Acyl phloroglucinol heteroterpenoid compound and application thereof in pharmacy
阅读说明:本技术 酰基间苯三酚杂萜类化合物及其在制药中的用途 (Acyl phloroglucinol heteroterpenoid compound and application thereof in pharmacy ) 是由 侯爱君 李静雅 贾心语 吴咏梅 雷春 虞燕燕 于 2019-04-30 设计创作,主要内容包括:本发明属医药技术领域,具体涉及从金丝梅中分离得到的天然酰基间苯三酚杂萜类化合物及其在制备防治炎症相关代谢性疾病药物中的用途。本发明从金丝梅中分离得到的式(I)和式(II)结构的酰基间苯三酚杂萜类化合物,经试验表明,所述化合物具有显著的NF-κB转录抑制活性,能有效抑制LPS诱导的巨噬细胞炎症反应,可用于制备新的预防或治疗与炎症相关代谢性疾病药物或先导化合物,所述疾病包括肥胖症、胰岛素抵抗、2型糖尿病、高脂血症、非酒精性脂肪肝、动脉粥样硬化或慢性肾病。<Image he="287" wi="700" file="DDA0002046439460000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the technical field of medicines, and particularly relates to a natural acyl phloroglucinol heteroterpenoid compound separated from golden plum and a preparation method thereofThe application of the compound in preparing medicaments for preventing and treating inflammatory-related metabolic diseases. Experiments show that the acyl phloroglucinol heteroterpenoid compounds with the structures shown in the formula (I) and the formula (II) separated from the hypericum japonicum have remarkable NF-kB transcription inhibiting activity, can effectively inhibit macrophage inflammatory reaction induced by LPS, and can be used for preparing novel medicines or lead compounds for preventing or treating metabolic diseases related to inflammation, wherein the diseases comprise obesity, insulin resistance, type 2 diabetes, hyperlipidemia, non-alcoholic fatty liver, atherosclerosis or chronic nephropathy.)
1. The structure of the acyl phloroglucinol heteroterpenoid compound is shown as a formula (I) and a formula (II),
wherein the content of the first and second substances,
the compound of formula (I) is (2S,4aR,6aR,7R,8S,9aS,10R,11S) -11-benzoyl-2, 6 a-dihydroxy-3, 3, 7-trimethyl-8, 10-bis (3-methyl)-2-butenyl) hexahydro-1H, 6H-7,4 a-ethanocyclopenta [3,4]Furo [2,3-b ] s]Pyran-6-one; the molecular formula is C32H42O6(ii) a The molecular weight is 522;
the compound of formula (II) is (2R,3aR,5aR,6R,7S,8aS,9R,10S) -2- (2-aminopropyl) -10-benzoyl-5 a-hydroxy-6-methyl-7, 9-bis (3-methyl-2-butenyl) hexahydro-5H-6, 3 a-ethanocyclopenta [ c]Furo [2,3-b ] s]Furan-5-one; the molecular formula is C32H43NO5(ii) a The molecular weight is 521;
the acyl phloroglucinol triterpenoid is prepared by the following method:
Pulverizing dried branches and leaves of Hypericum patulum Thunb, extracting with organic solvent or/and water to obtain total extract, extracting with alkane organic solvent, recovering solvent, and drying to obtain alkane extract;
performing silica gel column chromatography on the obtained alkane extract, performing gradient elution by using a petroleum ether-acetone system, and performing ODS reverse phase silica gel column chromatography, Sephadex LH-20 gel column chromatography and high performance liquid chromatography to obtain the acyl phloroglucinol heteroterpenoids compounds shown in the formulas (I) and (II).
2. The acylphloroglucinol triterpenoid of claim 1, wherein in the preparation process, the organic solvent is selected from ethanol or methanol.
3. The acylphloroglucinol triterpenoid of claim 2, wherein the organic solvent used in the preparation method is 95% by volume ethanol.
4. The acylphloroglucinol triterpenoid of claim 1, wherein in the preparation process, the alkane solvent is selected from petroleum ether or n-hexane.
5. The acylphloroglucinol triterpenoid compound according to claim 1, wherein in the preparation method, silica gel column chromatography is performed under normal pressure or pressurization, the eluent is a mixed solvent of petroleum ether and acetone, and gradient elution is adopted.
6. The acylphloroglucinol triterpenoid compound according to claim 1, wherein in the preparation method, ODS reverse phase silica gel column chromatography is performed under normal pressure or pressurized, an eluant is a mixed solvent of methanol and water, and gradient elution is adopted.
7. The acylphloroglucinol heteroterpenoids according to claim 1, wherein in the preparation method, Sephadex LH-20 gel column chromatography is performed under normal pressure or under pressure, and the eluent is a mixed solvent of methanol and dichloromethane.
8. The acylphloroglucinol triterpenoid of claim 1, which is prepared by a high performance liquid chromatography column C18Column, particle size of 5 μm, eluent acetonitrile-water (58:42), detection wavelength of 210nm and 254nm, flow rate of 4.0 mL/min-1。
9. Use of the acylphloroglucinol triterpenoid according to claim 1 in the preparation of a medicament or lead compound for preventing or treating a metabolic disease associated with inflammation.
10. The use according to claim 9, wherein said inflammatory-related metabolic disorder is obesity, insulin resistance, type 2 diabetes, hyperlipidemia, non-alcoholic fatty liver disease, atherosclerosis or chronic kidney disease.
