CN113045552A - Photinine derived from sponge epiphytic fungi as well as preparation method and application thereof - Google Patents

Photinine derived from sponge epiphytic fungi as well as preparation method and application thereof Download PDF

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CN113045552A
CN113045552A CN201911368001.0A CN201911368001A CN113045552A CN 113045552 A CN113045552 A CN 113045552A CN 201911368001 A CN201911368001 A CN 201911368001A CN 113045552 A CN113045552 A CN 113045552A
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林厚文
焦伟华
徐启航
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Renji Hospital Shanghai Jiaotong University School of Medicine
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Abstract

The invention relates to medicineThe technical field of medicines discloses flavonolidine from three sponge epiphytic fungi, and the chemical structural formula is as follows:

Description

Photinine derived from sponge epiphytic fungi as well as preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to xanthorrhizine from sponge epiphytic fungi and a preparation method and application thereof.
Background
The sponge is used as an important benthic invertebrate in the marine ecosystem, not only plays an important role in maintaining the marine ecosystem, but also forms a generated chemical defense substance together with the co-attached microorganisms of the sponge, thereby not only playing ecological functions of competing living space, protecting the multiplication of sponge population, resisting predation, pathogenic bacteria infection and the like1Also becomes one of the important sources for finding new marine drugs2。
Metabolic diseases such as obesity, hyperlipidemia and the like become important threats to modern life, and can induce multiple diseases such as arteriosclerosis, hypertension, fatty liver, gallstone, cerebral apoplexy, coronary heart disease, senile dementia, diabetes, hyperuricemia, male dysfunction and the like. The causes of the disease are various, including genetic factors, environmental factors, dietary habits, and the like. Among them, intake of high-fat foods is an important cause of metabolic diseases. Reducing the absorption of fat and lowering the blood lipid concentration through medicines becomes an important means for treating and preventing obesity and hyperlipidemia. Pancreatic lipase is essential for fat digestion and absorption in the intestinal tract 3,4. Fats in foods are hydrolyzed into monoacylglycerols and free fatty acids, and then absorbed in the intestinal tract such as blood, which then causes an increase in blood lipid concentration and accumulation of fats, thereby inducing various metabolic diseases. The pancreatic lipase inhibitor can inhibit the decomposition of fat and reduce the absorption of fat into blood, so that the development and utilization of the effective pancreatic lipase inhibitor for treating metabolic diseases are more and more emphasized by people5,6. Sponge-associated microorganisms are an important source of pancreatic lipase inhibitors because of the abundant chemical diversity they harbor.
Reference documents:
[1].Lele-Rahalkar U.,Pawar S.(2017)Marine Sponge-Associated Microbiome:Reservoir of Novel Bioactive Compounds.In:Kalia V.,Shouche Y.,Purohit H.,Rahi P.(eds)Mining of Microbial Wealth and MetaGenomics.Springer,Singapore.
[2].Indraningrat,A.A.G.；Smidt,H.；Sipkema,D.Bioprospecting Sponge-Associated Microbes for Antimicrobial Compounds.Mar.Drugs 2016,14,87.
[3].Winkler,F.K.；D’Arcy,A.；Hunziker,W.Nature 1990,343,771-774.
[4].Liu,D.Z.；Wang,F.；Liao,T.G.；Tang,J.G.；Steglich,W.；Zhu,H.J.；Liu,J.K.Org.Lett.2006,8,5749-5752.
[5].van Tilbeurgh,H.；Sarda,L.；Verger,R.；Cambillau,C.Nature 1992,359,159-162.
[6].Hou,X.D.；Ge,G.B.；Weng,Z.M.；Dai,Z.R.；Leng,Y.H.；Ding,L.L.；Jin,L.L.；Yu,Y.；Cao,Y.F.；Hou,J.Bioorg.Chem.2018,80,577-584.
disclosure of Invention
The invention discloses a sponge epiphytic fungus-derived flavonoline, which has the chemical structural formula as follows:
Figure BDA0002338941250000021
the second purpose of the invention is to disclose the preparation method of the sponginum epizobium derived from fungi, which comprises the following steps:
(a) separating and obtaining epiphytic fungus yellow handle Aspergillus (Aspergillus flavipes) from marine organisms, culturing by adopting a culture medium, extracting a fermentation product in the culture medium by cold immersion, and concentrating an extracting solution to obtain an extract;
(b) suspending the extract with water, methanol-water or ethanol-water, extracting with organic solvent, concentrating the extractive solution under reduced pressure, and separating by chromatography to obtain xanthorrhizone A, xanthorrhizone B and xanthorrhizone C.
