CN113304138B - Application of Vitisinol D in preparation of xanthine oxidase inhibition drugs - Google Patents

Application of Vitisinol D in preparation of xanthine oxidase inhibition drugs Download PDF

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CN113304138B
CN113304138B CN202110743804.0A CN202110743804A CN113304138B CN 113304138 B CN113304138 B CN 113304138B CN 202110743804 A CN202110743804 A CN 202110743804A CN 113304138 B CN113304138 B CN 113304138B
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xanthine oxidase
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CN113304138A (en
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廖尚高
廖兴江
何迅
徐国波
朱勤凤
关焕玉
周孟
董莉
董永喜
罗喜荣
邹淑涵
王磊
张金娟
陈腾祥
王栋
杨雅欣
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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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 Vitisinol D in preparation of xanthine oxidase inhibitorThe application in preparing the medicament, the xanthine oxidase inhibiting medicament is prepared by taking Vitisinol D as an effective component and other medicament excipients or carriers, and the molecular formula of the Vitisinol D is C28H22O6The Vitisinol D of the present invention is a monomeric compound isolated from the roots of Gentiana cardifolia and has high safety and strong xanthine oxidase inhibitory action.

Description

Application of Vitisinol D in preparation of xanthine oxidase inhibition drugs
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 Vitisinol D in preparation of a xanthine oxidase inhibition drug.
Background
At present, the prevalence rate of gout is increased year by year, and the prevalence rate is second to that of diabetes, so that gout becomes the second major metabolic disease; gout is a group of clinical syndromes caused by increased purine biological metabolism in vivo for a long time, uric acid production excess or excretion deficiency to cause uric acid increase in blood, and urate crystals are deposited on joints and the like, and continuous high uric acid level in blood is an essential condition for inducing gout. Uric acid is the final product of purine substances in vivo metabolism, and hyperuricemia is induced by the fact that the concentration of uric acid in vivo exceeds a normal range, so gout attack is caused.
Xanthine Oxidase (XO) is a complex flavoenzyme, is an important nucleotide metabolizing enzyme in organisms, and can catalyze purine compounds and aliphatic and aromatic aldehyde compounds in the organisms to be finally oxidized to form uric acid. An increase in xanthine oxidase activity leads to disorders of uric acid metabolism and may at the same time exacerbate disorders of carbohydrate metabolism. The xanthine oxidase inhibitor can inhibit the activity of xanthine oxidase to prevent hypoxanthine and xanthine from being metabolized into uric acid, so as to reduce the production of uric acid in vivo and treat gout, wherein allopurinol has obvious curative effect and definite action mechanism for inhibiting the production of uric acid, and is commonly used for reducing the content of uric acid, but has the side effects of hypersensitivity syndrome, Stevens Johnson syndrome, nephrotoxicity and the like. In 2009, the XO selective inhibitor febuxostat is approved to be marketed by FDA (food and drug administration) in the United states, the XO activity inhibition effect is further improved, the effect is better than that of allopurinol, but adverse reactions such as stomach pain, diarrhea, liver injury, muscle pain and the like still occur.
Therefore, finding a substance that effectively inhibits xanthine oxidase activity without adverse side effects is a key task in developing anti-gout drugs.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the application of Vitisinol D in preparing xanthine oxidase inhibition drugs.
The method is realized by the following technical scheme:
the application of Vitisinol D in preparing xanthine oxidase inhibiting medicine is characterized in that the xanthine oxidase inhibiting medicine can inhibit the activity of xanthine oxidase to reduce the generation of uric acid in vivo and prevent and treat diseases related to the xanthine oxidase activity, such as hyperuricemia, gout, diabetic nephropathy, cardiovascular diseases and the like.
The structure of the Vitisinol D is as follows:
Figure BDA0003142212190000021
the molecular formula of the Vitisinol D is C28H22O6The chemical name is (+) - (1R,5S,6S,7S) -6- (3,5-Dihydroxyphenyl) -7- (4-Dihydroxyphenyl) -4- [ (1E) -2- (4-Dihydroxyphenyl) ethyl]bicyclo[3.2.1]oct-3-ene-2,8-dione。
