CN113304139A - Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs - Google Patents
Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs Download PDFInfo
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- CN113304139A CN113304139A CN202110741146.1A CN202110741146A CN113304139A CN 113304139 A CN113304139 A CN 113304139A CN 202110741146 A CN202110741146 A CN 202110741146A CN 113304139 A CN113304139 A CN 113304139A
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- xanthine oxidase
- viniferifuran
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- oxidase inhibitory
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- 108010093894 Xanthine oxidase Proteins 0.000 title claims abstract description 41
- 102100033220 Xanthine oxidase Human genes 0.000 title claims abstract description 41
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- MTRJOEZPTJRJOB-UHFFFAOYSA-N viniferifuran Natural products C1=CC(O)=CC=C1C=CC1=CC(O)=CC2=C1C(C=1C=C(O)C=C(O)C=1)=C(C=1C=CC(O)=CC=1)O2 MTRJOEZPTJRJOB-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 230000005764 inhibitory process Effects 0.000 title claims abstract description 27
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- 230000000694 effects Effects 0.000 claims abstract description 24
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 18
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical group C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 claims abstract description 8
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- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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Abstract
The invention belongs to the technical field of application of effective components of traditional Chinese medicinal materials, and particularly relates to application of Viniferifuran in preparation of a xanthine oxidase inhibiting drug, wherein the Viniferifuran is a diphenyl ethylene dimer with a benzofuran structure and has a molecular formula of C28H20O6The compound has strong inhibition effect on xanthine oxidase, and can be used for preparing xanthine oxidase inhibition medicines or preventive medicines or therapeutic medicines for diseases related to xanthine oxidase.
Description
Technical Field
The invention belongs to the technical field of application of effective components of traditional Chinese medicinal materials, and particularly relates to application of Viniferifuran in preparation of a xanthine oxidase inhibitor.
Background
In recent years, the incidence of gout and hyperuricemia, which is a typical purine metabolic disease, is continuously increasing, and when a large amount of uric acid is deposited in the form of sodium salt at soft tissues and joints of the body, inflammation is induced to cause gout, and thus, the important biochemical basis of gout is hyperuricemia.
Uric acid is a final product of purine metabolism, Xanthine Oxidase (XO for short) can catalyze hypoxanthine to generate Xanthine, and further metabolize the Xanthine into uric acid and free radicals, and the Xanthine Oxidase is a key enzyme for generating uric acid and an important target point for reducing the generation of uric acid. Currently, xanthine oxidase inhibitors, as a clinically common uric acid-lowering drug, can be divided into two main categories in terms of components: in clinical application, the chemically synthesized xanthine oxidase inhibitors with better effect mainly comprise benzbromarone, allopurinol, probenecid, topiroxostat, febuxostat and the like, but the drugs have large toxic and side effects, so that a human body is obviously injured.
Obtaining low-toxicity xanthine oxidase inhibitors from natural plants becomes a research hotspot, for example, in the literature, "research on xanthine oxidase inhibition activity of 9 traditional Chinese medicine extracts", 9 traditional Chinese medicine extracts (flos puerariae lobatae, herba selaginellae root, herba orthosiphoni, centipeda minima, rhizoma galangae, gynostemma pentaphylla, abrus cantoniensis hance and honeysuckle) are investigated on the xanthine oxidase inhibition activity of the extracts of the 9 traditional Chinese medicine plants. The results show that the 9 traditional Chinese medicine extracts have better inhibitory activity at 2mg/mL, and the inhibition rate is different from 33% to 79%. The semi-inhibitory concentrations of the flower of kudzuvine, the Chinese alpine rush and the honeysuckle flower are respectively 0.65, 0.96 and 0.74mg/mL, and the inhibition types of the Chinese alpine rush and the flower of kudzuvine are composite inhibition mainly including competitive inhibition.
The literature, "screening of active ingredients of uric acid-lowering traditional Chinese medicine composition and research of preparation process thereof" discloses a pharmaceutical composition consisting of a liquorice alcohol extract, a galangal alcohol extract, a dandelion alcohol extract, a chicory water extract and a plantain alcohol extract in a ratio of 10:8:7:6:10, wherein the pharmaceutical composition has the best effect.
