CN110776517A - Flavanone compound and application thereof - Google Patents

Flavanone compound and application thereof Download PDF

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CN110776517A
CN110776517A CN201910973758.6A CN201910973758A CN110776517A CN 110776517 A CN110776517 A CN 110776517A CN 201910973758 A CN201910973758 A CN 201910973758A CN 110776517 A CN110776517 A CN 110776517A
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inflammatory
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王宜海
何祥久
许雪
徐静雯
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Guangdong Pharmaceutical University
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention discloses a flavanone compound, which has a structural formula as follows:

Description

Flavanone compound and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a flavanone compound and application thereof.
Background
Inflammation is a defense response of living tissues having a vascular system to the production of injury factors. Most diseases are accompanied by inflammation and participate in the occurrence and development process of a plurality of serious diseases such as human body infection, tumor, cardiovascular and cerebrovascular diseases, senile dementia, neurodegenerative diseases, allergic diseases, psychosis and the like. Clinically, anti-inflammatory drugs are the second largest class of drugs to anti-infective drugs.
Natural drugs, especially those derived from plants, have a wide variety of chemical structures and biological activities, and have been a major source of diseases prevention and treatment in humans. Many drugs applied clinically are directly or indirectly derived from natural products, and the natural products can be used not only as semi-synthetic precursors of drugs, but also as templates of chemical synthesis of drugs, thereby providing a new idea for the design of new drugs. Natural products have become one of the main sources for the discovery of new drugs or lead compounds.
Mulberry (Morusalbal.) is the fruit of Morus alba (Moraceae) Morus genus. Grown in mountain forest and roadside, cultivated all over the country, mainly produced in Xinjiang, Hebei, Sichuan, Yunnan, Shandong, Guangdong, etc. The mulberry contains abundant nutrient substances, can be eaten fresh and can be used as a traditional Chinese medicine, and has wide application as fruits and traditional Chinese medicines. Mulberry has cool nature, sweet and sour taste, and has the efficacies of nourishing yin and supplementing blood, promoting fluid production and moistening dryness, tonifying liver and kidney and the like, and is mainly used for treating symptoms such as liver-kidney yin deficiency, dark eyes and tinnitus, body fluid deficiency, internal heat and thirst quenching, joint discomfort and the like.
The main active ingredients of mulberry are phenolic components, such as flavone, phenolic acid, stilbenes, etc. Modern pharmacological experiment research shows that mulberry has the activities of resisting oxidation, resisting inflammation, reducing blood sugar, reducing blood fat and the like. The existing research is still not thorough enough to research the chemical components of mulberry, so the phenolic chemical components in mulberry are worthy of further research, development and utilization. We separated the phenolic components of mulberry to obtain a novel flavanone compound, the chemical structure and anti-inflammatory activity of which are not reported.
Disclosure of Invention
The invention aims to provide a flavanone compound and application thereof.
Therefore, in the first aspect of the invention, the invention provides a flavanone compound, which has a structural formula as follows:
Figure BDA0002232959540000011
in a second aspect of the present invention, the present invention provides an application of a flavanone compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of an anti-inflammatory drug, wherein the structural formula of the flavanone compound is as follows:
furthermore, the flavanone compound can be used alone or in combination with other drugs.
Further, the anti-inflammatory agent is suitable for inhibiting the production of inflammatory factor NO.
Further, the anti-inflammatory agent is suitable for inhibiting the expression of iNOS and/or COX-2 protein.
Further, the anti-inflammatory drug is suitable for treating alzheimer's disease.
Furthermore, the anti-inflammatory drug also contains pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutically acceptable auxiliary material is selected from at least one of a filler, a binder, a disintegrating agent, a lubricant, a flavoring agent, a coloring agent, a taste-masking agent, a pH adjuster, a buffer, a preservative, a stabilizer, an antioxidant, a wetting agent, a humidity adjuster, a surfactant, a suspending agent, and an absorption enhancer.
Further, the anti-inflammatory drug is an oral preparation, an injection, an infusion solution, a drop, a patch, a liniment, an enema or an implant.
In a third aspect of the present invention, the present invention provides an anti-inflammatory agent, comprising a flavanone compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural formula of the flavanone compound is:
Figure BDA0002232959540000022
further, the anti-inflammatory agent is suitable for inhibiting the production of inflammatory factor NO.
Further, the anti-inflammatory agent is suitable for inhibiting the expression of iNOS and/or COX-2 protein.
Further, the anti-inflammatory drug is suitable for treating alzheimer's disease.
Furthermore, the anti-inflammatory drug also contains pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutically acceptable auxiliary material is selected from at least one of a filler, a binder, a disintegrating agent, a lubricant, a flavoring agent, a coloring agent, a taste-masking agent, a pH adjuster, a buffer, a preservative, a stabilizer, an antioxidant, a wetting agent, a humidity adjuster, a surfactant, a suspending agent, and an absorption enhancer.
