CN111592537A - Sinomenium majus indole alkaloid for reducing hyperuricemia and application thereof - Google Patents
Sinomenium majus indole alkaloid for reducing hyperuricemia and application thereof Download PDFInfo
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Abstract
The invention relates to a sinomenium indole alkaloid applied to reducing hyperuricemia and application thereof, and provides indole alkaloid compounds extracted from a sinomenium medicinal material. The indole alkaloid for treating and preventing hyperuricemia obtained by the invention is derived from widely distributed Chinese herbal medicine centering vines, and plant resources are cheap and easily available; the structure of the compound is determined, and the action mechanism is clear; the preparation process is simple and easy to realize industrial large-scale production.
Description
Technical Field
The invention relates to indole alkaloid compounds extracted from Yao medicine Ardisia pipiens and a new application of the indole alkaloid compounds in preparation of a medicine for treating hyperuricemia. In particular to a Chinese medicinal preparation of orientvine Stem extract for reducing hyperuricemia and application thereof.
Technical Field
Hyperuricemia (HUA) is a metabolic disease caused by increased uric acid synthesis and/or decreased uric acid excretion, and often involves the formation of chronic interstitial nephritis, uric acid renal calculus and gouty nephropathy caused by the kidney. 90% of hyperuricemia is caused by impaired renal excretion, chronic kidney diseases are often accompanied by hyperuricemia in the development process, and the chronic kidney diseases can further damage the kidney, so that acute uric acid nephropathy, chronic uric acid nephropathy, uric acid renal calculus and other diseases are caused. At present, the medicines for treating hyperuricemia nephropathy are mainly western medicines, mainly include xanthine oxidase inhibitors, such as: allopurinol, febuxostat, and the like; or drugs that promote uric acid excretion, such as: probenecid, benzbromarone, and the like. However, the above drugs have serious side effects such as: renal toxicity, anaphylaxis, cardiovascular toxicity, hepatorenal toxicity, etc., which have caused serious limitations on the clinical use of these drugs. In recent years, the traditional Chinese medicine has low toxic and side effects, definite curative effect and strong superiority, so that the traditional Chinese medicine is widely regarded for treating the uric acid nephropathy. The present invention selects potassium oxonate as a chemical inducer to cause mice to generate polar hyperuricemia and also can damage renal function to increase urea nitrogen in blood. The method is simple and has good reproducibility.
The pathogenesis of hyperuricemia is currently considered to be related to purine metabolic disorders and/or uric acid excretion disorders. The invention discusses the action mechanism of reducing uric acid by detecting the contents of serum Uric Acid (UA) and urea nitrogen (BUN), liver Xanthine Oxidase (XOD) value, Adenosine Deaminase (ADA) activity and the expression of mRNA of kidney transporters mURAT1, mOAT1 and mGLUT 9.
Grapevine (Mappianthus iodoides hand-Mazz.) is the root and stem of the plants of the genus Callicarpa (Mappianthus hand-Mazz.), also known as: sweet fruit vine (Guangdong Hainan), wheat skimming vine, copperleaf, red vine, common Siberian beefsteak (Guangxi) and yellow horse placenta (Guangdong), which are produced in Fujian, Hunan, Guangdong, Hainan, Guangxi, Guizhou, Yunnan and the like in China, and are grown in thinning forest, bush and valley forest with elevation of 800 plus 1800 m. The drupes are oval, yellowish, hard and hairy, orange yellow or orange red at maturity, and thin and sweet pulp. Rhizoma gastrodiae or old rattan medicine, which is one of Yao medicine 'eighteen diamond', has the effects of promoting blood circulation to regulate menstruation, dispelling wind and removing dampness, and is mainly used for treating traumatic injury, jaundice, arthralgia and the like. To date, scholars have studied the chemistry of the grapevine plants and selected the producing areas of the plants mainly including Guangxi nanning, Jinxiu, Daming mountain, Cool town, Yunnan province, and the separated chemical components mainly include: monoterpene indole alkaloids, lignans, phenols, polysaccharides, sesquiterpene alcohols, and others, wherein some alkaloids have certain cytotoxicity and dihydrobenzofuran lignans have antiinflammatory activity. So far, reports that the indole alkaloid contained in the compound has the effect of reducing hyperuricemia are not found.