Preferably, in step (a), the marine organism is a sponge, a blue algae or a combination of the two.
Preferably, in step (a), the culture medium is a solid culture medium or a liquid culture medium, preferably a solid culture medium;
further, the culture medium may be selected from solid or liquid culture medium of rice, corn, soybean, potato dextrose, and wort, etc., preferably rice solid culture medium.
Preferably, in the step (a), the solvent used for the cold leaching extraction is one or two or more selected from methanol, acetone, ethanol, ethyl acetate and dichloromethane; methanol is preferred.
Preferably, in step (b), the extract is suspended by methanol-water.
Further, the volume content of methanol in methanol-water for suspension is 50% to 70%, preferably 55% to 65%, and more preferably 60%.
Preferably, in step (b), the organic solvent for extraction is ethyl acetate, dichloromethane or chloroform, preferably ethyl acetate.
Preferably, in step (b), the chromatographic separation step comprises:
performing vacuum silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate, and mixing the fractions containing alkaloid compounds;
performing reversed-phase medium-pressure ODS column chromatographic separation, and performing gradient elution by adopting an acetonitrile-water system to obtain fine fractions containing alkaloid compounds;
Separating by high performance liquid chromatography, eluting with 65% methanol/water to obtain xanthorrhizine A, xanthorrhizine B and xanthorrhizine C.
Furthermore, the gradient of an acetonitrile-water system adopted by the reversed-phase medium-pressure ODS column chromatographic separation is 50: 50-100: 0. Further, the acetonitrile-water system gradient changes were 50:50, 70:30, 80:20, 90:10, and 100: 0.
Further, the flow rate was 20mL/min in the case of reversed-phase, medium-pressure ODS column chromatography.
Further, the high performance liquid chromatography separation was carried out at a flow rate of 2.0mL/min and a detection wavelength of 254 nm.
Further, in the separation by high performance liquid chromatography, 0.01% TFA (trifluoroacetic acid) was added to 65% methanol/water.
The third purpose of the invention is to disclose the application of the flavonolignans from the sponge epiphytic fungi, in particular to the application of the flavonolignans in preparing medicines for preventing, diagnosing, detecting, protecting, treating and researching metabolic diseases or diseases induced by the metabolic diseases.
The activity test proves that the compounds of the invention, namely the xanthorrhizine A, the xanthorrhizine B and the xanthorrhizine C show very strong inhibition activity to lipase secreted by pancreas in vitro, so that the compounds can be used for preparing the medicines for treating metabolic diseases.
The metabolic disease especially refers to hyperlipidemia; the diseases induced by metabolic diseases are one or more of arteriosclerosis, hypertension, fatty liver, gallstone, cerebral apoplexy, coronary heart disease, senile dementia, diabetes, hyperuricemia and male dysfunction.
The medicine can be a hyperlipemia medicine, in particular to one or more medicines which are directly used for preventing, diagnosing, detecting, protecting, treating and researching hyperlipemia and directly related diseases thereof.
The medicament can be an arteriosclerosis medicament, and particularly refers to one or more of medicaments which are directly used for preventing, diagnosing, detecting, protecting, treating and researching arteriosclerosis and directly related diseases thereof.
The medicine can be a hypertension medicine, and particularly refers to one or more of medicines directly used for preventing, diagnosing, detecting, protecting, treating and researching hypertension and directly related diseases thereof.
The medicine can be fatty liver medicine, in particular to one or more of medicines directly used for preventing, diagnosing, detecting, protecting, treating and researching fatty liver and directly related diseases thereof.
The medicine can be a gallstone medicine, and particularly refers to one or more of medicines which are directly used for preventing, diagnosing, detecting, protecting, treating and researching gallstones and directly related diseases thereof.
The medicament can be a cerebral apoplexy medicament, in particular to one or more of medicaments which are directly used for preventing, diagnosing, detecting, protecting, treating and researching cerebral apoplexy and directly related diseases thereof.
The medicine can be a coronary heart disease medicine, and particularly refers to one or more of medicines directly used for preventing, diagnosing, detecting, protecting, treating and researching coronary heart disease and directly related diseases thereof.