Further, the anti-inflammatory drug is an oral preparation, an injection, an infusion solution, a drop, a patch, a liniment, an enema or an implant.
The invention has the beneficial effects that:
the invention provides a novel flavanone compound which has good anti-inflammatory activity and potential for developing a novel anti-inflammatory drug.
Drawings
FIG. 1: HR-ESI-MS spectrum of Compound 1;
FIG. 2: process for preparation of Compound 1 1H-NMR spectrum;
FIG. 3: process for preparation of Compound 1 13A C-NMR spectrum;
FIG. 4: DEPT-135 ° spectrum of compound 1;
FIG. 5: HSQC spectrum of compound 1;
FIG. 6: HMBC spectrum of compound 1;
FIG. 7: process for preparation of Compound 1 1H- 1HCOSY spectrum;
FIG. 8: (A) protein expression patterns of different concentrations of compounds on LPS-induced BV-2 cells iNOS and COX-2; (B) the protein expression level of (A) was quantified.
Detailed Description
The present invention will be described in further detail with reference to examples. It will also be understood that the following examples are included merely for purposes of further illustrating the invention and are not to be construed as limiting the scope of the invention, as the invention extends to insubstantial modifications and adaptations of the invention following in the light of the principles set forth herein. The specific process parameters and the like of the following examples are also only one example of suitable ranges, and the skilled person can make a selection within the suitable ranges through the description herein, and are not limited to the specific data of the following examples.
Example 1 extraction of the Compound
20kg of dry mulberry medicinal materials are taken, heated and refluxed for extraction for 4 times with 30 liters of 70% methanol, each time lasts for 3 hours, and the extracting solutions are combined and concentrated under reduced pressure to obtain extractum. Suspending the extract with 25L of 35% methanol, and sequentially extracting with equal volume of cyclohexane and chloroform to obtain 234.34g of chloroform layer (middle polar layer); subjecting the chloroform layer to silica gel column chromatography, and performing gradient elution with dichloromethane-methanol (CH) 2Cl 2100:1, 50:1, 30:1, 20:1, 10:1, 7:1, 5:1, 2: 1; v/v), wherein the 20:1 dichloromethane-methanol elution part is subjected to silica gel column chromatography again and is subjected to gradient elution by a cyclohexane-ethyl acetate mixed solution (50: 1-1: 1; v/v), dividing the fraction into 11 parts, carrying out gel column chromatography on the 11 th part (an elution part with the volume ratio of cyclohexane to ethyl acetate solution being 1: 1), eluting with dichloromethane-methanol (1:1, v/v), dividing the eluate into 4 parts, carrying out reverse phase thin layer chromatography analysis on the fraction 3, carrying out medium-low pressure ODS column chromatography on the fraction, and carrying out semi-preparative HPLC to obtain the compound 1.
EXAMPLE 2 identification of Compounds
Through physicochemical constants and a wave spectrum means (HR-ESI-MS, 1H-NMR、 13C-NMR, HSQC, HMBC and 1H- 1HCOSY spectrum) compound 1 was identified as follows:
yellow brown powder (methanol), readily soluble in methanol and acetone. By TLC (254nm)After the development, the fluorescent material has blue fluorescence under the ultraviolet of 365nm, dark spots under the ultraviolet of 254nm and 10% H 2SO 4Orange color after heat development of-EtOH [ α ]]2D5+72.4(c0.07, MeOH), HR-ESI-MS spectrum (FIG. 1) shows the excimer ion peak M/z323.1282[ M + H ]] +(CalcdforC 20H 19O 4323.1283) of the formula C 20H 18O 4。
In that 1H-NMR(600MHz,Acetone-d 6) In the spectrum (FIG. 2), δ H5.43(1H, dd, J ═ 13.0and2.8), 2.98(1H, dd, J ═ 16.7and13.0Hz) and 2.70(1H, dd, J ═ 16.7and2.8Hz) were presumed to be the flavanone nucleusCharacteristic hydrogen signals at positions 2, 3; delta H7.42(2H, d, J ═ 8.4Hz) and 7.90(2H, d, J ═ 8.4Hz) are AA 'BB' coupled system hydrogen signals; delta H7.64(H, d, J ═ 8.6Hz) and 6.60(1H, d, J ═ 8.6Hz) are ortho hydrogen signals on the phenyl ring; delta H4.88(1H, brs) and 4.73(1H, brs) are terminal olefinic hydrogen signals; delta H4.37(1H, dd,8.0and3.4) is the vicinal oxymethylene hydrogen signal; delta H3.04(1H, dd, J ═ 14.1and3.4) and 2.85(1H, m) are methylene hydrogen signals; 1.71(3H, s) is the methyl hydrogen signal.
