CN111909007B - P-hydroxyphenyl butanediol and its derivative, preparation method and application thereof - Google Patents
P-hydroxyphenyl butanediol and its derivative, preparation method and application thereof Download PDFInfo
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- CN111909007B CN111909007B CN202010816862.7A CN202010816862A CN111909007B CN 111909007 B CN111909007 B CN 111909007B CN 202010816862 A CN202010816862 A CN 202010816862A CN 111909007 B CN111909007 B CN 111909007B
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- C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
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Abstract
The invention belongs to the technical field of biological medicines, and particularly discloses p-hydroxyphenyl butanediol and a derivative thereof, and a preparation method and application thereof. The p-hydroxyphenyl butanediol provided by the invention is produced by fermenting Alternaria alternata (L.) karst in a specific culture medium, has anti-inflammatory and antioxidant activities, and can be used for preparing anti-inflammatory and antioxidant medicines. The invention provides a new compound source for the development of anti-inflammatory and antioxidant drugs.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to p-hydroxyphenyl butanediol and a derivative thereof, and a preparation method and application thereof.
Background
Inflammation itself is a biological defense reaction, and a series of physiological reactions, such as redness, fever, pain, and dysfunction, which are essential behaviors of the immune system to maintain normal tissue homeostasis during infection and tissue injury, are generated in order to eliminate harmful stimuli, remove necrotic cells, and repair damaged tissues. Inflammation is a complex process at a molecular level, during which macrophages promote the production of proinflammatory factors including tumor necrosis factor (TNF- α), various interleukins, Prostaglandins (PG), Nitric Oxide (NO), Reactive Oxygen Species (ROS), and the like. Nitric oxide is involved in many physiological and pathological processes of the body, in cytotoxic and immunoregulation of macrophages, in relaxing vascular smooth muscle, in inhibiting platelet aggregation, in transmitting neural information, etc., and also plays a complex role in inflammatory reactions. In order to cure inflammatory diseases, it is necessary to regulate the production of various chemical mediators secreted throughout the process. Worldwide, the most common drugs for inflammation and related diseases represent aspirin, indomethacin, ibuprofen, ketoprofen, flurbiprofen, and the like. Excessive or insufficient nitric oxide production plays an important role in the development of many diseases.
The oxidation reaction is closely related to the metabolism of the human body. When the human body is using oxygen to carry out metabolic reaction, some unstable free radicals are inevitably generated, and when the free radicals in the human body reach a certain degree, the health of the human body is damaged. Reactive oxygen Radicals (ROS), such as superoxide anion radicals (O), produced by the body during metabolism2 -OH, lipid peroxidation Radicals (ROO) and singlet oxygen (HO)1O2) Plays an important role in the processes of organism aging and diseases, normal immune metabolism, cell signal transduction and the like. Research shows that excessive free radicals in human body can damage normal cells and tissues of human body, so that a plurality of functional disorders and various diseases of the body are caused, such as aging, rheumatoid arthritis, cancer, cardiovascular and cerebrovascular diseases, Alzheimer's disease, diabetes, radiation injury and the like, and the antioxidant active ingredients can clear free radicals, reduce and oxidize substances and play a role in protecting the body. The ocean fungi is a natural antioxidant active ingredient resource with great development potential, a new active substance for eliminating in-vivo free radicals is searched from the ocean fungi, and the ocean fungi is also an important direction for the development of modern medicine and health care industries.
Alternaria (Alternaria) is a genus of Ascomycota, and the fungus of the genus is widely distributed, is a producing strain of various active substances, and is an important source of natural products such as taxanes, ergot sterones and the like. Some alternaria secondary metabolites, such as alternanol, alternan methyl ether and the like, can obviously inhibit cell proliferation by interfering cell cycle and also show strong cytotoxic activity, and some alternariol 5-O-methyl ether (AME) can specifically block HIV-1 virus from invading host cells. Therefore, the metabolite of Alternaria alternata has higher research value and potential development and application prospects. The fermentation condition investigation and the initial detection of anti-tumor products of the fungus alternaria alternata 114-1G from the ocean (volume 47, 3 of 3.2020 of International pharmaceutical research) investigates the fermentation condition of the fungus alternaria alternata 114-1G from the ocean, and a large amount of fermentation, separation and identification of metabolites are carried out, the activity of the metabolites is preliminarily evaluated, and a foundation is laid for subsequent research. On the basis, the invention prepares the p-hydroxyphenyl butanediol by fermentation, and discusses whether the substance has the inflammatory cytokine inhibitory action, the inoxidizability and the activity.