The medicine can be senile dementia medicine, in particular to one or more of medicines directly used for preventing, diagnosing, detecting, protecting, treating and researching senile dementia and directly related diseases thereof.
The medicament can be a diabetes medicament, and particularly refers to one or more of medicaments which are directly used for preventing, diagnosing, detecting, protecting, treating and researching diabetes and directly related diseases thereof.
The medicine can be a hyperuricemia medicine, and particularly refers to one or more of medicines which are directly used for preventing, diagnosing, detecting, protecting, treating and researching hyperuricemia and directly related diseases thereof.
The medicine can be male dysfunction medicine, in particular to one or more of medicines which are directly used for preventing, diagnosing, detecting, protecting, treating and researching male dysfunction and directly related diseases thereof.
The invention has the beneficial effects that: the preparation method is simple, and the compounds of the staphyline A, the staphyline B and the staphyline C prepared by the method show very strong inhibition activity to lipase secreted by pancreas in vitro. The invention provides a new lead compound for researching and developing a new medicament for treating hyperlipidemia and provides a scientific basis for developing and utilizing marine medicinal resources.
Drawings
FIG. 1 is a schematic representation of the key correlation of two-dimensional nuclear magnetic data for flavomargine A;
FIG. 2 is an X-ray single crystal diffractogram of aureobasidin A;
FIG. 3 is a comparison graph of measured ECD spectra of staurophylline A, staurophylline B and staurophylline C;
FIG. 4 is a dose-response curve and IC of the inhibition activity of flavipine on pancreatic secretion by flavipine A50A value;
FIG. 5 is a dose-response curve and IC of flavonoline B for inhibiting the lipase activity secreted by pancreas50A value;
FIG. 6 is a dose-response curve and IC of flavonoline C for inhibiting the lipase activity secreted from pancreas50The value is obtained.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.
EXAMPLE 1 preparation of the Compounds Formosanine A, Formosanine B, Formosanine C
The epiphytic fungus Aspergillus flavipes is obtained by separating from a sponge Dysidea sp collected from the sea area of Xisha Islands, and simultaneously the strain is also obtained by separating from a blue algae Lyngbya majulla sample collected from the sea area, LC-DAD/MS analysis shows that secondary metabolites of the Aspergillus flavipes A.flavipes from the sponge and the blue algae have the same ultraviolet absorption characteristic and mass spectrum characteristic, so the Aspergillus flavipes strain from the sponge is selected for fermentation culture, the fermentation product in the culture medium is extracted by cold soaking of methanol after the rice culture medium is cultured for 21 days, and then the extracting solution is concentrated to obtain a total extract; suspending the extract with 90% methanol-water, extracting with isovolumetric petroleum ether for 3 times to obtain petroleum ether layer, suspending the rest extract with 60% methanol-water, extracting with isovolumetric ethyl acetate for 3 times, and concentrating the extractive solution under reduced pressure to obtain petroleum ether layer and ethyl acetate layer. LC-DAD/MS detected the presence of staphyline A, staphyline B, and staphyline C in the ethyl acetate layer. Separating ethyl acetate layer with normal phase reduced pressure silica gel column, and gradient eluting with petroleum ether/ethyl acetate and dichloromethane/methanol sequentially to obtain a series of fractions. Then analyzing the fractions by LC-DAD/MS to obtain target fraction containing flaviperidine, performing reversed-phase medium-pressure ODS column chromatography, and performing gradient elution with acetonitrile-water system (50:50, 70:30, 80:20, 90:10 and 100:0) to obtain fine fraction containing alkaloid compounds; the obtained fine fraction containing alkaloid compounds is separated by high performance liquid chromatography (65% methanol water (added with 0.01% TFA), flow rate of 2.0mL/min, detection wavelength of 254nm) to obtain compound xanthophylline A (C) 42H41O8N5Cl2) Yellow anserine B (C)42H42O8N5Cl) and xanthophylline C42H42O8N5Cl). Physicochemical properties and nmr data for three compounds are as follows:
the yellow anserine A (1) is light yellow needle crystal; [ alpha ] to]D 23-11.5(c 0.2,MeOH)；UV(MeOH):λmax(logε)207(4.19),245(4.13),370(3.95)nm；CD(MeCN):λ(△ε)194(-6.8),218(+7.31),247(-1.92),273(+0.54)nm；1H NMR(600MHz)and 13C NMR(150MHz)in DMSO-d6See table 1; ESI-MS M/z814.3[ M ]]+/m/z 816.3[M+2]+/m/z 818.3[M+4]+(9:6:1)；HR-ESI-MS:m/z 814.2419[M+H]+(calcd for C42H42O8N5Cl2,814.2405).
