Application of compound in preparation of medicine for resisting hyperuricemia

Abstract

The invention discloses application of compounds in preparation of anti-hyperuricemia drugs, and the compounds are proved to be capable of reducing serum UA, Cr and BUN levels of a hyperuricemia mouse model to different degrees, relieving kidney injury and protecting renal functions, so that the compounds can be applied to the drugs for preventing, treating or relieving hyperuricemia, and the application of the compounds in preparation of the anti-hyperuricemia drugs in preparation of the anti-hyperuricemia drugs in preparation of the anti-hyperuricemia drugs in preparation of the anti-hyperuricemia drugs in preparation of the anti-hyperuricemia drugs. The traditional Chinese medicine composition can be used for treating gout and gout complications caused by hyperuricemia.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to use of a compound in preparing a drug for resisting hyperuricemia. Background Art

[0002] Gout is a group of diseases characterized by arthritis. It is caused by urate metabolism disorders and the deposition of monosodium urate crystals in joints and soft tissues. High serum urate concentration is the main risk factor for gout. Clinical manifestations include acute and chronic arthritis, tophi deposits, interstitial nephropathy and uric acid kidney stones. At present, gout drugs are mainly aimed at short-term treatment such as analgesia and anti-inflammatory during acute attacks, inhibition of uric acid production, and promotion of uric acid excretion. The main drugs for the treatment of acute gout attacks are colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone, glucocorticoids, etc.

[0003] Hyperuricemia (HUA) is a chronic metabolic disease characterized by excessively elevated serum uric acid concentration. Uric acid is the final oxidation product of purine catabolism. It is mainly synthesized and catalyzed by xanthine oxidase (XOD), which is widely distributed in the liver and then excreted by the kidneys. UA can induce the formation and deposition of monosodium urate crystals, ultimately leading to gout, so HUA is the main risk factor for gout. Studies have shown that long-term hyperuricemia can cause certain damage to blood vessels, heart, liver, and kidneys, and is closely related to the occurrence and development of metabolic syndromes such as hypertension, hyperlipidemia, obesity, and insulin resistance. Therefore, hyperuricemia has become one of the important diseases threatening human health. With the improvement of people's living standards and changes in eating habits, its prevalence has been rising worldwide. Serum uric acid concentration is an important indicator of human health. When the serum uric acid concentration of men exceeds 416.4μmol / L and the serum uric acid concentration of women exceeds 356.9μmol / L in the fasting state, it is defined as HUA.

[0004] The pathogenesis of HUA is excessive uric acid production and / or reduced renal and intestinal excretion, which ultimately leads to a long-term high level of serum uric acid concentration. Uric acid homeostasis in the human body is a complex and highly inherited process, which includes the biosynthesis of metabolic urate, the renal reabsorption of urate, and the excretion of urate by the kidneys and outside the kidneys. The main reasons for the high uric acid level in human blood are: (1) excessive exogenous ingestion of purine. A high-purine diet leads to an increase in the amount of uric acid produced by metabolism, which cannot be excreted from the body in time, causing hyperuricemia; (2) endogenous metabolic disorders, abnormalities in related enzymes involved in purine metabolism, resulting in accelerated nucleic acid decomposition and excessive uric acid produced by metabolism. Many studies have shown that xanthine oxidase (XOD) is the rate-limiting enzyme that catalyzes the production of UA. It is mainly synthesized in the liver and catalyzes hypoxanthine and xanthine to ultimately produce UA. Therefore, it is also one of the important indicators in anti-hyperuricemia research; (3) Reduced uric acid excretion. The kidney plays a key role in maintaining the circulating UA concentration, because more than 70% of UA excretion in the body is completed by the kidney. Renal excretion of UA is completed by two types of UA transporters: UA reabsorption transporters and UA excretion transporters. Among them, the renal reabsorption of uric acid is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9). ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) mediate uric acid secretion into the tubular lumen and are the transporters responsible for uric acid excretion. Therefore, promoting uric acid excretion by regulating these urate transporters remains an attractive therapeutic target for hyperuricemia.