Disclosure of Invention
In order to achieve the above objects, the present invention provides p-hydroxyphenyl butanediol, a derivative thereof, a preparation method and an application thereof, wherein the p-hydroxyphenyl butanediol is obtained by separating and purifying a metabolite of fermented product of Alternaria alternata 114-1G, which is a fungus from the Atlantic region, and has anti-inflammatory activity and antioxidant activity.
The invention adopts the following technical scheme:
in one aspect, the present invention provides a compound having a structure represented by formula (I), and a derivative or a pharmaceutically acceptable salt thereof, wherein:
R1、R7and R6Each independently is hydrogen, deuterium, alkyl, or haloalkyl;
R2、R3、R4、R5、R8、R9、R10、R11、R12and R13Each independently hydrogen, deuterium, halogen, hydroxy, alkyl or haloalkyl.
Further, said R1、R7And R6Each independently of the others is hydrogen, deuterium, C1-6Alkyl or C1-6A haloalkyl group.
Further, said R1、R7And R6Each independently of the others is hydrogen, deuterium, C1-4Alkyl or C1-4A haloalkyl group.
Further, said R1、R7And R6Each independently hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, tert-butyl, chloromethyl, or the like.
Further, said R2、R3、R4、R5、R8、R9、R10、R11、R12And R13Each independently hydrogen, deuterium, halogen, hydroxy, C1-6Alkyl or C1-6A haloalkyl group.
Further, said R2、R3、R4、R5、R8、R9、R10、R11、R12And R13Each independently hydrogen, deuterium, halogen, hydroxy, C1-4Alkyl or C1-4A haloalkyl group.
Further, said R2、R3、R4、R5、R8、R9、R10、R11、R12And R13Each independently hydrogen, deuterium, halogen, hydroxy, methyl, ethyl, isopropyl, n-propyl, tert-butyl, chloromethyl, or the like.
Further, the compound of the structure shown in the formula (I) is:
compound 1 is used herein instead.
In another aspect, the present invention provides a method for preparing a compound having a structure represented by formula (I), which is obtained by fermentation using a microorganism. Further, the microorganism is preferably Alternaria alternata 114-1G which is an origin of the Atlantic species.
Further, the preparation method comprises the following specific steps:
1) strain activation and fermentation culture: adding Alternaria alternata 114-1G from the ocean into a culture medium for fermentation culture; extracting fermentation liquor and mycelia by using ethyl acetate after fermentation is finished, and concentrating to obtain a fermentation crude extract;
2) separating a fermentation crude extract: subjecting the obtained crude fermentation extract to silica gel column chromatography adsorption elution, eluent concentration, column chromatography separation and elution to obtain eluent;
3) and (3) chromatographic purification and separation: concentrating the eluate, further separating and purifying by semi-preparative high performance liquid chromatography, and concentrating the purified solution under reduced pressure to obtain the compound with structure shown in formula (I).
Further, the culture medium is: 25g/L of mannitol, 15g/L of maltose, 10g/L of glucose, 10g/L of monosodium glutamate, 5g/L of soybean peptone and 3g/L of yeast extract powder.
Further, the silica gel column chromatography adopts 100-200 mesh silica gel column, and the eluent adopts ethyl acetate-methanol solution.
Further, the column chromatography separation adopts a Sephadex LH-20 column, and the eluent is methanol solution.
Further, the semi-preparative high performance liquid chromatography is C18-MS-II (10X 250mm), wherein the mobile phase is methanol-water (3: 7), the flow rate is 4mL/min, the detection wavelength is 200nm, and the injection volume is 1 mL.
In one aspect, the invention relates to a compound shown in the formula (I) or a pharmaceutically acceptable salt thereof, and the application of the compound or the pharmaceutically acceptable salt thereof in preparing a medicament, food or cosmetic additive for preventing or treating physiological changes or diseases caused by or related to oxygen radicals.
