CN115518069B - Application of hexahydrobenzophenanthridine alkaloids in protecting dopamine neurons - Google Patents
Application of hexahydrobenzophenanthridine alkaloids in protecting dopamine neurons Download PDFInfo
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- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 title abstract description 20
- 210000002569 neuron Anatomy 0.000 title abstract description 18
- UXUNBLONJMOCEN-UHFFFAOYSA-N 1,2,3,4,4a,5-hexahydrobenzo[k]phenanthridine Chemical class C1=CC=C2C=CC3=CNC(CCCC4)C4=C3C2=C1 UXUNBLONJMOCEN-UHFFFAOYSA-N 0.000 title abstract description 16
- 229960003638 dopamine Drugs 0.000 title abstract description 10
- 230000002633 protecting effect Effects 0.000 title abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims description 23
- 241000252212 Danio rerio Species 0.000 abstract description 21
- 230000000694 effects Effects 0.000 abstract description 17
- 238000000605 extraction Methods 0.000 abstract description 11
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- 238000002474 experimental method Methods 0.000 abstract description 10
- 206010061218 Inflammation Diseases 0.000 abstract description 9
- -1 alkaloid compound Chemical class 0.000 abstract description 9
- 230000004054 inflammatory process Effects 0.000 abstract description 9
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 abstract description 8
- 208000018737 Parkinson disease Diseases 0.000 abstract description 7
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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Abstract
The application provides application of hexahydrobenzophenanthridine alkaloids in protecting dopamine neurons, and belongs to the technical field of biological medicines. According to the application, the dactylicapnos is used as a raw material for the first time, two high-purity hexahydrobenzophenanthridine alkaloids are obtained through extraction, separation and purification, and experiments prove that the hexahydrobenzophenanthridine alkaloids have an inhibition effect on thrombus caused by arachidonic acid, an inhibition effect on zebra fish inflammation caused by copper sulfate and a strong protection effect on dopamine neurons, so that the alkaloid compound can be a novel and effective medicament for treating heart Parkinson diseases, and has good practical application value.
Description
The application relates to a hexahydrobenzophenanthridine alkaloid with the application number of 2021105224812, the application date of 2021, the year of 5 and the day of 13 and the application name of hexahydrobenzophenanthridine alkaloid, a preparation method and application.
Technical Field
The application belongs to the technical field of biological medicines, and particularly relates to application of hexahydrobenzophenanthridine alkaloids in protecting dopamine neurons.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the application and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Niunia (Dactylicapnos torulosa) is a Papaveraceae purple metal plant, an annual herb, and is currently only found in the northwest, west, middle to southeast of Yunnan, west of Guizhou, southwest of Sichuan and southeast of Tibet in China. Under natural state, the plant is under the forest, bush or ditch side or roadside with the altitude of 1-3 000m. The main active ingredients in the radix Dactylicapni are alkaloids, and have the effects of regulating cardiovascular system, relieving pain, relieving spasm, protecting liver, resisting anoxia and malaria. The chemical components of the Ningpo Yam rhizome are complex, the active components are difficult to separate, and few reports on separating specific high-purity hexahydrophenanthridine alkaloids are provided.
Inflammation also plays an important role in many epidemic disorders, such as Alzheimer's disease, parkinson's disease, liver cancer, lung cancer, and the like. In developed or developing countries, the neurodegenerative disease Parkinson's Disease (PD) caused by inflammation is a serious threat to human health and to human happiness. Parkinson's disease is one of extrapyramidal diseases which are mostly generated in middle-aged and elderly people, is also called paralysis agitans, is a second major nervous system disease which is next to Alzheimer's disease at present, has chronic progressive course, has no effective prevention method, and has multiple increased prevalence along with the increase of age.
It has been reported that the component protopine in the homozygote, namely, protopine, inhibits 5-hydroxytryptamine transporter and norepinephrine transporter, and has antidepressant effect in a mouse model, suggesting that the components can improve neurodegenerative disease activity. Protopine also has effects on the release of platelet active substances against platelet aggregation, suggesting a potential for antithrombotic activity. The inventors found that the previous inventors only performed systematic studies on the analgesic and cardiovascular effects of dactylicapnos. The benzophenanthridine alkaloid compounds in the dactylicapnos are reported in fresh medical biological activity.
