CN116354831A - Separation and application of compound 1-phenyl-1, 3-propanetriamine with uric acid reducing function in coix seed - Google Patents

Separation and application of compound 1-phenyl-1, 3-propanetriamine with uric acid reducing function in coix seed Download PDF

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CN116354831A
CN116354831A CN202310272591.7A CN202310272591A CN116354831A CN 116354831 A CN116354831 A CN 116354831A CN 202310272591 A CN202310272591 A CN 202310272591A CN 116354831 A CN116354831 A CN 116354831A
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ethanol
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uric acid
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徐德平
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Jiangnan University
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Abstract

The invention discloses separation and application of a compound 1-phenyl-1, 3-propanetriamine with uric acid reducing function in coix seeds, and belongs to the technical field of medicines. Pulverizing coix seeds, placing the pulverized coix seeds into an extraction tank, adding ethanol, stirring and extracting, filtering to obtain filtrate, repeatedly extracting filter residues once according to the method, combining the two filtrates, and concentrating under reduced pressure to obtain coix seed ethanol extract; the coix seed alcohol extract is firstly subjected to preliminary separation by an MCI column, then is subjected to further separation by an ODS column, so that a monomer compound is obtained, and the monomer compound is identified as 1-phenyl-1, 3-propanetriamine by mass spectrum and nuclear magnetic resonance analysis. The obtained compound has remarkable uric acid reducing effect, and can be used for treating hyperuricemia.

