CN115650944A - Compounds capable of reducing uric acid - Google Patents
Compounds capable of reducing uric acid Download PDFInfo
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- CN115650944A CN115650944A CN202211403856.4A CN202211403856A CN115650944A CN 115650944 A CN115650944 A CN 115650944A CN 202211403856 A CN202211403856 A CN 202211403856A CN 115650944 A CN115650944 A CN 115650944A
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- 229940116269 uric acid Drugs 0.000 title claims abstract description 33
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention particularly relates to a compound capable of reducing uric acid. Specifically provides 4 novel azophilic compounds. The 4 compounds have xanthine oxidase inhibitory activity, can reduce the concentration of blood uric acid, and have potential medicinal potential of reducing uric acid and treating gout.
Description
Technical Field
The invention belongs to the field of compounds, and particularly relates to a compound capable of reducing uric acid.
Background
Hyperuricemia means that the blood uric acid of men is higher than 420 mu mol/L, and the blood uric acid of women is higher than 360 mu mol/L. Gout refers to the disease of gouty nephropathy, gouty arthritis and the like caused by the deposition of mono-natriuretic urate crystals to joints, kidneys and other parts. Gout is directly related to hyperuricemia. Along with social development, the living standard of people is improved, the intake of exogenous purine is greatly increased, the purine metabolism in a human body is easy to be abnormal due to the change of life style, and the number of gout patients is increased year by year.
At present, the main method for treating gout is to reduce the concentration of blood uric acid in vivo, and the main medicines are two types: one is inhibitor for inhibiting xanthine oxidase which is key enzyme in the process of synthesizing uric acid, and the other is drug for promoting the excretion of uric acid in human body. There are several clinically used drugs for inhibiting the xanthine oxidase activity. However, most of the drugs have adverse effects on normal metabolism, and are easy to cause serious side effects such as liver and kidney injury, anaphylactic reaction and the like, which brings great limitation to clinical treatment. There is therefore a great need to develop new effective drugs.
The azaphilone compound (azaphilone) is a natural product produced mainly by filamentous fungi, and has diverse molecular structures. At present, researches on the azophilic ketone compound focus on Monascus spp (also called Monascus), the Monascus spp is mainly used as a natural food pigment, the researches on the physiological activity are less, reports for reducing the concentration of blood uric acid are not found, and even partial researches show that related products of Monascus metabolism have the effect of improving uric acid.
If specific azone compounds produced by monascus have the effect of reducing uric acid, the method has great significance for research and development of related foods and medicines.
Disclosure of Invention
The invention aims to provide a compound capable of reducing uric acid.
In order to realize the purpose of the invention, the technical scheme adopted by the invention is as follows: a diazotroph compound, the structural formula of which is any one of the following compounds:
correspondingly, the application of the azone compound in preparing a medicament for treating/relieving gout.
Correspondingly, the application of the azone compound in preparing a medicament for reducing uric acid is provided.
Correspondingly, the application of the azone compound in preparing the medicine for inhibiting the xanthine oxidase activity is provided.
Correspondingly, the monascus has the deposit number of ATCC 96218 and is applied to preparing the medicine for treating/relieving gout.
Correspondingly, the monascus has the deposit number of ATCC 96218 and is applied to the preparation of the medicine for reducing uric acid.
Correspondingly, the monascus has the deposit number of ATCC 96218 and is applied to the preparation of the medicine for inhibiting the xanthine oxidase activity.
Correspondingly, the application of the monascus in preparing the medicine for treating/relieving gout utilizes any one or more of the following compounds in the monascus fermentation product,
correspondingly, the application of the monascus in the preparation of the medicine for reducing uric acid utilizes any one or more of the following compounds in the monascus fermentation product,
correspondingly, the application of the monascus in preparing the medicine for inhibiting the xanthine oxidase activity utilizes any one or more of the following compounds in the monascus fermentation product,
the invention has the following beneficial effects: the invention provides 4 novel total azophilic ketone compounds, and the 4 compounds have xanthine oxidase inhibitory activity, can reduce the concentration of blood uric acid, and have potential medical potential of reducing uric acid and treating gout.
Drawings
FIG. 1 is a graph comparing in vitro inhibition of xanthine oxidase activity by isolated compounds of the invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum and a hydrogen spectrum of Compound 1;
FIG. 3 is a nuclear magnetic resonance carbon spectrum and a hydrogen spectrum of Compound 2;
FIG. 4 is a NMR carbon and hydrogen spectra of Compound 3;
FIG. 5 is a NMR carbon and hydrogen spectra of Compound 4;
FIG. 6 is a structural diagram of 4 separated azaphilone compounds in the invention;
FIG. 7 is a graph showing the effect of 4 diazotrophones on reducing mouse blood uric acid.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. The data obtained are the average values obtained after at least 3 repetitions, and each repetition is valid.