Disclosure of Invention
Based on the defects of the prior art, the hexahydrobenzophenanthridine alkaloids and the preparation method and application thereof are provided, the application takes the Ningpo dactylicapnos as a raw material for the first time, two high-purity hexahydrobenzophenanthridine alkaloids are obtained through extraction, separation and purification, and proved by experiments, the hexahydrobenzophenanthridine alkaloids have an inhibition effect on thrombus caused by arachidonic acid, an inhibition effect on zebra fish inflammation caused by copper sulfate and a strong protection effect on dopamine neurons, so that the alkaloid compound can be a novel and effective medicament for treating heart Parkinson diseases, and has good practical application value.
In a first aspect of the present application, there is provided a compound of formula (I):
wherein R may be selected from OCH 3 Or H;
when R is selected from OCH 3 In this case, compound 1: 4-methoxycylinine;
when R is selected from H, it is compound 2: chelidonine.
In some embodiments of the present application, hexahydrobenzophenanthridine alkaloids of formula (I) may be prepared in crystalline or amorphous form, and if crystalline, they may optionally be solvates, for example as hydrates.
In a second aspect of the present application, there is provided a process for the preparation of the above compound, said process comprising:
s1, soaking and extracting dactylicapnos with ethanol, and combining concentrated extracting solutions to obtain a crude extract;
s2, suspending the crude extract in dilute hydrochloric acid, filtering to obtain a filtrate, adjusting the pH to be alkaline, and extracting sequentially by using petroleum ether, dichloromethane and n-butanol;
s3, separating the dichloromethane extract by a silica gel column, performing gradient elution by using dichloromethane-methanol with a gradient of 200:1 to 1:1, collecting eluent in sections, performing chromatographic analysis, and combining and collecting a fraction section containing the compound 1;
s4, treating the n-butanol extract by an MCI column, performing gradient elution by using methanol-water with a gradient of 1:4 to 9:1, collecting eluent in sections, performing chromatographic analysis, and combining and collecting a fraction section containing the compound 2.
In a third aspect of the application there is provided the use of a compound as described above in any one or more of the following:
a) Inhibiting thrombosis and/or preparing a medicament related to inhibiting thrombosis;
b) Inhibiting inflammatory response and/or preparing a medicament related to inhibiting inflammatory response;
c) Protecting dopamine neurons and/or protecting dopamine neuron related drugs;
d) Treating the heart parkinsonism and/or preparing the related medicaments for treating the heart parkinsonism.
In a fourth aspect of the application, there is provided a method of treating heart parkinsonism comprising administering to a subject a therapeutically effective amount of a compound as described above.
The beneficial technical effects of one or more of the technical schemes are as follows:
according to the technical scheme, two hexahydrobenzophenanthridine alkaloids are separated from the dactylicapnos, and are obtained efficiently, so that the comprehensive utilization of natural medicine resources is realized, and an effective way is provided for searching new medicine active ingredients.
Meanwhile, through the test experiments and the structure-activity relationship researches of anti-inflammatory, antithrombotic and anti-MPTP-induced parkinsonism activities of alkaloid compounds separated from the Ningpo-tree root bark, the result shows that hexahydro-benzophenanthridine alkaloids have an inhibiting effect on thrombus caused by arachidonic acid, zebra fish inflammation caused by copper sulfate has an inhibiting effect and a strong protecting effect on dopamine neurons, and the alkaloid compounds possibly can be novel and effective medicaments for treating heart parkinsonism diseases, so that the alkaloid compounds have good practical application prospects.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application.
FIG. 1 is a HR-ESI-MS spectrum of 4-methoxychelidonine isolated in accordance with the present application.
