of arctium compound on agonist endothelin-1.
The resulting signal response was converted to data export using Imager Beta v3.7 software, and the exported data was processed with Microsoft Excel 2010 and GraphPad Prism 6 software to give a signal impact graph of 8 compounds on endothelin-1 on PC3 cell line (fig. 7).
Experimental results show that at 67 mu M concentration, the arctigenin inhibits the signal of ET-1 to 34% of the original signal, and shows better ETA receptor activity, and at 200 mu M concentration, arctigenin D, arctigenin E, arctigenin, isosarctigenin C and arctiin respectively inhibit the signal of ET-1 to 18%, 49%, 58%, 61% and 78% of the original signal, and show ETA receptor inhibition activity.
Claims (4)
1. The application of the lignan compound arctigenin in preparing medicaments for treating or assisting in treating, preventing or assisting in preventing, inhibiting or assisting in inhibiting, relieving or assisting in relieving one or more than two diseases regulated by ETA receptor active ligands or in preparing ETA receptor antagonists is characterized in that the lignan compound arctigenin is a compound shown in a formula I,
(formula I).
2. The use according to claim 1, wherein the disorder modulated by ETA receptor activity ligand comprises one or more of pulmonary hypertension, cardiac hypertrophy, coronary spasticity associated with ETA receptor modulation, or the disorder modulated by ETA receptor activity ligand comprises one or more of prostate cancer, ovarian cancer associated with ETA receptor modulation.
3. The use of claim 1, wherein the adjuvant therapy, adjuvant prophylaxis, adjuvant suppression or adjuvant remission medication comprises adjuvant cancer nano-administration.
4. A pharmaceutical and/or co-pharmaceutical product comprising the compound of claim 1, arctigenin as active ingredient, with or without the addition of pharmaceutically or dietetically acceptable carriers or excipients, as ETA receptor antagonist.
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