Further, the compound with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof is a metabolite of Alternaria alternata 114-1G which is derived from the ocean.
Further, the Alternaria alternata 114-1G from the ocean is preserved in the China center for culture Collection of marine microorganisms with the preservation number MCCC3A 01117.
Furthermore, the physiological change or disease caused by or associated with oxygen radicals refers to liver injury, senile dementia, cardiovascular and cerebrovascular diseases, aging, diabetic complications, and the like.
In one aspect, the invention provides a compound with a structure shown in formula (I) or a pharmaceutically acceptable salt thereof, and the compound or the pharmaceutically acceptable salt thereof is used for preparing a physiological change or disease caused by or related to inflammation.
Further, the compound with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof is a metabolite of Alternaria alternata 114-1G which is derived from the ocean.
Further, the Alternaria alternata 114-1G from the ocean is preserved in the China center for culture Collection of marine microorganisms with the preservation number MCCC3A 01117.
Further, the proinflammatory factors generated by the inflammation are TNF-a, IL-1B, IL-6, NO with inflammatory properties and the like.
Further, the physiological change or disease caused by or associated with inflammation refers to: systemic Inflammatory Response Syndrome (SIRS), sepsis, septic shock, multiple organ dysfunction syndrome, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, rheumatoid arthritis, inflammatory bowel disease, hypertension, coronary heart disease, myocardial infarction, heart failure, diabetes, systemic lupus erythematosus, lupus nephritis, scleroderma, sarcoidosis, dermatomyositis, Behcet's disease, psoriasis, depression, respiratory viral infection, chronic obstructive pulmonary disease, asthma, pancreatitis, liver cirrhosis, acquired immunodeficiency syndrome, Castleman's disease, Parkinson's disease, Alzheimer's disease, vascular headache, central nervous injury, cerebral infarction, acute cerebral hemorrhage, brain injury, infectious complications after brain injury, influenza viral encephalopathy, chronic renal insufficiency, primary nephrotic syndrome, reflux nephropathy, vascular headache, central nervous system injury, cerebral infarction, acute cerebral hemorrhage, chronic inflammatory syndrome, chronic inflammatory bowel disease, sarcoidosis, chronic inflammatory bowel disease, sarcoidosis, chronic inflammatory bowel disease, glomerulonephritis, hemorrhagic shock, obstructive sleep apnea syndrome, cardiac myxoma, acute myelogenous leukemia, multiple myeloma, myelodysplastic syndrome, tumors, pyoderma gangrenosum, graft-versus-host disease, uveitis, periodontal disease, bacterial infection, obesity, and the like.
In one aspect, the invention relates to a compound shown in the formula (I) or a pharmaceutically acceptable salt thereof, and the application of the compound or the pharmaceutically acceptable salt thereof in preparing a medicine, food or cosmetic additive for preventing or treating physiological changes or diseases caused by or related to oxygen radicals, or the medicine, food or cosmetic additive for preventing or treating physiological changes or diseases caused by or related to inflammation.
Further, the compound with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof is a metabolite of Alternaria alternata 114-1G which is derived from the ocean.
Further, the Alternaria alternata 114-1G from the ocean is preserved in the China center for culture Collection of marine microorganisms with the preservation number MCCC3A 01117.
Furthermore, the physiological change or disease caused by or associated with oxygen radicals refers to liver injury, senile dementia, cardiovascular and cerebrovascular diseases, aging, diabetic complications, and the like.
Further, the proinflammatory factors generated by the inflammation are TNF-a, IL-1B, IL-6, NO with inflammatory properties and the like.