FIG. 2 is a schematic illustration of 4-methoxyspline isolated according to an embodiment of the present application 1 HNMR spectra (600 MHz, in CD) 3 OD)。
FIG. 3 is a schematic illustration of 4-methoxyspline isolated according to an embodiment of the present application 13 CNMR atlas (400 MH)z，in CD 3 OD)。
FIG. 4 is a HSQC spectrum (400 MHz, in CD) of 4-methoxyspline isolated according to the example of the present application 3 OD)
FIG. 5 is a HMBC pattern (400 MHz, inCD) of 4-methoxyspline isolated according to an embodiment of the present application 3 OD)。
FIG. 6 shows the isolated (+) -chelidonine according to the examples of the present application 1 HNMR spectra (600 MHz, in CDCl) 3 )。
FIG. 7 shows the isolated (+) -chelidonine according to the examples of the present application 13 CNMR spectra (400 MHz, in CDCl) 3 )。
FIG. 8 is a graph showing the results of experiments in which compounds 1 and 2 of the present application inhibited copper sulfate-induced inflammation in zebra fish at 3 different concentrations; wherein a is an actual measurement chart of inflammatory reaction, and b is a statistical chart of test data.
FIG. 9 shows the results of antithrombotic activity assays of compounds 1 and 2 of the examples of the application at 3 different concentrations; wherein a is an actually measured graph of antithrombotic activity, and b is a statistical graph of test data.
FIG. 10 shows the results of a dopamine-protecting neuron assay for compounds 1 and 2 according to examples of the present application; wherein a is a length statistical graph of DA neurons in each group; b is a condition chart of observing DA neurons of young fish by each group of fluorescence microscope; and c is a motion trail graph of each group of zebra fish.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments in accordance with the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
As described above, there are reports on the biological activity of benzophenanthridine alkaloid compounds in Ningpo Yam rhizome and its medical use.
In view of this, in one exemplary embodiment of the present application, there is provided a benzophenanthridine alkaloid compound represented by formula (I):
wherein R may be selected from OCH 3 Or H;
when R is selected from OCH 3 In this case, compound 1: 4-methoxycylinine;
when R is selected from H, it is compound 2: chelidonine.
In some embodiments of the present application, hexahydrobenzophenanthridine alkaloids of formula (I) may be prepared in crystalline or amorphous form, and if crystalline, they may optionally be solvates, for example as hydrates.
In still another embodiment of the present application, there is provided a method for preparing the above compound, comprising:
s1, soaking and extracting dactylicapnos with ethanol, and combining concentrated extracting solutions to obtain a crude extract;
s2, suspending the crude extract in dilute hydrochloric acid, filtering to obtain a filtrate, adjusting the pH to be alkaline, and extracting sequentially by using petroleum ether, dichloromethane and n-butanol;
s3, separating the dichloromethane extract by a silica gel column, performing gradient elution by using dichloromethane-methanol with a gradient of 200:1 to 1:1, collecting eluent in sections, performing chromatographic analysis, and combining and collecting fraction sections containing the compound 1;
s4, treating the n-butanol extract by an MCI column, performing gradient elution by using methanol-water with a gradient of 1:4 to 9:1, collecting eluent in a segmented manner, performing chromatographic analysis, and combining and collecting a fraction section containing the compound 2.
The extraction preparation method gradually separates the high-purity monomer components of the compound from the dactylicapnos scandens in a coarse-to-fine mode.
The gradient elution in the application means that the concentration ratio of the mobile phase is continuously changed in the elution process, but the initial concentration and the final concentration are fixed, for example, the gradient elution is carried out by using dichloromethane-methanol with a gradient of 200:1 to 1:1, which means that: the dichloromethane-methanol is subjected to gradient elution according to the initial volume ratio of 200:1 and the elution end volume ratio of 1:1.
The individual steps of the preparation process of the application can be further improved, for example:
in yet another embodiment of the present application, in the step S1,
in the step S1, the raw material of the dactylicapnos root comprises an underground part and an overground part of the dactylicapnos root;
the ratio of solvent to feed liquid used for leaching has an effect on the impurity content of the crude extract and the extraction rate of the active ingredients. The solvent is preferably 90 to 95% ethanol solution, more preferably 95% ethanol solution. Feed liquid ratio of dactylicapnos root to ethanol is 1kg:2 to 7L (preferably 1.06kg: 3L). More specifically, the leaching is performed using a multiple leaching process. The impurity content in the crude extract is effectively reduced by adopting the leaching conditions, so that the extraction rate of hexahydrobenzophenanthridine alkaloids is further improved.
In yet another embodiment of the present application, in the step S2,
the dilute hydrochloric acid is 0.5% -5%, and the concentration of the hydrochloric acid is controlled to be 0.5%, 1%, 2%, 3% or 5%;
in the step of adjusting the pH to be alkaline, 20-30% ammonia water is adopted to adjust the pH of the filtrate to 9-12.