Description

Separation and application of compound 1-phenyl-1, 3-propanetriamine with uric acid reducing function in coix seed
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to separation and application of a compound 1-phenyl-1, 3-propanetriamine with uric acid reducing function in coix seeds.
Background
Coix seed (Coix lacrma-jobi l.var. Mayuen (roman.) Stapf) is a dry mature seed of Coix seed of the family Gramineae, and has been used for thousands of years as a pharmaceutical and dietetic material for diuretic treatment of rheumatism, warts and chronic ulcers. Modern pharmacological researches show that coix seed has various biological activity functions of resisting inflammation, easing pain, regulating immunity, reducing serum uric acid and the like. These physiological activities of coix seed extract are attributed to their unique phytochemicals such as polysaccharides, phenolic compounds, flavonoids, phytosterols, etc. However, few studies on the efficacy components of coix seed for uric acid lowering effect are conducted. At present, researches show that the coix seed polyphenol extract can effectively reduce serum uric acid level of hyperuricemia rats, but at present, the separation of coix seed uric acid reducing active ingredients is seldom studied, and the chemical structure identification is seldom performed.
Disclosure of Invention
The invention aims at the current situation, after the coix seeds are crushed, the coix seeds are placed in an extraction tank, ethanol is added, the mixture is stirred for extraction, the filtrate is filtered and taken, the filter residues are repeatedly extracted once according to the method, and the two filtrates are combined. Concentrating under reduced pressure to obtain Coicis semen ethanol extract. The coix seed alcohol extract is firstly subjected to preliminary separation by an MCI column, and then is subjected to further separation by an ODS column to obtain a monomer compound, and the monomer compound is identified as 1-phenyl-1, 3-propanetriamine by mass spectrum and nuclear magnetic resonance analysis, wherein the structural formula is as follows:
Figure SMS_1
an object of the present invention is to provide a compound of the structure represented by formula (1) or a pharmaceutically acceptable salt thereof,
Figure SMS_2
in one embodiment of the invention, the pharmaceutically acceptable salt comprises an inorganic or organic salt; inorganic salts include hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
The invention also provides a preparation method of the compound, which comprises the following steps:
(1) Pulverizing Coicis semen, placing in an extraction tank, adding 30-70% ethanol, stirring at 30-60deg.C, standing, filtering to obtain filtrate, repeatedly extracting the residue in the same process, and mixing the filtrates; concentrating the filtrate to obtain Coicis semen ethanol extract;
(2) Primarily separating the coix seed alcohol extract by an MCI column, sequentially performing water eluent, 30% ethanol eluent, 50% ethanol eluent and 95% ethanol eluent, and collecting 50% ethanol eluent part; separating 50% ethanol eluate by ODS column, gradient eluting with water, 10%,30% and 50% ethanol, and collecting 30% ethanol eluate; and then separating 30% ethanol eluate by ODS column, sequentially performing gradient elution with 20% ethanol and 30% ethanol, and collecting 30% ethanol eluate to obtain the compound with structure shown in formula (1).
The invention also provides a uric acid reducing medicament containing the compound with the structure shown in the formula (1) or pharmaceutically acceptable salts thereof.
The invention also provides application of the compound with the structure shown in the formula (1) or pharmaceutically acceptable salt thereof in preparing a medicament for treating hyperuricemia.
In one embodiment of the present invention, the medicine further comprises pharmaceutical excipients, including: solvents, propellants, solubilizing agents, co-solvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure modifiers, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-binding agents, integration agents, permeation promoters, pH modifiers, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, flocculant and deflocculant, filter aids, and release retarders.
In one embodiment of the invention, the medicament further comprises a pharmaceutically acceptable carrier selected from the group consisting of microcapsules, microspheres, nanoparticles and liposomes.
In one embodiment of the invention, the dosage form of the medicament comprises: injection, freeze-dried powder for injection, suspension, implant, suppository, capsule, tablet, pill and oral liquid.
In one embodiment of the invention, animal experiments show that the optimized composition has remarkable uric acid reducing effect. The inhibition of xanthine oxidase activity shows that the inhibitor has strong inhibition effect on the XOD activity, and the inhibition rate reaches 49.52 percent.
The beneficial effects are that:
the invention utilizes the model of hyperuricemia mice induced by the combination of potassium oxazinate and hypoxanthine, and evaluates the anti-hyperuricemia activity by indexes such as serum uric acid, liver function and the like. The functional components with uric acid reducing effect are obtained from the coix seed alcohol extract by utilizing a plurality of chromatographic methods, thereby providing a new therapeutic approach for reducing uric acid.
Drawings
FIG. 1 shows the coixene obtained in example 1 13 C NMR spectrum.
FIG. 2 shows the coixene obtained in example 1 135 DEPT NMR spectra.
FIG. 3 is a mass spectrum of coixene obtained in example 1.
Detailed Description
The present invention is illustrated in detail by the following examples, but is not meant to be limited thereto, as detailed below.
Example 1
Weighing 10kg of coix seed, crushing, placing into a 100L extraction tank, adding 70% ethanol according to a feed liquid ratio of 1:10 (g: mL), stirring and extracting for 3h at 60 ℃ (stirring for 150 revolutions per minute), standing, filtering to obtain filtrate, repeatedly extracting filter residues once according to the method, and combining the two filtrates. Concentrating under reduced pressure at 60deg.C to obtain Coicis semen ethanol extract. The coix seed alcohol extract is firstly passed through MCI column (10X 150 cm), and eluted by water, and then eluted by four different eluting components of 30% ethanol eluent, 50% ethanol eluent and 95% ethanol eluent, wherein the eluting quantity is 5 liters each time. Separating 50% ethanol eluate with ODS (5×100 cm) column, gradient eluting with water, 10%,30% and 50% ethanol, each eluting with 3 liters, collecting 30% ethanol eluate, separating with ODS column, gradient eluting with 20%, 30% ethanol, and collecting 30% ethanol eluate to obtain monomer compound.
The compound is yellow powder, and is soluble in water and methanol and ethanol. Mass spectrometry analysis of compound 1 showed its excimer ion peak [ M-H ]] - M/z= 164.0395, from which the molecular formula is inferred to be C 9 H 15 N 3 (calculated as 165.2233).
1 H NMR δ7.25 (4H, t, j=8.0 Hz), δ7.19 (1H, d, j=7.0 Hz), δ4.10 (1H, t, j=12.0 Hz), 2.97 (1H, d, j=12.0 Hz), 2.78 (1H, m) and 2.47 (1H, m). 13 C NMRδ138.7，129.5，129.1，128.1，127.9，126.1，71.5，55.6，40.3。
From the slave 1 H NMR spectra showed that the presence of hydrogen signals δ7.25 (4H, t, j=8.0 Hz) and δ7.19 (1H, d, j=7.0 Hz) indicated the presence of a mono-substituted benzene ring. δ4.10 (1 h, t, j=12.0 Hz), 2.97 (1 h, d, j=12.0 Hz), 2.78 (1 h, m) and 2.47 (1 h, m) have four hydrogen signals. At the position of 13 Six aromatic carbon signals δ138.7, 129.5, 129.1, 128.1, 127.9, 126.1, binding can be observed in the C NMR spectrum 135 The DEPT NMR spectrum can determine that δ138.7 is a quaternary carbon signal, which also demonstrates the presence of a monosubstituted benzene ring. Three carbon signals at δ71.5, 55.6 and 40.3 infer from chemical shift values that δ40.3 is the carbon signal on methylene, carbon at δ55.6ppm should be attached to one nitrogen atom, and carbon at δ71.5ppm should be attached to two nitrogen atoms. In summary, compound 1 was identified as 1-phenyl-1, 3-propanetriamine, which has a molecular weight and molecular formula consistent with mass spectrometry information. The compound is a new alkaloid which is separated from natural products for the first time, is named as coix seed alkali and has the following structural formula:
Figure SMS_3
example 2
Biological Activity test of Coix seed base 1-phenyl-1, 3-propanetriamine obtained in example 1:
in vivo test: SPF-grade male ICR mice (body weight 18-22 g) were purchased for 40, fed free diet drinking water under standard environmental conditions (20-26 ℃, 40-70%), adaptively kept for seven days, and randomly divided into 4 groups (n=10): (NC) normal control group, (M) hyperuricemia model group, (P) allopurinol positive control group (10 mg/kg), coix seed alkali group (100 mg/kg). Before the last dose for 1h, the mice of each group were intraperitoneally injected with potassium oxazinate and hypoxanthine except for the normal control group to establish a hyperuricemia model. One hour after the seventh day of administration, a blood sample of the mice was collected and centrifuged at 3500r/min for 15min at 4℃to obtain serum, and uric acid and creatinine levels in the serum were detected by a full-automatic biochemical analyzer. The results are shown in Table 1 below.
TABLE 1 serum uric acid and creatinine levels
Figure SMS_4
The results show that the coix seed alkali group has remarkable uric acid reducing effect.
In vitro test: coix seed base and xanthine oxidase were dissolved in phosphate buffer (0.2 m, ph 7.5). 0.8mL of xanthine oxidase solution (0.1U/mL) was mixed with the same volume of coix seed base (200. Mu.g/mL), then incubated at 37℃for 5 minutes, the absorbance of the mixture was measured at 295nm every 10 seconds with xanthine added, and the measurement was continued for 5 minutes. Zeroing with phosphate buffer, allopurinol (200. Mu.g/mL) was set as a positive control. The inhibition ratio of xanthine oxidase was calculated according to the following equation: inhibition = (R) 0 -R A )/R0×100％；R 0 Is the reaction rate of the negative control group, R A Is the reaction rate of the coix seed alkali group. The specific results are shown in Table 2.
TABLE 2 Effect of Coix seed alkali on XOD Activity
Figure SMS_5
Figure SMS_6
Note that: the XOD control group refers to equivalent xanthine oxidaseDissolving in phosphate buffer solution without adding other drugs. In comparison with the XOD control group, ** P<0.01。
as a result, the coix seed alkali group has obvious effect of inhibiting xanthine oxidase so as to achieve uric acid reducing effect.
The above examples are not intended to limit the scope of the invention nor the order of execution of the steps described. The present invention is obviously modified by a person skilled in the art in combination with the prior common general knowledge, and falls within the scope of protection defined by the claims of the present invention.