Yellow anserine B (2) is light yellow powder; [ alpha ] to]D 23-14.7(c 0.1,MeOH)；UV(MeOH):λmax(logε)202(4.29),242(4.05),312(3.45),364(3.69)nm；CD(MeCN):λ(△ε)193(-13.6),220(+8.23)nm；1H NMR(600MHz)and 13C NMR(150MHz)in DMSO-d6See table 1; ESI-MS M/z 780.3[ M ]]+/m/z 782.3[M+2]+(3:1)；HR-ESI-MS:m/z 780.2818[M+H]+(calcd for C42H43O8N5Cl,780.2800).
Yellow anserine C (3) is light yellow powder; [ alpha ] to]D 23-15.6(c 0.6,MeOH)；UV(MeOH):λmax(logε)202(4.23),240(3.99),369(3.79)nm；CD(MeCN):λ(△ε)194(-11.2),218(+6.72)nm；1H NMR(600MHz)and 13C NMR(150MHz)in DMSO-d6See table 1; ESI-MS M/z 780.3[ M ]]+/m/z 782.3[M+2]+(3:1)；HR-ESI-MS:m/z 780.2795[M+H]+(calcd for C42H43O8N5Cl,780.2800).
TABLE 1 nuclear magnetic resonance spectroscopy data (DMSO-d) for the compounds flavomargine A, B and C6)
Figure BDA0002338941250000061
Figure BDA0002338941250000071
Fig. 1 is a schematic diagram showing the key correlation of two-dimensional nuclear magnetic data of a compound of the xanthorrhizone A, and an X-ray single crystal diffraction pattern in fig. 2 can determine that the structural formula of the xanthorrhizone A (1) is as follows:
Figure BDA0002338941250000081
fig. 3 shows the measured ECD (electron circular dichroism) curves for staurone a (1), staurone b (2) and staurone c (3), determining the absolute configuration of 3 compounds.
The structural formula of the flavonoline B (2) is as follows:
Figure BDA0002338941250000082
the structural formula of the flavonoline C (3) is as follows:
Figure BDA0002338941250000083
example 2 evaluation experiment of pancreatic Lipase inhibitory Activity
The compounds of the present invention, xanthorrhizine A (1), xanthorrhizine B (2) and xanthorrhizine C (3), were subjected to an evaluation experiment of pancreatic lipase inhibitory activity, and simultaneously, a parallel experiment was carried out using kaempferol as a positive control. The samples were dissolved in DMSO and stored at low temperature. Each sample was set with 5 replicate wells in the test.
The specific experimental steps are as follows:
inhibitory activity against pancreatic lipase (PL, Sigma type II) 4-methylumbelliferyl late (4-MUO) was used as substrate. The incubation mixture, in a total volume of 200. mu.L, was composed of a lipase solution (final concentration 10. mu.g/mL), 0.1M citrate phosphate buffer (0.1M cit)rate-Na2HPO4, pH 7.4) and inhibitor, using kaempferol as a positive control. After a preincubation at 37 ℃ for 10 minutes, the reaction started after the addition of 4-MUO (final concentration 2.5. mu.M). The concentrations of staurone A (1), staurone B (2) and staurone C (3) were 0.313, 0.625, 1.25, 2.5, 5, 10 μ M in this order, and after all incubations with or without inhibitors, 4-MU (hydrolysis metabolite of 4-MUO) was further analyzed by a multimodal microplate reader (Molecular Devices SpectraMax iD3, USA). The fluorescent signal of the hydrolyzed metabolite (4-MU) was monitored in real time at 60 seconds intervals under physiological conditions (pH 7.4 at 37 ℃) within 30 minutes of 30 minute incubation. The excitation wavelength of the hydrolyzed metabolite (4-MU) was set at 340nm and the emission wavelength was 460 nm. The PMT gain value was set to 100V and the integration time was set to 10 msec. The remaining activity of lipase was calculated using the following formula:
the remaining activity (%) (fluorescence intensity in the presence of inhibitor)/fluorescence intensity in negative control (DMSO only): 100%
And calculating the half inhibitory concentrations IC of the two compounds on pancreatic lipase activity50The value is obtained.