The first embodiment is as follows: isolation, purification and characterization of Compounds
1. And (5) culturing monascus. A potato dextrose agar medium (PDA medium) slant culture of Monascus purpureus ATCC 96218 was inoculated into potato dextrose liquid medium (PDB medium) and cultured at 28 ℃ and 140rpm for 10 days. Inoculating the fermentation product into fresh PDB culture medium at an inoculum size of 10% (v/v), and culturing at 28 deg.C and 140rpm for 10 days to obtain Monascus ruber fermentation broth.
2. And (4) extracting the compound. And (3) homogenizing the monascus fermentation liquor by using a homogenizer, and crushing hyphae to obtain uniform fermentation liquor. Anhydrous methanol of 2 times the volume of the fermentation broth was added, and the mixture was incubated at 50 ℃ for 2 hours under ultrasonic conditions of 100w power, followed by centrifugation at 12000rpm for 20 minutes, and the supernatant and the precipitate were collected, respectively. The supernatant was dehydrated with anhydrous sodium sulfate to obtain a methanol solution of the compound. The precipitate was mixed with 20 volumes of petroleum ether (20 mL of petroleum ether for 1g of precipitate), extracted under ultrasonic wave (100 w power) at 50 ℃, centrifuged at 12000rpm after 2 hours to remove the precipitate, and the supernatant was collected to give a petroleum ether solution of the compound.
3. And (4) purifying the compound. The petroleum ether solution and methanol solution of the compound are subjected to low-pressure rotary evaporation, most of organic solvents are removed and combined, and a small amount of anhydrous methanol is used for dissolving. And (3) separating and purifying the compound by using a semi-preparative high performance liquid chromatograph. The chromatographic separation conditions are as follows: the mobile phase A was pure water and the mobile phase B was acetonitrile, both containing 0.05% (v/v) phosphoric acid, at a flow rate of 20mL/min. The chromatographic running procedure was: 0-5 minutes, 60% mobile phase A; the concentration of the mobile phase A is linearly reduced from 60 percent to 5 percent in 5 to 25 minutes; 25-30 minutes, 5% mobile phase a; the concentration of the mobile phase A is linearly increased from 5 percent to 35 percent within 30 to 35 minutes; 35-40 minutes, 50% mobile phase a (remaining volume mobile phase B). 14 compounds were isolated.
4. In vitro xanthine oxidase activity inhibition assay. Xanthine Oxidase (XOD) is a key enzyme in uric acid synthesis, and can convert xanthine to produce uric acid. The inhibitory effect of the 14 compounds isolated in step 3 on xanthine oxidase activity was determined using the Xanthine Oxidase (XOD) activity assay kit (cat # BC 1095) available from beijing solibao technologies ltd. The specific use was performed as described in the kit instructions, and the xanthine oxidase activity was calculated according to the kit instructions. Specifically setting: blank control group, negative control group (equal amount of PDB medium instead of each compound), each compound group, positive control group (equal amount of allopurinol instead of each compound), each group was set for 6 replicates.
As shown in FIG. 1, 4 of the 14 compounds were able to inhibit xanthine oxidase activity in vitro, and the amounts of the compounds were 0.5mg/mL. Of the 4 compounds, the average inhibition rate of the compound 1 on the xanthine oxidase activity is the highest and reaches 85.3%, the average inhibition rate of the compound 2 on the xanthine oxidase activity is 84.7%, and the other 2 compounds also have strong inhibition effects. The mean inhibition rate of allopurinol (positive control group) on xanthine oxidase was 92.3%. The compound separated out by 4 is proved to have obvious inhibitory activity to xanthine oxidase and has the potential of treating hyperuricemia.
5. And (4) identifying the 4 compounds with xanthine oxidase inhibitory activity in the step (4), detecting the 4 compounds by a nuclear magnetic resonance technology, and analyzing and determining the molecular structures of the 4 compounds according to a C spectrogram and an H spectrogram. The C spectrum and the H spectrum of the compound 1 are shown in figure 2, the C spectrum and the H spectrum of the compound 2 are shown in figure 3, the C spectrum and the H spectrum of the compound 3 are shown in figure 4, and the C spectrum and the H spectrum of the compound 4 are shown in figure 5.