Further, the physiological changes or diseases caused by or associated with inflammation are: systemic Inflammatory Response Syndrome (SIRS), sepsis, septic shock, multiple organ dysfunction syndrome, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, rheumatoid arthritis, inflammatory bowel disease, hypertension, coronary heart disease, myocardial infarction, heart failure, diabetes, systemic lupus erythematosus, lupus nephritis, scleroderma, sarcoidosis, dermatomyositis, Behcet's disease, psoriasis, depression, respiratory viral infection, chronic obstructive pulmonary disease, asthma, pancreatitis, liver cirrhosis, acquired immunodeficiency syndrome, Castleman's disease, Parkinson's disease, Alzheimer's disease, vascular headache, central nervous injury, cerebral infarction, acute cerebral hemorrhage, brain injury, infectious complications after brain injury, influenza viral encephalopathy, chronic renal insufficiency, primary nephrotic syndrome, reflux nephropathy, vascular headache, central nervous system injury, cerebral infarction, acute cerebral hemorrhage, chronic inflammatory syndrome, chronic inflammatory bowel disease, sarcoidosis, chronic inflammatory bowel disease, sarcoidosis, chronic inflammatory bowel disease, glomerulonephritis, hemorrhagic shock, obstructive sleep apnea syndrome, cardiac myxoma, acute myelogenous leukemia, multiple myeloma, myelodysplastic syndrome, tumors, pyoderma gangrenosum, graft-versus-host disease, uveitis, periodontal disease, bacterial infection, obesity.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The compounds disclosed in the present invention, including their salts, are also available in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.
In another aspect, the present specification discloses a method of anti-inflammatory, anti-oxidant activity and/or for preventing, treating or reducing an inflammatory infection or a physiological change or disease caused by or associated with oxygen radicals in a patient, comprising administering to the patient an effective amount of a compound disclosed in the present specification or a pharmaceutical composition disclosed in the present specification.
When therapeutically useful, a therapeutically effective amount of the indicated compounds may be administered as the raw chemical or may be provided as the active ingredient of a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound in one or more pharmaceutically acceptable carriers, diluents or excipients. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation, which process comprises mixing a compound of the present invention, especially a compound or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show meaningful patient benefit (e.g., reduction in viral load). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that, when combined, administered sequentially or simultaneously, result in a therapeutic effect. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The pharmaceutical preparations may be in unit dosage form, each unit dosage containing a predetermined amount of the active ingredient. Dosage levels of the compounds of the present disclosure are between about 0.01 and about 250, preferably between about 0.05 and about 100, mg/kg body weight/day, and are often used as monotherapies for the prevention or treatment of inflammatory, aging disorders. The pharmaceutical compositions of the present disclosure may be administered generally about 1 to 5 times per day or as a continuous infusion. Such administration may be used as a long term or short term therapy. The amount of active ingredient mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the time of treatment and the age, sex, body weight and condition of the patient. Preferred unit dosage forms are those containing a daily or divided dose or suitable fraction thereof of the active ingredient described herein above. Treatment can be initiated with small doses, which are clearly below the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved in this case. In general, the compounds are most desirably administered at concentration levels that generally provide effective results in lowering blood glucose without causing any harmful or toxic side effects.
Has the advantages that:
the compound can effectively remove DPPH free radicals, has strong oxidation resistance, and can be used for preparing antioxidant drugs, foods or cosmetic additives.
The compound can inhibit LPS (LPS) to induce RAW264.7 cells to generate NO, and can be used for preparing anti-inflammatory drugs. The preparation method has the advantages of small side effect, safety and good application prospect in the development of anti-inflammatory drugs.
In an experiment on the influence of p-hydroxyphenyl butanediol on NO release of RAW264.7 cells, the concentration of NO in a reaction system can be obviously reduced, and the compound has anti-inflammatory activity and is used for developing medicaments for treating inflammatory diseases; the DPPH free radical scavenging experiment result shows that the compound has antioxidant activity and can be used for relieving human body aging diseases.
The compound provided by the invention provides a new compound source for developing and treating inflammatory diseases and physiological changes or diseases caused by or related to oxygen radicals.