Disclosure of Invention
Aiming at the discovery, the invention provides an indole alkaloid compound for treating hyperuricemia, which is extracted from a medicinal material of sinomenium chinense Miller.
The structural mother nucleus of the indole alkaloid compound is shown as a structural formula (I):
the structural formula of the indole alkaloid compound is as follows:
the structural formula of the indole alkaloid compound is as follows:
the structural formula of the indole alkaloid compound is as follows:
a preparation method of a Chinese medicinal preparation for reducing hyperuricemia comprises the following steps:
1) pulverizing dried root and rattan of caulis et folium piperis, extracting with 95% ethanol under heating and refluxing, filtering, mixing filtrates, and concentrating under reduced pressure to obtain extract;
2) suspending the extract with appropriate amount of water, and extracting with chloroform to obtain water layer and chloroform layer;
3) evaporating the water layer to obtain extract, dissolving in methanol, passing through MCI column, and gradient eluting with mixed solution of ethanol and water to obtain fraction;
4) subjecting each fraction to reverse phase silica gel column chromatography, eluting with mixed solution of acetonitrile and water to obtain second fraction;
5) removing pigment from the second fraction with mixed solution of chloroform and methanol via Sephadex LH-20 to obtain alkaloid mixture;
6) purifying the alkaloid mixture by semi-preparative liquid chromatography to obtain monomer compounds 1, 2 and 3.
7) The monomer compounds 1 to 3 are comprehensively analyzed by using spectral data such as MS, 1HNMR, 13C NMR and the like and literature data, and the structures are identified as follows: compound 1(3 α -5 α -tetrahydrodeoxycodifoline lactam), compound 2(5(S) -5-carboxystrobidine), compound 3 (stricotisic acid).
The beneficial technical effects of the invention are as follows: the indole alkaloid for treating and preventing hyperuricemia obtained by the invention is derived from widely distributed Chinese herbal medicine centering vines, and plant resources are cheap and easily available; the structure of the compound is determined, and the action mechanism is clear; the preparation process is simple and easy to realize industrial large-scale production.
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FIG. 1 Effect of Compound 1 on mRNA expression in the kidney mURAT1, mGLUT9, mOAT1 of model mice ((
N ═ 10) note: # p < 0.01 compared to blank; compared to model groups, p < 0.001, p < 0.01, p < 0.05. KB was blank group, MX was hyperuricemia mouse model group, BPLC was allopurinol group, DL was compound 1 low dose group, DH was compound 1 high dose group.
Detailed Description
Example extraction separation and Structure identification of indole alkaloids in Corynomene Stem
1.1 isolation of the Compound
5kg of dried root and rattan of the oriental stephania, crushing, heating and refluxing with 80% ethanol for 3 times, 1 hour each time, filtering, combining filtrates, and concentrating under reduced pressure to obtain an extract. Suspending the extract with appropriate amount of water, and extracting with chloroform to obtain water layer and chloroform layer. Steaming the water layer to obtain extract.