However, most of schemes are the combination of multiple active ingredients, the inhibition effect of a single ingredient is still not ideal, and the inventor also finds that the broom extract has a certain effect of inhibiting the xanthine oxidase activity through years of research, but the main active ingredients of the broom extract are unknown, so that the research on the medication rule and the medicine preparation process is greatly influenced. Therefore, the inventor researches on the extract of the maidenhair which is safe and effective in treating the clinical gout on the basis of previous researches to discover a compound which can be used for preparing a safe and effective xanthine oxidase inhibiting medicament.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the application of Viniferifuran in preparing xanthine oxidase inhibiting medicines.
The method is realized by the following technical scheme:
the application of the Viniferifuran in preparing a xanthine oxidase inhibition drug is characterized in that xanthine oxidase inhibition is realized by inhibiting the activity of xanthine oxidase to reduce the generation of uric acid in vivo, and diseases related to xanthine oxidase activity, such as hyperuricemia, gout, diabetic nephropathy, cardiovascular diseases and the like, are prevented and treated.
The Viniferifuran is a stilbene dimer with a benzofuran structure, and the molecular formula of the stilbene dimer is C28H20O6The chemical name is 5- {6-Hydroxy-2- (4-hydroxyphenyl) -4- [ (Z) -2- (4-hydroxyphenyl) vinyl]-1-benzofuran-3-yl}-1,3-benzenediol。
The structural formula of the Viniferifuran is as follows:
the Viniferifuran is extracted from natural medicines (such as sparrow roots) or is synthesized by taking stilbene as a monomer through oxidative coupling as a key reaction.
The xanthine oxidase inhibitor is prepared by taking Viniferifuran as an active ingredient and a pharmaceutically acceptable carrier or excipient.
The xanthine oxidase inhibitor is an oral preparation or an injection.
The oral preparation is one or more of granules, capsules, tablets, powder, dripping pills and sustained release preparations.
Has the advantages that:
the inventor discovers that: the stilbene dimer Viniferifuran with the benzofuran structure has a strong inhibition effect on xanthine oxidase, is an effective component of the Chinese medicinal broom root with the gout resisting effect, and can be used for preparing xanthine oxidase inhibition medicaments or medicaments for preventing or treating diseases related to the xanthine oxidase. The drug effect proves that under the condition of low concentration, the compound still has obvious xanthine oxidase activity inhibition effect and IC thereof50(13.9 mu mol/L) is obviously superior to clinical allopurinol (IC)5071.7 mu mol/L) has better xanthine oxidase inhibition activity compared with clinical allopurinol.
The Viniferifuran of the invention has the antibacterial, anti-inflammatory, antiviral, antioxidant, anti-AIDS activity and liver protection effects in the history of clinical application for many years, and also has high safety performance.
The Viniferifuran provided by the invention has good adaptability, and can be prepared into various dosage forms such as injections, granules, capsules, tablets, powder, dropping pills, sustained-release agents and the like.
Drawings
FIG. 1 shows the inhibitory effect of different concentrations of Viniferuran on xanthine oxidase.
Detailed Description
The following is a detailed description of the embodiments of the present invention, but the present invention is not limited to these embodiments, and any modifications or substitutions in the basic spirit of the embodiments are included in the scope of the present invention as claimed in the claims.
Example 1
Application of Viniferiferan in preparation of xanthine oxidase inhibition drugs, wherein Viniferan is diphenyl ethylene dimer with benzofuran structure, and molecular formula of Viniferan is C28H20O6The chemical name is 5- {6-Hydroxy-2- (4-hydroxypentyl) -4- [ (Z) -2- (4-hydroxyphenyl)vinyl]-1-benzofuran-3-yl}-1,3-benzenediol；
The structural formula of the Viniferifuran is as follows:
the Viniferifuran is extracted from natural medicines (such as sparrow roots) or is synthesized by taking stilbene as a monomer through oxidative coupling as a key reaction.
The xanthine oxidase inhibition is characterized in that the xanthine oxidase inhibition is used for inhibiting the activity of the xanthine oxidase, reducing the generation of uric acid in vivo and preventing and treating diseases related to the xanthine oxidase activity, such as hyperuricemia, gout, diabetic nephropathy, cardiovascular diseases and the like.