[0005] At present, drugs for treating hyperuricemia are mainly divided into three categories: drugs that reduce uric acid production, drugs that promote uric acid excretion, and drugs that can convert uric acid into easier excretion and highly water-soluble drugs. The most commonly used drugs are XOD inhibitors, such as allopurinol and febuxostat, but the use of allopurinol will cause serious side effects and cause certain damage to the kidneys. Febuxostat has stronger efficacy and fewer side effects, but it is more expensive and is still an alternative to allopurinol. In clinical practice, probenecid and benzbromarone are mainly used to inhibit the reabsorption of uric acid by the renal tubules, increase the excretion of urate, and thus reduce the blood uric acid content in patients, but they will have a series of side effects on the patient's kidneys. With the continuous advancement of science and technology, researchers have developed new uric acid-lowering drugs that inject uricase into the patient's body to decompose uric acid and produce allantoin, which is metabolized and excreted by the kidneys, but they are limited by immune problems, which makes their use time very short.

[0006] Although there are many therapeutic drugs and programs for the treatment of hyperuricemia, they will cause certain damage to the body and have many side effects. Therefore, it is very necessary to find highly effective and safe drugs. Summary of the invention

[0007] In order to solve the above problems, the present invention proposes the use of 10 compounds in the preparation of anti-hyperuricemia drugs.

[0008] In order to achieve the above object, the present invention proposes the use of a compound in the preparation of an anti-hyperuricemia drug, the compound is named 7-epiaustdiol, and the structural formula is: Or the compound name is kipukasins D, and the structural formula is: Or the compound name is (7S,8S,9R)-7,8dihydroxy-9-propyl-5-nonen-9-olide, and the structural formula is: Or the compound name is phomopsissolide A, and the structural formula is: Or the compound name is chaetoviridine A, and the structural formula is: Or the compound name is Sterigmatocystin, and the structural formula is: Or the compound name is obeticholic acid, and the structural formula is: Or the compound name is Tropifexor, and the structural formula is: Or the compound name is pyrroloquinoline quinone, and the structural formula is: Or the compound name is S-adenosylmethionine, and the structural formula is:

[0009]

[0010] According to the above 10 compounds of the present invention, it has been verified that the 10 compounds can reduce the serum UA, Cr, and BUN levels of the hyperuricemia mouse model to varying degrees, alleviate kidney damage, and have a protective effect on renal function.

[0011] The present invention also proposes the use of the compound in the preparation of a drug for preventing, treating or alleviating hyperuricemia. The compound is named 7-epiaustdiol and has the structural formula: Or the compound name is kipukasinsD, and the structural formula is: Or the compound name is (7S,8S,9R)-7,8dihydroxy-9-propyl-5-nonen-9-olide, and the structural formula is: Or the compound name is phomopsissolide A, and the structural formula is: Or the compound name is chaetoviridine A, and the structural formula is: Or the compound name is Sterigmatocystin, and the structural formula is: Or the compound name is obeticholic acid, and the structural formula is: Or the compound name is Tropifexor, and the structural formula is: Or the compound name is pyrroloquinoline quinone, and the structural formula is: Or the compound name is S-adenosylmethionine, and the structural formula is:

[0012]

[0013] According to the above 10 compounds of the present invention, it has been verified that the 10 compounds can reduce the serum UA, Cr, and BUN levels of hyperuricemia mouse models to varying degrees, and thus can be used as drugs for preventing, treating or alleviating hyperuricemia.

[0014] Optionally, the hyperuricemia includes gout and gout complications caused by hyperuricemia.

[0015] Furthermore, the gout complications include tophi, gouty arthritis, chronic kidney disease, and interstitial nephritis.

[0016] Optionally, the drug further comprises a pharmaceutically acceptable carrier.

[0017] Optionally, the drug is added with conventional excipients and prepared according to conventional processes into clinically acceptable tablets, capsules, oral liquids, powders, pills, granules or injections.

[0018] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a flow chart of the preparation of the compound Sterigmatocystin according to Example 1 of the present invention;

[0020] Figure 2 is the compound Sterigmatocystin according to Example 1 of the present invention 1 H NMR spectrum;

[0021] Figure 3 is the compound Sterigmatocystin according to Example 1 of the present invention 13 C-NMR spectrum;

[0022] Figure 4 Effects of compounds 1-9 according to the examples of the present invention on serum UA (A), CRE (B) and BUN (C) levels in HUA mice, and effects of compound 10 on serum UA (D), CRE (E) and BUN (F) levels in HUA mice;

[0023] Figure 5 Effects of compounds 1-10 according to examples of the present invention on renal index (A, B) and renal appearance (C) of HUA mice;

[0024] Figure 6 The effects of compounds 1-10 according to the examples of the present invention on the pathological changes of renal tissues in HUA mice. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is described below through specific examples. It should be understood that the one or more method steps mentioned in the present invention do not exclude the existence of other method steps before and after the combination step or the insertion of other method steps between these explicitly mentioned steps; it should also be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention. Moreover, unless otherwise specified, the numbering of each method step is only a convenient tool for identifying each method step, and is not intended to limit the order of arrangement of each method step or to limit the scope of the present invention. The change or adjustment of the relative relationship thereof shall also be regarded as the scope of the present invention without substantially changing the technical content.