In that 13C-NMR(126MHz,Acetone-d 6) The spectrum (FIG. 3) gives a total of 20 carbon signals, δ C191.0, 80.4 and 44.6 are characteristic carbon signals of the central three carbons of flavanone; delta C148.2 and 110.1 are alkene carbon signals; delta C76.4 is the oxymethylene carbon to oxygen signal; delta C30.5 is methylene carbon signal; delta C18.5 is the methyl carbon signal.
From the DEPT-135 ℃ spectrum (FIG. 4), the molecule has 1 primary carbon, 3 secondary carbons, 9 tertiary carbons and 7 quaternary carbons.
In the HSQC spectrum (FIG. 5), the position is delta HHydrogen signals and delta of 4.88 and 4.73(H-5 ″) CThe carbon signal of 110.1 (C-5') is directly related, at delta HHydrogen signals and delta of 3.04 and 2.85 (H-3') CThe carbon signal of 30.5 (C-3') is directly related.
In HMBC spectrum (FIG. 6), from δ H3.04 (H-3') starting from the point of view, delta can be found C163.8(C-7), 162.1(C-9), 148.2(C-4 "), 114.4(C-8) and 76.4 (C-2") are remotely associated therewith.
Comprehensively utilizes DEPT, 1H- 1HCOSY (FIG. 7), HSQC, and HMBC can assign signals of compounds.
From the optical rotation ([ α ]2D5+72.4) and the positive Cotton effect at 330nm in circular dichroism spectrum, the absolute configuration of the compound is 2S.
As described above, Compound 1 was identified as (2S) -2,3,8,9-tetrahydro-5-hydroxy-8- (1-methythenyl) -2- (4-hydroxyphenyl) -4H-furo [2,3-H ] -1-benzopyran-4-one
Process for preparation of Compound 1 1H and 13C-NMR data are shown inTable 1, structural formula:
Figure BDA0002232959540000041
TABLE 1 preparation of Compound 1 of the present invention 1H-NMR and 13C-NMR spectroscopic data (Acetone-d) 6)
Figure BDA0002232959540000051
Example 3 anti-inflammatory Activity assay
An in vitro anti-inflammatory activity test is carried out on the compound 1, and an in vitro inflammation model is established by adopting BV-2 (mouse microglia) cells induced by LPS (lipopolysaccharide). MTT and Griess experiments are adopted to investigate the influence of the compound on the release of inflammatory mediator NO by BV-2 cells induced by LPS. The anti-inflammatory drug minocycline (minocycline) was used as a positive control.
(1) MTT assay
BV-2 cells are inoculated in a 96-well plate, after being cultured for 24 hours, a test sample to be tested is added, and after being cultured for 24 hours, the MTT method is used for determining the inhibition rate of the sample on the BV-2 cell proliferation. The cell proliferation inhibition rate was calculated according to the following formula, and the half Inhibitory Concentration (IC) of the test sample was calculated using CalcuSyn software 50)。
The cell proliferation inhibition rate is (average of OD values of negative control group-average of OD values of sample group) ÷ (average of OD values of negative control group-average of OD values of blank control group) × 100%.
(2) Griess experiment
BV-2 cells are inoculated in a 96-well plate, after 24 hours of culture, a test sample to be tested is added, after 24 hours of culture, 50 mu L of culture solution of each well is absorbed, 50 mu L of LGriessA reagent and 50 mu L of LGriessB reagent are added and mixed evenly, an OD value is measured at 546nm by an enzyme-labeling instrument, the inhibition rate of NO generation is calculated according to the following formula, and the half Inhibition Concentration (IC) of the tested sample is calculated by Calcusyn software 50)。
NO inhibition ═ NO inhibition (mean OD value of model control group-mean OD value of sample group) ÷ (mean OD value of model control group-mean OD value of negative control group) × 100%.
The results are shown in Table 2.
TABLE 2 MTT and Griess test results for Compound 1and Positive drugs
Figure BDA0002232959540000061
From the experimental data in table 2, it can be seen that compound 1 has a better anti-inflammatory activity in vitro.
(3) WesternBlot experiment
Cells in exponential growth phase were seeded in 96-well plates and different concentrations of Compound 1(20.0, 40.0, 80.0. mu. mol. L) were added -1) After stimulation, each set of total proteins was extracted at the corresponding time point, electrophoresed in 10% polyacrylamide gel, transferred to NC membrane, sealed, incubated, developed using ECL kit and imaged. Each set of experiments was repeated 3 times.