The chemical structural formulas of the 4 azone compounds are identified and obtained and are shown in figure 6. The numbers under each compound in figure 6 represent the compound number. For example, the number 1 corresponds to the structural formula representing compound 1. The names of the 4 compounds are (abbreviated in parentheses): compound 1: monascusone a (MSA), compound 2: FK17-P2B2 (FP 2), compound 3: acetyl-monasfluorol A (AMFA), compound 4 Acetyl-monasfluorol B (AMFB).
The inventors conducted fermentation product compound isolation and xanthine oxidase activity inhibition tests on a plurality of monascus of different origins, and also conducted xanthine oxidase activity inhibition tests on each fermentation product mixture. The results show that: most monascus fermentation mixtures contain the above 4 compounds, but substantially all are present in low or very low amounts. Moreover, most of the fermentation mixtures of monascus including ATCC 96218 have no or little xanthine oxidase inhibitory activity, probably because the above 4 compounds are low in the fermentation mixture or contain other compounds having a resistance/adverse effect and the like.
The second embodiment: animal experiments with Compounds
Mice were administered 4 compounds of example one and observed for efficacy in reducing uric acid. The specific operation is as follows: 63 male Kunming mice, 8 weeks old, were selected, randomized into 7 groups of 9 replicates per group: a blank control group, a hyperuricemia model group (only fructose and oteracil potassium are fed, and no medicine for reducing uric acid or a compound to be tested is fed), hyperuricemia + each compound to be tested group (1 group is respectively arranged for each compound, 4 groups are counted), and hyperuricemia + allopurinol (positive control) group. Mice were bred adaptively for 7 days before modeling and dosing. Except the blank control group drinking clear water normally, the other groups drinking water is 15% fructose water. After 1h of grain breaking every day (the concrete operation is that the grain of the mouse is removed every day, the mouse can not eat food for 1 h), the mouse is continuously gavaged for 14 days by using 250 mg/kg. D oteracil potassium for other groups except the blank control group, and the mouse of the blank control group is continuously gavaged for 14 days by using 0.5 percent sodium carboxymethylcellulose solution. For the two groups (hyperuricase + compound group, hyperuricase + allopurinol group) to be administered, after completing intragastric administration of potassium oxonate for 1h, the administration dose of the compound group was 10 mg/kg. D, and the administration dose of the allopurinol group was 5 mg/kg. D. After the completion of the gavage on day 14, the eyeballs of the mice are picked up, blood samples of the mice are collected from the orbit, after natural coagulation at room temperature, the blood serum is centrifuged at 3000rpm for 15min, and the concentration of uric acid in the blood serum is measured.
The results are shown in fig. 7, compared with the blank control group, the blood uric acid content of the mice in the hyperuricemia model group is obviously increased, which indicates that the hyperuricemia mice are successfully modeled. The compounds 1 and 2 can obviously reduce the content of blood uric acid, and the effect is equivalent to that of a positive drug allopurinol. The other 2 compounds can also significantly reduce the blood uric acid content of mice. The compounds 1-4 have excellent effect of improving hyperuricemia, and have great application potential in the aspects of preparing foods, health care products and medicines for reducing blood uric acid and preventing gout.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various changes, modifications, alterations, and substitutions which may be made by those skilled in the art without departing from the spirit of the present invention shall fall within the protection scope defined by the claims of the present invention.
Claims (10)
1. A diazotroph compound is characterized in that the structural formula of the compound is any one of the following compounds:
2. use of the azone compound of claim 1 in the preparation of a medicament for treating/relieving gout.
3. The use of the azaphilone compound of claim 1 in the preparation of a medicament for reducing uric acid.
4. The use of a azone compound of claim 1 in the manufacture of a medicament for inhibiting xanthine oxidase activity.
5. The application of monascus in preparing the medicine for treating/relieving gout is characterized in that: the monascus has the deposit number of ATCC 96218.
6. The application of the monascus in preparing the medicine for reducing uric acid is characterized in that: the monascus has the deposit number of ATCC 96218.
7. The application of monascus in preparing the medicine for inhibiting the xanthine oxidase activity is characterized in that: the monascus has a deposit number of ATCC 96218.
8. The application of monascus in preparing the medicine for treating/relieving gout is characterized in that: the application utilizes any one or more of the following compounds in the monascus fermentation product,
9. the application of the monascus in preparing the medicine for reducing uric acid is characterized in that: the application utilizes any one or more of the following compounds in the monascus fermentation product,
10. the application of monascus in preparing the medicine for inhibiting the xanthine oxidase activity is characterized in that: the application utilizes any one or more of the following compounds in the monascus fermentation product,
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| CN114478565A (en) * | 2021-12-08 | 2022-05-13 | 安徽农业大学 | Monascus A with glycosidase inhibiting activity and immunoregulation activity and preparation method thereof |
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