[0026] In order to better understand the above technical scheme, the exemplary embodiments of the present invention are described in more detail below. Although exemplary embodiments of the present invention are shown, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided in order to enable a more thorough understanding of the present invention and to enable the scope of the present invention to be fully communicated to those skilled in the art.

[0027] The test materials used in the present invention are all common commercial products and can be purchased in the market.

[0028] Compound 1 name: 7-epiaustdiol, CAS: 1227500-86-8. The chemical structure of this compound is as follows:

[0029] Among them, compound 1 has been published in the CNKI database "Wang Xiaoyao; Research on the structure and biological activity of secondary metabolites of marine fungus Acremoniumcitrinum and symbiotic fungus Scytalidium cuboideum [D]; Xiamen University; 2020".

[0030] The name of compound 2: kipukasins D, CAS: 948574-00-3. The chemical structure of this compound is as follows:

[0031] Among them, compound 2 has been published in the CNKI database "Liao Zujian; Research on active ingredients that specifically activate ERα in two endophytic fungi of golden thread vine Annulohypoxylon cf.stygium (ARTCL-05) and Diaporthe sp. (ARL-09) [D]; Xiamen University; 2017".

[0032] The name of compound 3: (7S,8S,9R)-7,8dihydroxy-9-propyl-5-nonen-9-olide, CAS: 297174-24-4. The chemical structure of this compound is as follows:

[0033] Among them, compound 3 has been published in the CNKI database "Zhang Xinmin: Research on secondary metabolites of two fungi with HIV latent activation activity [D]; Xiamen University; 2022".

[0034] Compound 4 name: phomopsissolide A. The chemical structure of this compound is as follows:

[0035] Among them, compound 4 has been published in the CNKI database "Zhang Xinmin: Research on secondary metabolites of two fungi with HIV latent activation activity [D]; Xiamen University; 2022".

[0036] Compound 5 name: chaetoviridine A, CAS: 297174-24-4. The chemical structure of this compound is as follows:

[0037] Among them, compound 5 has been published in the CNKI database "Liao Zujian; Research on active ingredients that specifically activate ERα in two endophytic fungi of golden thread vine Annulohypoxylon cf.stygium (ARTCL-05) and Diaporthe sp. (ARL-09) [D]; Xiamen University; 2017".

[0038] Compound 6 name: Sterigmatocystin, CAS: 10048-13-2. The chemical structure of this compound is as follows:

[0039]

[0040] Compound 7 name: obeticholic acid, CAS: 459789-99-2, purchased from Shanghai Myrel Biochemical Technology Co., Ltd. The chemical structure of this compound is as follows:

[0041]

[0042] Compound 8 name: Tropifexor, CAS: 1383816-29-2, purchased from Shanghai Xinbo Chemical Technology Co., Ltd. The chemical structure of this compound is as follows:

[0043]

[0044] Compound 9 name: pyrroloquinoline quinone, vitamin PQQ, pyrroloquinoline quinone PQQ, pyrroloquinoline quinone acid (PQQ), CAS: 72909-34-3, purchased from Fuzhou Kangtai Biotechnology Co., Ltd. The chemical structure of this compound is as follows:

[0045]

[0046] The name of compound 10: S-adenosylmethionine, CAS: 17176-17-93, purchased from Xiamen Sencos Technology Co., Ltd. The chemical structure of this compound is as follows:

[0047]

[0048] The abbreviations in the present invention are as follows: hyperuricemia HUA; xanthine oxidase XOD; uric acid UA; serum uric acid SUA; hypoxanthine HX; oxonate potassium PO; allopurinol AP; carboxymethylcellulose sodium CMC-Na; creatinine CRE; urine nitrogen BUN.

[0049] The present invention is described below with reference to specific embodiments. It should be noted that these embodiments are merely illustrative and do not limit the present invention in any way.