Dissolving the extract of the grapevine with a proper amount of methanol, passing through an MCI column, and purifying with ethanol: water gradient elution (0:100, 20:80, 40:60, 60:80, 80:20, 90:10) gave fractions Fr.A (37.5g), Fr.B (45.0g), Fr.C (26.2g), Fr.D (11.1g), Fr.E (19.0g), Fr.F (7.3g), acetone wash column. The fractions were further subjected to reverse phase silica gel column chromatography and eluted with acetonitrile-water. Eluting Fr.A with acetonitrile-water (0:100, 5:95, 10:90) gradient to obtain Fr.A1(80.0g), Fr.A2(8.1g), Fr.A3(6.0g) Fr.A4(0.2g), and removing pigment with chloroform-methanol (1:1) via Sephadex LH-20 respectively. And Fr.A2 is purified by semi-preparative liquid chromatography, and acetonitrile-water (5:95) is eluted isocratically to obtain the compound 1. Fr.C was eluted with an acetonitrile-water (10:90, 15:85, 20:80, 25:75, 30:70) gradient to give Fr.C1(14.1g), Fr.C2(5.7g), Fr.C3(3.0g), Fr.C4(1.9g), Fr.C5(0.1714g), and the pigments were removed with chloroform methanol (1:1) via Sephadex LH-20, respectively. And Fr.C3 is purified by semi-preparative liquid chromatography, and acetonitrile-water (15: 85) is eluted at equal degrees to obtain a compound 2 and a compound 3.
1.2 structural characterization of Compounds
By applying MS,1H NMR、13C NMR、HSQC、1H-1Comprehensively analyzing and separating spectral data such as H COSY, HMBC, NOESY, HR-ESI-MS and the like to obtain 3 compounds, and identifying the structures of the compounds. The results were:
compound 1: white powder, soluble in DMSO, formula C27H30N2O 10; 1H-NMR (600MHz, DMSO-d 6). 5.04(1H, br s, H-3),5.35 to 5.32(1H, m, H-5),3.67(1H, d, J ═ 11.8Hz, H-6),2.62 to 2.58(1H, m, H-6),7.42(1H, d, J ═ 7.8Hz, H-9),6.99(1H, t, J ═ 7.5Hz, H-10),7.10 to 7.06(1H, m, H-11),7.35(1H, d, J ═ 8.1Hz, H-12),2.48(1H, dd, J ═ 5.6,3.6Hz, H-14),2.02(1H, ddd, J ═ 13.7,11.9,5.0, H-14), 3.3.3, H-3, H-19, 1H, ddd, J ═ 13.7,11.9,5.0, H-14), 1H-3.05H-15, 1H-19, 17H, 17, 1H-6, 1H-17, J ═ 1H, H-9, 1H-9, J ═ 9, H-9, 1H-9, J ═ 10, 5.61(1H, dt, J ═ 17.1,9.9Hz, H-19),2.69 to 2.63(1H, m, H-20),5.40(1H, d, J ═ 1.9Hz, H-21),4.45(1H, d, J ═ 7.9Hz, H-1'),3.15 to 2.77(C-H-2',3',4',5 '); 13C-NMR (150MHz, DMSO-d6):134.8(C-2),54.4(C-3),58.2(C-5),22.0(C-6),108.5(C-7),126.9(C-8),117.9(C-9),119.0(C-10),121.3(C-11),111.5(C-12),136.1(C-13),26.1(C-14),23.6(C-15),107.4(C-16),147.2(C-17),120.3(C-18),133.2(C-19),42.9(C-20),96.2(C-21),165.6(C-22),171.0(C-23),99.3(C-1 '), 72.8 (C-2'), 77.2(C-3 '), 69.9 (C-4'), 76.8(C-5 '), 61.0 (C-6'). The structure of the compound is consistent with that of the known compound 3 alpha-5 alpha-tetrahydrodeoxycydifoline lactam through the examined literature; the structural formula is as follows:
compound 2: white powder, soluble in methanol, C27H32N2O 11; 1H-NMR (600MHz, Methanol-d 4). 4.61(1H, d, J-11.6 Hz, H-3),3.92(1H, dd, J-12.1, 5.0Hz, H-5),3.03(1H, ddd, J-16.2, 12.2,2.5Hz, H-6), 3.44-3.39 (1H, m, H-6),7.30(1H, dd, J-8.2, 1.0Hz, H-9),7.11(1H, ddd, J-8.2, 7.0,1.1Hz, H-10),7.03(1H, ddd, J-8.0, 7.0,1.0Hz, H-11),7.45(1H, dd, J-8.0, 1.0, H-12, 1H-43, 1.0Hz, 1.0 dt-11), 7.45(1H, ddd, J-8.0, 1.0, H-12, 7.43H-12H, 1.7.7.7H, 14H-5H, 14H-5, 14H-7.7.7.7, 14H-7.7.7H, 1H-7.7.7, 1H-7.7, 1H, 1H-7.7, 1, 1.7.7.7.7, 1H-7, 1H, 1, 1.4Hz, H-18),5.25(1H, dt, J ═ 10.6,1.3Hz, H-18),5.88 to 5.80(1H, m, H-19),2.78 to 2.73(1H, m, H-20),5.91(1H, d, J ═ 9.2Hz, H-21),3.79(3H, s, H-COOCH3),4.82(1H, d, J ═ 7.9Hz, H-1'),4.01(1H, dd, J ═ 11.8,2.1Hz, H-6'),3.67(1H, dd, J ═ 11.8,7.0Hz, H-6 '); 13C-NMR (150MHz, Methanol-d 4). 130.4(C-2),52.9(C-3),59.5(C-5),24.0(C-6),108.3(C-7),127.5(C-8),119.2(C-9),120.6(C-10),123.4(C-11),112.2(C-12),138.5(C-13),34.6(C-14),32.6(C-15),108.6(C-16),157.2(C-17),119.8(C-18),135.2(C-19),45.3(C-20),97.4(C-21),171.8(C-COOCH3),53.1(C-COOCH3),173.5(C-COOH),100.4(C-1'),74.6(C-2'),78.0(C-3'),71.8(C-4'),78.8 (C-4'), 63.5 (C-6'). The compound is determined to be 5(S) -5-carboxystrobin by examining the structure of the compound and the structure of the known compound 5(S) -5-carboxystrobin. The structural formula is as follows:
compound 3: white powder, soluble in methanol, C27H32N2O11；1H-NMR(600MHz,Methanol-d4)。0:4.45(1H,d,J＝11.9Hz,H-3),7.47(1H,d,J＝8.0Hz,H-9),7.05(1H,ddd,J＝8.0,7.1,1.0Hz,H-10),7.16～7.12(1H,m,H-11),7.33(1H,d,J＝8.2Hz,H-12),2.17～2.10(1H,m,H-14),2.41～2.34(1H,m,H-14),3.01～2.98(1H,m,H-15),7.58(1H,s,H-17),5.33(1H,d,J＝17.3Hz,H-18),5.22(1H,d,J＝10.7Hz,H-18),5.88(1H,ddd,J＝17.6,10.5,7.4Hz,H-19),2.77～2.66(1H,m,H-20),5.84(1H,d,J＝9.4Hz,H-21),4.84(1H,d,J＝7.9Hz,H-1'),3.72～3.22(6H,m,suger proton)；13C-NMR(150MHz,Methanol-d4). 131.8(C-2),52.3(C-3),43.1(C-5),19.8(C-6),107.4(C-7),127.6(C-8),119.0(C-9),120.5(C-10),123.3(C-11),112.2(C-12),138.2(C-13),35.3(C-14),34.1(C-15),113.7(C-16),153.2(C-17),118.9(C-18),136.3(C-19),45.8(C-20),96.6(C-21),174.7(C-22),100.3(C-1),78.7(C-2),78.0(C-3),71.8(C-4),74.7(C-5),63.1 (C-6). The structure of the compound is consistent with that of a known compound stricotisinic acid through a review document, so that the compound is determined to be stricotisinic acid; the structural formula is as follows:
EXAMPLE two Compounds 1-3 assay for uric acid lowering Activity
2.1 Experimental methods
2.1.1 preparation of liquid medicine the highest content compounds 1, 2 and 3(H1, H2 and H3) were prepared by adding water to low dose of 20mg/kg and high dose of 50mg/kg respectively and refrigerating at 4 deg.C.