The results of the experiment are shown in fig. 6, wherein "#" in the figure represents the significance of LPS relative to CTL, "#" represents the significance of compound 1 relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ( ###p＜0.001； *p＜0.05， ***p＜0.01， ***p＜0.001)。
As can be seen from fig. 8: when the concentration is 40.0 and 80.0 mu mol & L respectively -1In the process, the compound 1 can obviously reduce the expression of iNOS and COX-2 proteins of BV-2 cells induced by LPS, which shows that the compound 1 can reduce the biosynthesis of NO by inhibiting the expression of iNOS and COX-2, and finally shows an anti-inflammatory effect.
The above results show that compound 1 can inhibit the production of inflammatory factor NO and inhibit the expression of iNOS and COX-2 proteins, indicating that compound 1, its tautomer, and pharmaceutically acceptable salts thereof have considerable advantages for the preparation of novel anti-inflammatory drugs.
The disease is characterized by two kinds of death, namely mental death and then somatic death, which bring heavy burden to the patient, family and society, along with the prolonging of the life of the human and the increasing prominence of the aging problem of the society, the number and the proportion of AD patients are continuously increased, the AD is related to aging but has the essence of distinguishing from normal aging, autopsy of the patient shows that brain tissue atrophy, particularly hippocampal and forebrain neuron loss, two most characteristic pathological changes of the brain tissue atrophy are extracellular β -amyloid deposition and neuron fibrillar tangle amyloid, and the research shows that β -amyloid protein plays a role in the inflammation reaction of AD, so that the inflammation reaction of AD, also called Alzheimer's Disease (AD), is a new type of medicine, also called Alzheimer's Disease (AD), so that the medicine has a remarkable role in activating a plurality of inflammatory cell BV, BV-2-induced by a plurality of inflammatory cell-inducing factors, BV-2-BV-induced by a plurality of inflammatory cell-induced by a plurality of inflammatory factors, such as a medicament, a plurality of Alzheimer's disease, Alzheimer.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (10)

1. A flavanone compound has a structural formula:
2. use of a flavanone compound, its tautomer, or its pharmaceutically acceptable salt according to claim 1 for the preparation of an anti-inflammatory drug.
3. Use according to claim 2, characterized in that: the anti-inflammatory agent is suitable for inhibiting the production of inflammatory factor NO.
4. Use according to claim 2, characterized in that: the anti-inflammatory agent is suitable for inhibiting the expression of iNOS and/or COX-2 proteins.
5. Use according to claim 2, characterized in that: the anti-inflammatory agent is suitable for the treatment of alzheimer's disease.
6. Use according to any one of claims 2 to 5, wherein: the anti-inflammatory drug also contains pharmaceutically acceptable auxiliary materials.
7. Use according to claim 6, characterized in that: the pharmaceutically acceptable adjuvant is selected from at least one of filler, binder, disintegrant, lubricant, flavoring agent, colorant, taste-masking agent, pH regulator, buffer, preservative, stabilizer, antioxidant, wetting agent, humidity regulator, surfactant, suspending agent and absorption enhancer.
8. Use according to any one of claims 2 to 5, wherein: the anti-inflammatory drug is oral preparation, injection, infusion solution, drop, patch, liniment, enema or implant.
9. An anti-inflammatory agent characterized by: containing a flavanone compound according to claim 1, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
10. An anti-inflammatory agent as in claim 9, wherein: the anti-inflammatory drug also contains pharmaceutically acceptable auxiliary materials, preferably, the pharmaceutically acceptable auxiliary materials are selected from at least one of filling agents, binding agents, disintegrating agents, lubricating agents, flavoring agents, coloring agents, taste masking agents, pH regulators, buffering agents, preservatives, stabilizing agents, antioxidants, wetting agents, humidity regulators, surface active agents, suspending agents and absorption enhancers; further, the anti-inflammatory drug is an oral preparation, an injection, an infusion solution, a drop, a patch, a liniment, an enema or an implant.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013060397A (en) * 2011-09-14 2013-04-04 Nisshin Pharma Inc Method for producing protoisoflavones
CN103705502A (en) * 2014-01-09 2014-04-09 江苏省中国科学院植物研究所 Application of flavonoid compound in treating inflammatory diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013060397A (en) * 2011-09-14 2013-04-04 Nisshin Pharma Inc Method for producing protoisoflavones
CN103705502A (en) * 2014-01-09 2014-04-09 江苏省中国科学院植物研究所 Application of flavonoid compound in treating inflammatory diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHENGJIAN ZHENG ET AL.: "Pruinosanones A-C, anti-inflammatory isoflavone derivatives from Caragana pruinosa", 《SCIENTIFIC REPORTS》 *
GUANGMING XU ET AL.: "Saniculamins A and B, two new flavonoids from Sanicula lamelligera Hance inhibiting LPS-induced nitric oxide release", 《PHYTOCHEMISTRY LETTERS》 *

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