[0050] Example 1 Preparation of Compound 6 (Compound Sterigmatocystin)

[0051] like Figure 1 As shown, the fermentation product of the seawater filter fungus Pallidocercospora crystallina (derived from the South China Sea seawater) (strain SF21) was extracted by soaking with ethyl acetate-methanol mixed solvent (4:1, v / v), and then separated by octadecylsilane (ODS) column chromatography and reversed-phase high-performance liquid chromatography (HPLC) in sequence. According to the MTT activity results, fractions 7, 8, 9, 10, 11, and 12 were selected for separation and purification by high-performance liquid chromatography and other methods. According to high-performance liquid phase analysis, SF21 active sub-fractions 7-12 have the same product, so these six sub-fractions were combined and separated to obtain one of them as the compound Sterigmatocystin. Its chemical structure was then elucidated by spectral data.

[0052] The compound Sterigmatocystin is light yellow needle-shaped. The 1H-NMR (600 MHz) and 13C-NMR (150 MHz) data of the compound Sterigmatocystin in DMSO solvent are shown in Table 1. Figure 2 and Figure 3 shown.

[0053] Table 1 1H-NMR (600 MHz) and 13C-NMR (150 MHz) data of compound Sterigmatocystin in DMSO solvent

[0054]

[0055] By comparing with the literature, it was found that its NMR data was consistent with that of Sterigmatocystin, so it was identified as Sterigmatocystin.

[0056]

[0057] Example 2 Anti-hyperuricemia and renal protective effects of the compound

[0058] (1) Mouse modeling and grouping: After one week of adaptive feeding, 4-week-old male ICR mice were randomly divided into 13 groups, each with 3 mice, according to the principle of balance and consistency, including normal control group (Con), model group (HUA), allopurinol group (AP, 5 mg / kg, as a positive control drug) and experimental group. The hyperuricemia mouse model was established based on previous studies using potassium oxonate (PO) and hypoxanthine (HX) combined administration. In short, except for the Con group, the mice in the other groups were intraperitoneally injected with 300 mg / kg PO and gavaged with 500 mg / kg HX for 15 consecutive days in order to establish a hyperuricemia model. The Con group was intraperitoneally administered with the same volume of normal saline (0.9%) and gavaged with 0.5% sodium carboxymethylcellulose (CMC-Na) as the hyperuricemia group.

[0059] (2) Drug administration: AP and each drug group were gavaged with the corresponding drug one hour after PO / HX treatment for 15 consecutive days. The daily gavage dose of compounds AP, 3, 4, 6, 7, 8, and 10 was 5 mg kg -1 (Dissolved in 0.5% CMCNa solution to prepare 5 mg mL -1 The daily oral dose of compounds 1, 2, and 5 was 10 mg kg -1 (Dissolved in 0.5% CMCNa solution to prepare 10 mg mL -1 The daily oral dose of compound 9 was 30 mg kg -1 (Dissolved in 0.5% CMCNa solution to prepare 10 mg mL -1 The Con group and the HUA group were given the same amount of 0.5% CMCNa solution in the same time period.

[0060] (3) Sample collection: On the 15th day of intragastric administration, mice were fasted 12 hours before being killed and weighed. Blood samples were collected from all mice by eyeball bleeding 1 hour after the last administration, and the samples were allowed to stand at room temperature for 1 hour. Serum was obtained by centrifugation at 4°C, 3500 r / min for 10 minutes using a low-temperature centrifuge to obtain serum and stored in a -80°C refrigerator. The levels of uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) in serum were measured using a kit. The mice were dissected, and liver and kidney tissues were obtained. The appearance of the liver and kidneys was observed, photographed, recorded, and weighed. The mice were cleaned with phosphate buffer. A portion of the liver and one kidney tissue of the mice were placed on ice and stored at -80°C until they were used in the subsequent liver xanthine oxidase (XOD) activity assay and Western blot detection experiments; the other kidney was fixed in 4% paraformaldehyde solution for histopathological experiments.

[0061] (4) Detection index: SUA was measured to examine the uric acid-lowering efficacy of compounds 1-10. Serum creatinine (CRE) and urea nitrogen (BUN) were measured to evaluate their effects on renal filtration function, body weight and kidney weight were recorded, and kidney index (kidney index = kidney weight g / mouse weight g) was calculated to estimate its general toxicity in hyperuricemia mice, and H&E staining of mouse kidney sections was performed to evaluate the effects on renal tissue pathological changes.