The results are given in table 2 below:
TABLE 2 inhibition of pancreatic lipase by xanthorrhizine A, B and C (n ═ 5)
Figure BDA0002338941250000091
FIGS. 4, 5 and 6 show the inhibitory activity, IC, of flavonoline A (1), flavonoline B (2) and flavonoline C (3) on pancreatic lipase50The values are 0.23 + -0.03, 0.07 + -0.01 and 0.14 + -0.02 respectively, and have good dose dependence.

Claims (10)

1. A xanthorrhizine from sponge epiphytic fungi has a chemical structural formula as follows:
Figure FDA0002338941240000011
2. the process for the preparation of flavomargine from the sponge epiphytic fungi of claim 1, comprising the steps of:
(a) separating and obtaining epiphytic fungus aspergillus flavipes from marine organisms, culturing by adopting a culture medium, extracting a fermentation product in the culture medium by cold immersion, and concentrating an extracting solution to obtain an extract;
(b) suspending the extract with water, methanol-water or ethanol-water, extracting with organic solvent, concentrating the extractive solution under reduced pressure, and separating by chromatography to obtain xanthorrhizone A, xanthorrhizone B and xanthorrhizone C.
3. The method of claim 2, wherein in step (a), the marine organism is a sponge, a cyanobacteria, or a combination thereof.
4. The method of claim 2, wherein in step (a), the medium is rice medium, corn medium, soybean medium, potato dextrose medium, or wort medium; the solvent for cold soaking extraction is one or more selected from methanol, acetone, ethanol, ethyl acetate and dichloromethane.
5. The method of claim 2, wherein in step (b), the organic solvent used for extraction is ethyl acetate, dichloromethane or chloroform.
6. The method of claim 2, wherein in step (b), the step of chromatographically separating comprises:
performing vacuum silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate, and mixing the fractions containing alkaloid compounds;
performing reversed-phase medium-pressure ODS column chromatographic separation, and performing gradient elution by adopting an acetonitrile-water system to obtain fine fractions containing alkaloid compounds;
separating by high performance liquid chromatography, eluting with 65% methanol/water to obtain xanthorrhizine A, xanthorrhizine B and xanthorrhizine C.
7. The method of claim 6, wherein in step (b), the reversed-phase medium-pressure ODS column chromatography is performed with an acetonitrile-water system gradient of 50:50 to 100:0 and a flow rate of 20 mL/min; the flow rate is 2.0mL/min and the detection wavelength is 254nm during the separation by high performance liquid chromatography.
8. Use of flavomargine derived from epiphyte sponges as claimed in claim 1 for the preparation of a medicament for the prevention, diagnosis or treatment of metabolic diseases or diseases induced by metabolic diseases.
9. The use according to claim 8, wherein the metabolic disease is hyperlipidemia, and the metabolic disease-induced disease is one or more of arteriosclerosis, hypertension, fatty liver, gallstone, cerebral stroke, coronary heart disease, senile dementia, diabetes, hyperuricemia, and male dysfunction.
10. The use according to claim 8, wherein one, any two or three of staphyline A, staphyline B and staphyline C is used for its pancreatic lipase inhibitor activity.
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CN109704945A (en) * 2018-12-11 2019-05-03 上海交通大学医学院附属仁济医院 A kind of miscellaneous terpenoid in sponge source and the preparation method and application thereof
CN109761948A (en) * 2017-11-09 2019-05-17 上海交通大学医学院附属仁济医院 Miscellaneous terpenoid Dysiarenone in sponge source and the preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102234250A (en) * 2010-04-27 2011-11-09 中国人民解放军第二军医大学 Antitumor bioactive alkaloid compound in Agelas clathrodes
CN109761948A (en) * 2017-11-09 2019-05-17 上海交通大学医学院附属仁济医院 Miscellaneous terpenoid Dysiarenone in sponge source and the preparation method and application thereof
CN109704945A (en) * 2018-12-11 2019-05-03 上海交通大学医学院附属仁济医院 A kind of miscellaneous terpenoid in sponge source and the preparation method and application thereof

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