The xanthine oxidase inhibiting medicine is prepared with Vitisinol D as effective component and other medicine excipient or carrier.
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 Vitisinol D is a monomer compound separated from the roots of the Chinese medicinal sparrow, is an effective component of the Chinese medicinal sparrow roots with the effect of resisting gout, has no report of related toxic or side effect, has strong xanthine oxidase inhibition effect and IC thereof50(19.8 mu mol/L) is obviously superior to clinical allopurinol (IC)5071.7 mu mol/L), Viisinol D is an effective component of Chinese medicine Genistein for resisting gout, and has better xanthine oxidase inhibition activity compared with clinical allopurinol.
The medicine prepared by taking Vitisinol D as an active ingredient can effectively inhibit xanthine oxidase activity and avoid adverse reactions such as stomachache, diarrhea, liver injury, muscle pain and the like.
Vitisinol D has definite pharmacological action and obvious drug effect, the pharmacological action is similar to that of allopurinol and febuxostat, and the Vitisinol D is expected to be developed into allopurinol and febuxostat substitutes for clinical application.
Drawings
FIG. 1 shows the inhibitory effect of Vitisinol D on xanthine oxidase at various concentrations.
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
The application of Vitisinol D in preparing xanthine oxidase inhibiting medicine is characterized in that the xanthine oxidase inhibiting medicine can inhibit the activity of xanthine oxidase to reduce the generation of uric acid in vivo and prevent and treat diseases related to the xanthine oxidase activity, such as hyperuricemia, gout, diabetic nephropathy, cardiovascular diseases and the like.
The molecular formula of the Vitisinol D is C28H22O6The chemical name is (+) - (1R,5S,6S,7S) -6- (3,5-Dihydroxyphenyl) -7- (4-Dihydroxyphenyl) -4- [ (1E) -2- (4-Dihydroxyphenyl) ethyl]bicyclo[3.2.1]oct-3-ene-2,8-dione, having the formula:
Figure BDA0003142212190000041
the xanthine oxidase inhibition drug is prepared by taking Vitisinol D as an effective component and other pharmaceutical excipients or carriers;
the xanthine oxidase inhibitor is an oral preparation or an injection; wherein the oral preparation is one or more of granules, capsules, tablets, powder, dripping pills and sustained release preparations;
the Vitisinol D is extracted from natural medicine (such as Gentiana malachita L.) and is used for preparing medicine for preventing and treating diseases related to xanthine oxidase; including but not limited to: drugs for diseases associated with xanthine oxidase activity, such as hyperuricemia, gout, diabetic nephropathy, and cardiovascular diseases;
in order to demonstrate that the application of the Vitisinol D of the present invention in the preparation of xanthine oxidase inhibitory drugs achieves good effects, the following will further explain the effects achieved by the present invention in combination with specific experiments.
Experimental example 1XO inhibitory activity test:
at 25 ℃ in a 96-well plate, a total reaction volume of 200. mu.L was measured, and 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 solution (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 Graphpad prism6.0 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 Vitisinol D is precisely weighed, dissolved by DMSO, and diluted by 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 of XO by Vitisinol D at various concentrations and half-maximal Inhibitory Concentration (IC)50)
Figure BDA0003142212190000061
As can be seen from Table 1: IC compared with positive allopurinol50(71.7. mu. mol/L) and a lower inhibition rate at low concentrations (8.3% and 4.2% at 12.5 and 6.25. mu. mol/L, respectively), the IC of Vitisinol D as claimed in the present application5019.8 mu mol/L, still has higher inhibition rate under low concentration (38.5 percent and 16.1 percent respectively at 12.5 and 6.25 mu mol/L), has outstanding inhibition effect on xanthine oxidase and is obviously better than allopurinol.

Claims (1)

  1. The application of Vitisinol D in preparing the medicine for preventing and treating hyperuricemia and gout by inhibiting xanthine oxidase activity is characterized in that the Vitisinol D has the following structural formula:
    Figure DEST_PATH_IMAGE002
    ；
    the VitisiThe molecular formula of nol D is C28H22O6The chemical name is (+) - (1R,5S,6S,7S) -6- (3,5-Dihydroxyphenyl) -7- (4-Dihydroxyphenyl) -4- [ (1E) -2- (4-Dihydroxyphenyl) ethyl]bicyclo[3.2.1]oct-3-ene-2,8-dione。
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