Drawings
FIG. 1 shows the inhibition rate of the proliferation of RAW264.7 cells by p-hydroxyphenylbutanediol (Compound 1) prepared according to the example of the present invention;
FIG. 2 Effect of p-hydroxyphenylbutanediol (Compound 1) prepared in the present example on NO release from RAW264.7 cells, note:*p＜0.05；**p＜0.01；****p＜0.0001；
FIG. 3 DPPH clearance of p-hydroxyphenylbutanediol (Compound 1) prepared in accordance with the present invention.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
EXAMPLE 1 preparation of p-hydroxyphenylbutanediol Compound
(1) Adding Alternaria alternata 114-1G (preserved in China center for culture Collection of marine microorganisms and strains, storage number MCCC3A01117) into a culture medium, and fermenting and culturing at 20 ℃ and 150rpm for 15 d. Wherein, the culture medium comprises the following components: 25g/L of mannitol, 15g/L of maltose, 10g/L of glucose, 10g/L of monosodium glutamate, 5g/L of soybean peptone and 3g/L of yeast extract powder. After fermentation, extracting fermentation liquor and mycelia by using ethyl acetate, and concentrating the extracting solution under reduced pressure to obtain a fermentation crude extract;
(2) performing 100-200-mesh silica gel column chromatography adsorption on the fermentation crude product in the step 1, eluting by using ethyl acetate-methanol solution (volume ratio is 1: 1), and combining the eluates by TLC detection;
(3) concentrating the eluent in the step 2, performing Sephadex LH-20 column chromatography separation, eluting by adopting a methanol solution, and combining the eluates through TLC detection;
(4) concentrating the eluate obtained in step 3, and further separating and purifying by using a semi-preparative High Performance Liquid Chromatograph (HPLC), wherein a semi-preparative chromatographic column is C18-MS-II (10 × 250mm), a mobile phase is methanol-water (3: 7), the flow rate is 4mL/min, the detection wavelength is 200nm, the sample injection volume is 1mL, and the purified solution is subjected to reduced pressure concentration to obtain a purified compound;
(5) using the compound obtained in step 41H-NMR and13C-NMR analysis, 4 aromatic proton signals deltaH6.72(2H, d, J-8.4 Hz, H-3/5) and 7.05(2H, d, J-8.4 Hz, H-2/4) indicate the presence of a para-substituted phenyl ring system, 1O-methine signal (. delta.) (Delta.,. delta.,. sup.H3.89, 1H, m, H-8), 1 Oxymethylene Signal (. delta.) (S)H3.70, 2H, m, H-10), 2 methylene signals [ (delta ] sH2.64，dd，J＝13.5，6.3Hz，H-7a；δH2.71, dd, J ═ 13.5, 6.8Hz, H-7b) and (δ)H1.59，m，H-9a；δH1.72，m，H-9b)]. In that13C NMR Spectroscopy (CD)3OD, 100MHz) of 10 carbon resonance signals, binding1H NMR spectra and carbon chemical potentialThe shift value can determine 6 aromatic carbons (. delta.)C116.6X 2, 130.9, 131.4X 2, 156.7), 1 methine group (. delta.)C71.4), 3 methylene groups (. delta.))C39.9, 44.5, 60.3). In the COSY spectrum, an oxygen-containing methylene group H is found210 protons and H2-9/H-8/H2-7 constitutes a self-selecting coupling system, whereby the-CH is derived2-CH(OH)-CH2-CH2An OH structural fragment. In HMBC spectra, the methylene proton H2-7 and C-1 (. delta.)C130.9)、C-2(δC131.4)、C-6(δC131.4)、C-8(δC71.4) and C-9 (. delta.))C39.9) there is a remote correlation, which deduces that the above-identified structural fragment is linked at the C-1 position of the phenyl ring; aromatic proton H-3 with C-1, C-4 (. delta.)C156.7) and C-5 (. delta.))C116.0) there is also a remote correlation. Finally, the hydroxyl group connected with the C-4 position can be determined by combining the molecular weight and the C-4 low-field chemical shift. In conclusion, compound 1 was identified as 4- (4-hydroxyphenyl) -1, 3-butanediol having a novel structure.
TABLE 1 preparation of Compound 11H (400MHz) and13c (100MHz) Nuclear magnetic data (CD)3OD)
EXAMPLE 2 evaluation of anti-inflammatory Activity in vitro of p-hydroxyphenylbutanediol (Compound 1) prepared in example 1
(1) RAW264.7 cell culture and administration
The pair of RAW264.7 cells in the logarithmic growth phase were seeded at a density of 1 × 104 cells/well in a 96-well plate (6 multiple wells per group), and the cells were administered after 24 hours of culture. Experimental Control group (Control), model group (1. mu.g/mL LPS stimulation), positive Control group (1. mu.g/mL LPS stimulation + BAY11-7085 at a concentration of 10. mu.M) and administration group (1. mu.g/mL LPS stimulation + Compound 1 at a concentration of 20. mu.M) were incubated at 37 ℃ for 24 hours in a carbon dioxide incubator, supernatants from each well were collected, and the NO content was measured according to step 2.