2.1.2 mice were divided and administered 90 mice after 1 week acclimation, and the mice were randomly divided into 9 groups of 10 mice each by body weight, namely a blank control group, a hyperuricemia model group, a positive drug group (allopurinol 10 mg. kg-1), and a high/low dose group (50 mg. kg-1, 20 mg. kg-1) of Compound 1 (H1). The control group and the model group are given purified water with corresponding volume, and the mice are administrated after 1 times of intragastric administration for 7 days and final 1 time of model building for 0.5h according to 15 mL/kg-1.
2.1.3 hyperuricemia mouse model establishing intraperitoneal injection of 350 mg.kg-1 oteracil potassium salt for 0.5h before the last administration. The blank group (control group) was intraperitoneally injected with a 0.8% CMC-Na solution of the same concentration, and the other groups were administered as described in item 2.2.2. After 0.5h of administration, blood is collected from the retroorbital venous plexus of the mouse, the kidney and the liver of the mouse are quickly separated, and the mouse is placed in an ultra-low temperature refrigerator at minus 80 ℃ for storage. Centrifuging whole blood at 4 deg.C and 5000r min-1 for 10min, collecting upper layer serum, and refrigerating at 4 deg.C.
2.1.4 detection of Uric Acid (UA) and Urea Nitrogen (BUN) levels in serum to be detected serum is taken to perform measurement and calculate the UA and BUN levels of the serum respectively according to the operation of a reagent instruction.
2.1.5 liver XOD measurement after liver tissue weighing, add precooled normal saline to make 10% liver tissue homogenate. Centrifuging at 4 deg.C for 10min at 3500 r.min-1, collecting supernatant, determining XOD and total protein content in tissue homogenate according to kit instruction, and calculating XOD activity.
2.1.6 RT-PCR detection of kidney 3 uric acid transporter mRNA expression 10 kidneys were frozen out of each group, 50mg kidney cortex was excised, and total RNA was extracted by TRIZOL method. After integrity was identified, 2. mu.L of total RNA was taken and cDNA was synthesized according to the reverse transcription kit instructions. The cDNA template was subjected to RT-PCR amplification using primers (see Table1 for details of primer sequence information). Performing 30 cycles of hot start at 94 ℃ for 3min, denaturation for 30s, annealing at 55 ℃ for 30s and extension at 72 ℃ for 1min, and then extending for 5 min. Electrophoresis is carried out in 1.2% agarose gel, the agarose gel is stained by ethidium bromide, the agarose gel is placed in a gel image analyzer for imaging, the absorbance of a band is analyzed, the expression quantity of the gene to be detected and the internal reference GAPDH is calculated, and the relative expression value of the gene of OAT1, URAT1 and GluT9 is obtained.
2.1.7 statistical analysis of data statistical analysis SPSS19.0 software analysis, results are in mean. + -. standard deviation
And (4) showing. The comparison among the groups adopts a single factor methodDifferential analysis, group comparisons using t-test. The statistical significance is that P is less than 0.05.
TABLE1 PCR primer sequence/table 1 PCR primer sequence
2.2 results of the experiment
2.2.1 Effect of Compounds 1-3 on uric acid and Urea Nitrogen in serum of mice with hyperuricemia
As can be seen from Table 2, the uric acid and urea nitrogen levels in the model group were significantly increased (P < 0.01) compared to the blank group. After one week of administration, the positive allopurinol group and the high/low dose group of compounds 1-3 isolated from Aristolochia dioica were able to significantly lower serum uric acid and urea nitrogen levels (P < 0.01) in hyperuricemia mice, compared to the model group.
TABLE 2 Effect of Compounds 1, 2 and 3 on uric acid and Urea Nitrogen in serum of mice with hyperuricemia: (
,n＝10)
Note: in comparison with the blank set, the results,##p is less than 0.01; in comparison with the set of models,**p＜0.05，*p＜0.01。
2.2.2 Effect of Compounds 1-3 on the Activity of XOD and ADA in the liver of mice with hyperuricemia
As can be seen from Table 3, liver XOD and ADA activities were significantly increased in the model group compared to the blank group (P < 0.01). After 1 week of administration, compared with the model group, the liver XOD activity of the mice with hyperuricemia in the allopurinol group, the high/low dose group of the compounds 1-3 is remarkably reduced, the inhibition rate of the liver XOD exceeds that of the positive medicine group, but the inhibition rate is in a descending trend along with the increase of the compound dose.