The xanthine oxidase inhibitor is prepared by taking Viniferifuran as an active ingredient and a pharmaceutically acceptable carrier or excipient.
The xanthine oxidase inhibitor is an oral preparation or an injection;
the oral preparation is one or more of granules, capsules, tablets, powder, dripping pills and sustained release preparations;
experimental example 1
XO inhibitory activity test: using a 96-well plate at 25 ℃ in a total reaction volume of 200. mu.L, 50. mu.L of the enzyme solution (final reaction concentration: 0.05U/mL) and 50. mu.L of the sample solution were added first, and after incubation at 25 ℃ for 15min, 50. mu.L of the xanthine substrate (final concentration: 150. mu. mol/L) was added to initiate the reaction. After incubation at 25 ℃ for 20min, the reaction was stopped by adding 50. mu.L of 1mol/L hydrochloric acid solution. The absorbance values were measured at 290 nm. Taking the difference value of the value and the OD value at the time of incubation for 0min as a final detection result; the OD value of the blank sample (i.e., the sample solution was replaced with PBS containing 5% DMSO to determine the maximum reactivity of the enzyme without the test drug) was measured in the same manner, and the inhibition rate of each extract was calculated according to the following formula: inhibition (%) × (1 — average OD value of test sample/average OD value of blank sample) × 100%. Data analysis was performed using Graphpadprism 6.0 software. Calculating the drug concentration at which half of the xanthine oxidase is inhibited, i.e. IC50. Allopurinol is used as a positive drug; the activity results are shown in table 1;
wherein, the preparation of the enzyme solution: weighing a proper amount of XO, and dissolving with 1mL of water to obtain XO stock solution with the concentration of 100U/mL; the stock solution was dispensed into 10mL EPP tubes at 50. mu.L per tube, and stored in a refrigerator at-80 ℃. Taking a proper amount of the stock solution, and diluting with PBS to obtain XO solution with the concentration of 0.2U/mL. After the solution is prepared, the solution is immediately stored in a refrigerator at 0 ℃.
Preparation of sample solution: an appropriate amount of Viniferifuran is precisely weighed, dissolved in DMSO and diluted with PBS to prepare a sample mother solution with the mass concentration of 1000 mug/mL. And diluting the mother liquor step by using PBS containing DMSO as a solvent by a double dilution method to prepare sample solutions with the mass concentrations of 1000, 500, 250, 125, 62.5, 31.3 and 15.6 mu g/mL respectively, wherein the DMSO content is 1%.
Preparation of allopurinol control solution: accurately weighing a proper amount of allopurinol, dissolving the allopurinol in DMSO, and adding a proper amount of PBS for dilution to prepare allopurinol mother liquor with the mass concentration of 500 mug/mL for later use. The mother liquor is diluted step by using PBS containing DMSO as a solvent by a double dilution method to prepare control solutions with the mass concentrations of 500, 250, 125, 62.5, 31.3, 15.63, 7.82 and 3.91 mu g/mL respectively, wherein the DMSO content is 1%.
Preparation of xanthine substrate solution: weighing a proper amount of xanthine, adding PBS, adjusting the pH to 7.5 by NaOH and HCl solutions at room temperature, and performing ultrasonic dissolution to prepare xanthine substrate solutions with the concentrations of 1200, 1000, 800, 600 and 400 mu mol/L respectively.
TABLE 1 inhibition and median Inhibition (IC) of XO by Viniferifuran at different concentrations50)
As can be seen from Table 1: IC compared with positive allopurinol50(71.7. mu. mol/L) and a lower inhibition at low concentrations (8.3% and 4.2% at 12.5 and 6.25. mu. mol/L, respectively), the IC of Viniferifuran claimed in the present application5013.9. mu. mol/L inThe inhibitor still has higher inhibition rate (59.1 percent and 32.1 percent respectively at 12.5 and 6.25 mu mol/L) under low concentration, has outstanding inhibition effect on xanthine oxidase and is obviously superior to allopurinol.
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