Technical Field
The invention belongs to the technical field of medicines, relates to an acyl phloroglucinol triterpenoid compound and application thereof in pharmacy, and particularly relates to a natural acyl phloroglucinol triterpenoid compound separated from golden plum and application thereof in preparing medicines for preventing and treating inflammation-related metabolic diseases.
Background
It has been reported that obesity and metabolic diseases such as insulin resistance associated with obesity,
The research discloses that the macrophage is the most main immune cell for mediating the inflammatory reaction, the expression and the secretion of inflammatory genes can be regulated and controlled by changing the number and the phenotype of the macrophage or interacting with metabolic cells under different environmental stimuli, and the macrophage is closely related to the occurrence and the development of various metabolic diseases such as obesity, insulin resistance,
Researches prove that inflammation is closely related to metabolic diseases such as obesity, insulin resistance,
Hypericum patulum Thunb is a plant of the genus Hypericum of the family Guttiferae. The Chinese medicine dictionary records the whole medicine, has the functions of clearing heat, promoting urination, soothing liver and activating collaterals, and is mainly used for treating heat stranguria, hepatitis, cold, tonsillitis, arthralgia and myalgia, traumatic injury and the like. The Japanese scholars found acylphloroglucinol heteroterpenoids from the leaves of Hypericum perforatum and reported that they have certain antibacterial activity (Organic Letters,2016,18(20): 5360); from this plant, Chinese scholars found acylphloroglucinol heteroterpenoids and had the activity of inhibiting NO production (Organic Letters,2018,20(24): 7953).
Based on the current state and the basis of the prior art, the inventors of the present application intend to provide acyl phloroglucinol triterpenoids and their use in pharmacy.
Disclosure of Invention
The invention aims to provide acyl phloroglucinol triterpenoid and application thereof in pharmacy based on the current situation and the foundation of the prior art; in particular to a natural acyl phloroglucinol heteroterpenoid compound separated from hypericum and application thereof in preparing medicaments for preventing and treating inflammation related metabolic diseases.
The invention provides a new compound, and the acyl phloroglucinol heteroterpene natural compounds with the structures shown in the formulas (I) and (II) are separated from the branches and leaves of golden plum;
the compound of the invention is prepared by the following method:
pulverizing dried branches and leaves of Hypericum japonicum Thunb, extracting with organic solvent (such as alcohol, methanol, etc.), preferably 95% (by volume) ethanol, and/or water to obtain total extract; dispersing the total extract in water, extracting with alkane solvent (such as petroleum ether or n-hexane), and recovering solvent to obtain alkane extract;
performing silica gel column chromatography on the alkane extract, performing gradient elution by using a petroleum ether-acetone system, purifying by using ODS (ozone depleting substance) reverse phase silica gel column chromatography and Sephadex LH-20 gel column chromatography, and preparing into compounds (I) and (II) by using a high performance liquid; the structure of compound (I) was identified spectroscopically aS (2S,4aR,6aR,7R,8S,9aS,10R,11S) -11-benzoyl-2, 6 a-dihydroxy-3, 3, 7-trimethyl-8, 10-bis (3-methyl-2-butenyl) hexahydro-1H, 6H-7,4 a-ethanocyclopenta [3,4] furo [2,3-b ] pyran-6-one, and the structure of compound (II) was (2R,3aR,5aR,6R,7S,8aS,9R,10S) -2- (2-aminopropyl) -10-benzoyl-5 a-hydroxy-6-methyl-7, 9-bis (3-methyl-2-butenyl) hexahydro-5H-6, 3 a-ethanocyclopenta [ c ] furo [2,3-b ] furan-5-one.
It is a further object of the invention to provide pharmaceutical uses of the compounds; NF-kB transcription inhibition activity tests are carried out on the compounds shown in the formula (I) and the formula (II), and the influence on macrophage inflammatory response induced by LPS is investigated, and the results show that the compounds shown in the formula (I) and the formula (II) have remarkably strong NF-kB transcription inhibition activity, can effectively inhibit the expression of RAW 246.7 macrophage line and mouse primary marrow macrophage BMDM inflammatory genes induced by lipopolysaccharide LPS, and can be used for preparing a novel medicament or a lead compound for preventing and treating inflammation-related metabolic diseases.
The invention provides an acyl phloroglucinol triterpenoid compound which has obvious NF-kB transcription inhibition activity and can effectively inhibit macrophage inflammatory reaction induced by Lipopolysaccharide (LPS), in particular to the acyl phloroglucinol triterpenoid compounds shown in a formula (I) and a formula (II), and the compounds can be used for preparing a novel medicine or a lead compound for resisting inflammatory related metabolic diseases; the metabolic diseases related to inflammation comprise obesity, insulin resistance,
Drawings
FIG. 1 is a graph showing the effect of the compounds (I) and (II) of the present invention on LPS-induced inflammatory gene expression of RAW 246.7 macrophages in example 3,
FIG. 2 is a graph showing the effect of compounds (I) and (II) of the present invention on LPS-induced inflammatory gene expression in primary BMDM macrophages as described in example 4,
in fig. 1 and 2, P <0.05, P <0.01, and P < 0.001.
Detailed Description
The invention is further illustrated, but not limited, by the following examples.
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