(2) Determination of the NO content
Taking 1mmol/L nitrite (NaNO2) standard solution in the kit, and diluting into solutions with NO 2-concentration of 3.125. mu. mol/L, 6.25. mu. mol/L, 12.5. mu. mol/L, 25. mu. mol/L and 50. mu. mol/L respectively.
According to the experimental dosage, equal volumes of the reagent A and the reagent B are mixed to prepare the Griess reagent. Reagent A: 1mg/ml N-1-naphthyl ethylenediamine hydrochloride solution. And (3) reagent B: 10mg/mL of a sulfanilic acid solution.
Adding 75 mu L of nitrite standard solution or a sample to be tested into a 96-well plate, adding 10 mu L of Griess reagent and 65 mu L of deionized water into each well, oscillating the 96-well plate to fully and uniformly mix the solution in the wells, reacting for 30min at room temperature, and testing the absorbance of the reaction solution at 548 nm. And (5) performing regression on the series of concentrations of the standard sample by using the OD548 value to obtain a standard curve. The concentration of the sample to be measured is calculated by a standard curve method.
(3) Testing samples for toxic effects on RAW264.7 cells
After 24h of administration, the cells in the 96-well plate were washed with PBS, complete medium containing 10% CCK-8 reagent by volume fraction was added to each well, and after incubation in a cell incubator for 1h, OD458 was measured for each well and the cell viability was calculated.
(4) Result processing
The inhibition rate of the sample on RAW264.7 cells was calculated according to the following formula.
The inhibition rate (%) [1- (Ai-A0)/(Aj-A0) ] x 100%
In the formula (I), the compound is shown in the specification,
ai-absorbance of the sample set;
a0 — absorbance of blank;
aj-absorbance of normal control group.
(5) Results of the experiment
The experimental results of fig. 1 show that: the compound has no inhibition effect on the proliferation of RAW264.7 cells, which indicates that the compound has no toxic effect and can ensure that an anti-inflammatory experiment is carried out under the condition that a sample has no obvious influence on the growth of the cells. The experimental results of fig. 2 show that: the compound can effectively inhibit LPS (LPS) to induce RAW264.7 cells to generate NO, and the analysis is carried out by combining the determination result of the NO content, so that the compound has obvious anti-inflammatory activity.
Example 3 evaluation of in vitro antioxidant Activity of p-hydroxyphenylbutanediol (Compound 1) prepared in example 1
(1) Preparation of DPPH solution
Weighing a proper amount of DPPH powder, dissolving the DPPH powder with a small amount of ethanol, transferring the DPPH powder to a volumetric flask, and then fixing the volume to 100mL with ethanol, namely, DPPH solution with the concentration of 0.5mmol/L, and storing the DPPH powder in a dark place.
(2) Test method
Preparing a compound sample to be detected into a solution with the concentration of 0.5mg/mL by using ethanol, diluting the solution into five gradients when in use, respectively detecting the concentrations of the diluted sample solutions to be 0.500mg/mL, 0.100mg/mL, 0.02mg/mL, 0.004mg/mL and 0.0008mg/mL, and detecting the OD (optical density) of the sample solutions with different concentrations at 517nm517The value is obtained. Taking 10mL of sample solution, adding 2mL of 0.5mmol/L DPPH solution, standing for reaction for 30min at room temperature in a dark place, and detecting OD of the sample solution at 517nm after the reaction is finished517The value is obtained.
(3) Result processing
The antioxidant capacity of the sample was calculated according to the following formula:
clearance (%) - (1- (A)i-Aj)/A0]×100％
In the formula (I), the compound is shown in the specification,
Ai-adding the absorbance of the reacted DPPH solution;
Ajthe absorbance of the sample solution itself;
A0absorbance of DPPH solution with no sample added.