The specific method for extracting by sequentially using petroleum ether, dichloromethane and n-butanol comprises the following steps:
adding petroleum ether, standing and extracting for 10-30 min, collecting supernatant, namely extracting solution, recovering petroleum ether under reduced pressure at 40-50deg.C, and recovering petroleum ether for extraction again until the final obtained extracting solution is light green in color, and recovering petroleum ether under reduced pressure to obtain petroleum ether extract; extracting sequentially with dichloromethane and n-butanol according to petroleum ether extraction process to obtain dichloromethane extract and n-butanol extract respectively;
in yet another embodiment of the present application, in the step S3,
the specific procedure for gradient elution with methylene chloride-methanol is: volume ratio of dichloromethane to methanol = 200:1, 180:1, 150:1, 100:1, 60:1, 250:1, 10:1, 5:1, 2:1, and 1:1; by adopting the optimized gradient condition, the separation degree can be improved;
further, TLC thin layer chromatography and mass spectrum tracking detection are adopted, fractions mainly containing target components are collected and concentrated, the obtained extract silica gel thin layer detection is carried out, and similar components are combined, so that 8 components, namely S1-S8, are obtained; the S3 fraction was subjected to liquid chromatography (1.5 mL/min, meOH-H) 2 O (0.1% TEA) 77:23) gives compound 1, 4-methoxychelidonine (t) R ＝28.0min)；
The liquid chromatography parameters were as follows:
chromatograph: agilent 1260-DAD;
chromatographic column: agilent YMC-Pack ODS-AS-5 μm,12nm (250 mm. Times.10 mm) -C18;
the eluent is as follows: mobile phase B methanol, mobile phase a 0.1% triethylamine water, flow rate: 1.5mL/min of the total weight of the mixture,
isocratic elution: 0 to 15min, B:77vol%, A:23vol%.
The high-purity compound 1 can be directly obtained by adopting the liquid chromatography separation.
In yet another embodiment of the present application, in the step S4,
the methanol and water are used for gradient elution, and the specific gradient elution procedure is as follows: volume ratio of methanol to water = 1:4, 2:3, 3:2, 4:1 and 9:1.
Further, fractions containing mainly the target component were collected by TLC thin layer chromatography and mass spectrometry tracking detection to obtain 4 components (3I 1-3I 4). 3I4 gradient eluting with methanol and water (V/v=3:1); 9 components (3I 4 O1.fwdarw.3I 4O 9) were obtained by separation with ODS column. Recrystallization from 3I4O5 gives compound 2, chelidonine.
In yet another embodiment of the present application, there is provided the use of the above compound in any one or more of the following:
a) Inhibiting thrombosis and/or preparing a medicament related to inhibiting thrombosis;
b) Inhibiting inflammatory response and/or preparing a medicament related to inhibiting inflammatory response;
c) Protecting dopamine neurons and/or protecting dopamine neuron related drugs;
d) Treating the heart parkinsonism and/or preparing the related medicaments for treating the heart parkinsonism.
In yet another embodiment of the present application, there is provided a method of treating heart parkinsonism comprising administering to a subject a therapeutically effective amount of a compound as described above.
The subject of the present application is an animal, preferably a mammal, most preferably a human, who has been the subject of treatment, observation or experiment.
The therapeutically effective amount of the present application refers to that amount of the active compound or pharmaceutical formulation, including the compound of the present application, which results in a biological or medical response of the tissue system, animal or human being sought by the researcher, veterinarian, medical doctor or other medical personnel, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.
The range of therapeutically effective amounts that can be used is known to researchers, veterinarians, doctors, or other medical personnel in the art from clinical trials or other means known in the art.
The application is further illustrated by the following examples, which are not to be construed as limiting the application. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application.