[0062] Mouse serum test results Figure 4 As shown, compounds 1-10 can reduce the UA level in the serum of HUA mice to varying degrees. The serum CRE and BUN levels indicate that the HUA model can increase the renal damage of mice and the positive drug AP has a greater damage to the renal function of mice, while compounds 2, 3, 4, 7, 8, 9, and 10 have a certain protective effect on renal function.

[0063] Mouse renal index and renal tissue Figure 5 As shown in Figure 2, the renal index of mice in the HUA group was slightly higher than that in the Con group. However, after treatment with compound 9 and compound 10, the increase in the renal index of mice was reversed. Figure 5 As shown in (C), the kidneys of mice in the Con group appeared dark red. Compared with the Con group, the renal tissues of the HUA group were pale and deformed, and the deformities were more severe after treatment with the positive drug AP. Treatment with compounds 1-10 improved renal damage to varying degrees.

[0064] Effects of compounds on pathological changes in mouse kidney tissue Figure 6 As shown in the figure, after HE staining, it can be observed that the glomeruli in the normal control group are normal in morphology, obvious edema and dilation appear in the renal tubular cavity, the glomerular capillary structure is clear, and no inflammatory cell infiltration is observed in the renal interstitium. Compared with the normal control group, the renal glomeruli of the mice in the model group were significantly damaged, the glomeruli were atrophied, the renal tubules were dilated, the epithelial cells were shed, the internal brush-like edge structure disappeared, there was slight edema, and there was slight inflammatory cell infiltration in the renal interstitium. The positive drug allopurinol further enhanced the damage to the renal tissue, and the dilation of the renal tubules and the swelling of the epithelial cells were more obvious. After treatment with compounds 2, 6, 8, 9, and 10, the pathological lesions of the renal tissue were significantly reduced, showing a morphology similar to that of the normal control, and compounds 1, 3, 4, 5, and 7 slightly reduced the histological damage to the kidney.

[0065] In summary, compounds 1-10 can reduce the serum UA, Cr, and BUN levels of the hyperuricemia mouse model to varying degrees, alleviate kidney damage, and have a protective effect on renal function.

[0066] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms should not be understood as necessarily referring to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification.

[0067] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. Use of a compound in the preparation of a drug for treating hyperuricemia, characterized in that: The compound name is 7-epiaustdiol and the structural formula is: Or the compound name is kipukasins D, and the structural formula is: Or the compound name is (7S,8S,9R)-7,8dihydroxy-9-propyl-5-nonen-9-olide, and the structural formula is: Or the compound name is phomopsissolide A, and the structural formula is: Or the compound name is chaetoviridine A, and the structural formula is: Or the compound name is Sterigmatocystin, and the structural formula is: Or the compound name is obeticholic acid, and the structural formula is: Or the compound name is Tropifexor, and the structural formula is: Or the compound name is pyrroloquinoline quinone, and the structural formula is: Or the compound name is S-adenosylmethionine, and the structural formula is:

2. Use of a compound in the preparation of a drug for preventing, treating or alleviating hyperuricemia, characterized in that: The compound name is 7-epiaustdiol and the structural formula is: Or the compound name is kipukasins D, and the structural formula is: Or the compound name is (7S,8S,9R)-7,8dihydroxy-9-propyl-5-nonen-9-olide, and the structural formula is: Or the compound name is phomopsissolide A, and the structural formula is: Or the compound name is chaetoviridine A, and the structural formula is: Or the compound name is Sterigmatocystin, and the structural formula is: Or the compound name is obeticholic acid, and the structural formula is: Or the compound name is Tropifexor, and the structural formula is: Or the compound name is pyrroloquinoline quinone, and the structural formula is: Or the compound name is S-adenosylmethionine, and the structural formula is:

3. The use according to claim 2, characterized in that The hyperuricemia includes gout and gout complications caused by hyperuricemia.

4. The use according to claim 3, characterized in that The gout complications include tophi, gouty arthritis, chronic kidney disease, and interstitial nephritis.

5. The use according to claim 2, characterized in that The medicament further includes a pharmaceutically acceptable carrier.

6. The use according to claim 2, characterized in that The drug is added with conventional excipients and prepared into clinically acceptable tablets, capsules, oral liquids, powders, pills, granules or injections according to conventional processes.

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