(4) Results of the experiment
The experimental result of figure 3 shows that the compound has a clearance rate of 46.12% to DPPH free radicals at a concentration of 0.5mg/mL, which indicates that the compound has antioxidant capacity, can effectively clear DPPH free radicals, and has the potential of further developing into drugs, foods or cosmetic additives for resisting oxidation and damages caused by free radicals.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. A compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound having a structure represented by formula (I) is:
。
2. a method for preparing a compound of formula (I) according to claim 1, wherein the compound of formula (I) is obtained by fermentation using a microorganism,
the method comprises the following specific steps:
1) strain activation and fermentation culture: adding Alternaria alternata 114-1G from the ocean into a culture medium for fermentation culture; extracting fermentation liquor and mycelia by using ethyl acetate after fermentation is finished, and concentrating to obtain a fermentation crude extract;
2) separating a fermentation crude extract: subjecting the obtained crude fermentation extract to silica gel column chromatography adsorption elution, eluent concentration, column chromatography separation and elution to obtain eluent;
3) and (3) chromatographic purification and separation: concentrating the eluate, further separating and purifying by semi-preparative high performance liquid chromatography, and concentrating the purified solution under reduced pressure to obtain compound with structure shown in formula (I);
the culture medium is as follows: 25g/L of mannitol, 15g/L of maltose, 10g/L of glucose, 10g/L of monosodium glutamate, 5g/L of soybean peptone and 3g/L of yeast extract powder; fermenting and culturing at 20 deg.C and 150rpm for 15d
The silica gel column chromatography adopts a 100-200-mesh silica gel column, and the eluent adopts an ethyl acetate-methanol solution;
the column chromatography separation adopts a Sephadex LH-20 column, and the eluent is methanol solution;
the semi-preparative high performance liquid chromatography is C18-MS-II (10X 250mm), wherein the mobile phase is methanol-water (3: 7), the flow rate is 4mL/min, the detection wavelength is 200nm, and the sample injection volume is 1 mL.
3. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the preparation of a medicament, food or cosmetic additive for the prevention or treatment of physiological changes or diseases caused by or associated with oxygen radicals.
4. The use according to claim 3, wherein the physiological change or disease caused by or associated with oxygen radicals is liver damage, senile dementia, cardiovascular and cerebrovascular disorders, aging or diabetic complications.
5. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the preparation of a medicament, food or cosmetic additive for a physiological change or disease caused by or associated with inflammation, the inflammatory pro-inflammatory factor being NO having an inflammatory character, the physiological change or disease caused by or associated with inflammation being: systemic Inflammatory Response Syndrome (SIRS), septic shock, multiple organ dysfunction syndrome, arthritis, inflammatory bowel disease, hypertension, coronary heart disease, myocardial infarction, heart failure, diabetes, systemic lupus erythematosus, depression, liver cirrhosis, acquired immunodeficiency syndrome, alzheimer's disease, vascular headache, central nervous system injury, tumors, bacterial infections, obesity.
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Non-Patent Citations (6)
| Title |
|---|
| Alashinols F and G, two lignans from stem bark of Syringa pinnatifolia;Feng, Xiao 等;《NATURAL PRODUCT RESEARCH》;20171231;第31卷(第13期);第1555-1560页 * |
| Oxidative cyclorelease from soluble polymeric supports;Liu, H 等;《JOURNAL OF ORGANIC CHEMISTRY》;20050513;第70卷(第10期);附加信息第S11-S12页 * |
| Radical alpha-C-H hydroxyalkylation of ethers and acetal;Yoshimitsu, T 等;《JOURNAL OF ORGANIC CHEMISTRY》;20050318;第70卷(第6期);第2343页右栏化合物25 * |
| REGISTRY数据库;无;《STN》;20180103 * |
| Tandem hydroboration/reduction of trisubstituted beta,gamma-unsaturated esters for the asymmetric synthesis of chiral 1,3-diols;Fordred, Paul S. 等;《TETRAHEDRON LETTERS》;20130102;第54卷(第1期);第29页table1化合物12c * |
| 大洋来源真菌链格孢菌114-1G发酵条件考察与抗肿瘤产物初探;廖宇琛;《国际药学研究杂志》;20200331;第47卷(第3期);第220-228页 * |
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