Claims (10)

1. A compound of the structure shown in formula (1) or a pharmaceutically acceptable salt thereof,
Figure FDA0004135206240000011
2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises an inorganic salt or an organic salt; inorganic salts include hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
3. A process for the preparation of a compound as claimed in claim 1, comprising the steps of:
(1) Pulverizing Coicis semen, placing in an extraction tank, adding 30-70% ethanol, stirring at 30-60deg.C, standing, filtering to obtain filtrate, repeatedly extracting the residue in the same process, and mixing the filtrates; concentrating the filtrate to obtain Coicis semen ethanol extract;
(2) Primarily separating the coix seed alcohol extract by an MCI column, sequentially performing water eluent, 30% ethanol eluent, 50% ethanol eluent and 95% ethanol eluent, and collecting 50% ethanol eluent part; separating 50% ethanol eluate by ODS column, gradient eluting with water, 10%,30% and 50% ethanol, and collecting 30% ethanol eluate; and then separating 30% ethanol eluate by ODS column, sequentially performing gradient elution with 20% ethanol and 30% ethanol, and collecting 30% ethanol eluate to obtain the compound with structure shown in formula (1).
4. A uric acid lowering drug comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
5. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hyperuricemia.
6. The uric acid lowering drug of claim 4, further comprising a pharmaceutical excipient.
7. The uric acid lowering drug of claim 6, wherein the pharmaceutical excipients comprise: solvents, propellants, solubilizing agents, co-solvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure modifiers, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-binding agents, integration agents, permeation promoters, pH modifiers, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, flocculant and deflocculant, filter aids, and release retarders.
8. The uric acid lowering drug of claim 4, further comprising a pharmaceutically acceptable carrier.
9. The uric acid lowering drug of claim 8, wherein the pharmaceutically acceptable carrier is selected from the group consisting of microcapsules, microspheres, nanoparticles, and liposomes.
10. The uric acid lowering drug of claim 4, wherein the dosage form of the drug comprises: injection, freeze-dried powder for injection, suspension, implant, suppository, capsule, tablet, pill and oral liquid.
CN202310272591.7A 2023-03-20 2023-03-20 Separation and application of compound 1-phenyl-1, 3-propanetriamine with uric acid reducing function in coix seed Pending CN116354831A (en)

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