Table 3 effects of H1 on liver XOD and on liver ADA viability: (
,n＝10)
Note: # p < 0.01 compared to blank; in comparison with the set of models,**p＜0.05，*p＜0.01。
2.2.3 Effect of Compound 1 on the expression of mURAT1, mGLUT9, mOAT1mRNA in model mice
As shown in fig. 1, the expression of mrnas of the model mouse kidney transporter mruat 1 was significantly increased compared to the blank group (a)##p < 0.01), mGLUT9 mRNA expression was significantly elevated (###p < 0.01), OAT1 expression is significantly reduced (p < 0.01). Compared with the model group, the allopurinol group and the compound 1 low-dose group both significantly down-regulate the kidney mURAT1mRNA expression and mGLUT9 mRNA expression of mice with hyperuricemia***p is less than 0.001); the compound 1 high-dose group can obviously reduce the expression of the kidney mURAT1mRNA of the model mouse (**p < 0.01), allopurinol group and compound 1 high/low dose group significantly up-regulated mRNA expression of OAT1 in hyperuricemic mice (p < 0.001).
Claims (7)
1. A kind of indole alkaloid of Paederia sinensis for reducing hyperuricemia, characterized by that: is indole alkaloid compounds extracted from medicinal materials of oriental stephania root.
2. The sinomenine alkaloid for reducing hyperuricemia according to claim 1, wherein: the structural mother nucleus of the indole alkaloid compound is shown as a structural formula (I):
3. the sinomenine alkaloid applied to the hyperuricemia reduction according to the claim 2, characterized in that: the structural formula of the indole alkaloid compound is as follows:
4. the sinomenine alkaloid applied to the hyperuricemia reduction according to the claim 2, characterized in that: the structure of the indole alkaloid compound is shown as the following structural formula:
5. the sinomenine alkaloid applied to the hyperuricemia reduction according to the claim 2, characterized in that: the structural formula of the indole alkaloid compound is as follows:
6. a preparation method of sinomenine alkaloid for reducing hyperuricemia is characterized by comprising the following steps: the method comprises the following steps:
1) pulverizing dried root and rattan of caulis et folium piperis, extracting with 95% ethanol under heating and refluxing, filtering, mixing filtrates, and concentrating under reduced pressure to obtain extract;
2) suspending the extract with appropriate amount of water, and extracting with chloroform to obtain water layer and chloroform layer;
3) evaporating the water layer to obtain extract, dissolving in methanol, passing through MCI column, and gradient eluting with mixed solution of ethanol and water to obtain fraction;
4) subjecting each fraction to reverse phase silica gel column chromatography, eluting with mixed solution of acetonitrile and water to obtain second fraction;
5) removing pigment from the second fraction with mixed solution of chloroform and methanol via Sephadex LH-20 to obtain alkaloid mixture;
6) subjecting the alkaloid mixture to semi-preparative liquid chromatography and preparative liquid chromatography for further purification to obtain compounds 1, 2 and 3;
7) the structure of the monomer compound is analyzed and confirmed to be the compound structural formula.
7. Use of the hypouricemic indole alkaloid of any one of claims 1 to 5 for the preparation of a medicament for the treatment of hyperuricemia.
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| WO2008046155A1 (en) * | 2006-10-20 | 2008-04-24 | Dia-B Tech Limited | Methods for regulating glucose homeostasis and agents therefor |
| CN101792449A (en) * | 2010-04-09 | 2010-08-04 | 浙江大学 | Raubasine derivative, preparation and application thereof |
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| CN111920808A (en) * | 2020-09-03 | 2020-11-13 | 江西中医药大学 | Application of alkaloid component in caulis et folium piperis longi in preparing medicine for treating ischemic heart disease |
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