Examples extraction separation experiments
1) The raw material of Niuzhuo dactylicapnos (10.6 Kg: 1.1Kg root plus 9.5Kg aerial part) was immersed in a cold solution of 95% ethanol (3X 30L, first 7 days, second 10 days, third 3 days)Extracting by the method, mixing the three extractive solutions, concentrating the extractive solution (water pan temperature 55 deg.C, vacuum degree-0.06 Mpa) with large rotary evaporator of Ministry of China Instrument Limited liability company to obtain 500g crude extract. Suspending part of crude extract (483.2 g) in 1% diluted hydrochloric acid (3L), suction filtering to obtain filtrate, adjusting pH of the filtrate to 10 with 25% ammonia water, sequentially extracting with petroleum ether (3×3L) to obtain PE extract (1.7 g), extracting with CH 2 Cl 2 (800 mL,700mL,800mL and 700 mL) to give CH 2 Cl 2 Extract (3.9 g) and n-BuOH (400 mL, 300mL and 300 mL) gave nBuOH extract (5.6 g) with the remaining aqueous fraction (140.3 g).
Specifically, the steps of extraction using petroleum ether, methylene chloride and n-butanol include: adding petroleum ether, standing and extracting for 10-30 min, collecting supernatant, namely extracting solution, recovering petroleum ether under reduced pressure at 55 ℃, and recovering petroleum ether again for extraction until the finally obtained extracting solution is light green in color, and recovering petroleum ether under reduced pressure to obtain petroleum ether extract; and extracting by sequentially adopting dichloromethane and n-butanol according to the petroleum ether extraction process to obtain dichloromethane extract and n-butanol extract respectively. The components in the dactylicapnos root extract are complex, and the primary separation and enrichment of the effective components are realized by adopting organic solvents with sequentially increased polarities.
2) Mixing dichloromethane extract (3.7 g) with silica gel, loading onto column, gradient eluting with dichloromethane-methanol system, and performing liquid chromatography separation on the obtained extract by TLC thin layer chromatography and mass spectrometry tracking detection simultaneously with dichloromethane-methanol volume ratio=10:1, 5:1 and 1:1. Gradient V/v=200:1, 180:1, 150:1, 150:1, 130:1, 100:1, 80:1, 60:1, 40:1, 25:1, 15:1, 10:1,8:1,4:1,2:1,1:1, 100-200 mesh silica gel is selected as packing material (250×1000 mm), every 200mL of eluent is taken as one fraction, 160 fractions are collected in total, similar fractions are combined according to thin layer chromatography and ultraviolet coloration (254 nm or 365 nm), the solvent is recovered, components S1 to S8 are obtained, and the target component is found to be mainly present in S3 by detection. S3, adopting high performance liquid chromatography for separation.
Liquid chromatography parameters: chromatograph: agilent 1260-DAD;
chromatographic column: agilent YMC-Pack ODS-A S-5 μm,12nm (250 mm. Times.10 mm); the eluent is as follows: the mobile phase B is methanol, the mobile phase A is 0.1% (mass percent) triethylamine water, and the flow rate is as follows: 1.5mL/min, isocratic elution: 0 to 15min, B:77vol%, A:23vol%. S3 can directly obtain the high-purity 4-methoxychelidonine (t) through liquid chromatography separation R ＝28.0min)。
3) The nBuOH extract (5.6 g) was treated with MCI column, eluted continuously with methanol and water, followed by detection by TLC thin layer chromatography and mass spectrometry, and the fraction containing the main target component was collected, followed by separation with ODS column using methanol and water as eluent, followed by recrystallization to give the compound-chelidonine.
Specifically, gradient elution is performed by using a methanol-water system, the volume ratio of methanol-water=1:4, 2:3, 3:2, 4:1 and 9:1, simultaneously TLC thin layer chromatography and mass spectrum tracking detection are adopted, fractions mainly containing target components are collected and concentrated, 234 fractions are collected every 200mL and combined according to Thin Layer Chromatography (TLC) and ultraviolet coloration (254 nm or 365 nm), and the solvent is recovered under reduced pressure to obtain 4 components (3I 1-3I 4). Gradient elution (V/v=3:1) was performed using reverse silica gel as packing material (50×300 mm) with methanol-water system as eluent, 165 fractions were collected per 100mL of eluent, and similar fractions were combined according to TLC and uv color development (254 nm or 365 nm), and the solvent was recovered under reduced pressure to obtain 9 components (3I 4O1 to 3I4O 9). Recrystallization of 3I4O5 affords (+) -chelidonine.
Effect verification
Experimental example 1:
the experiment establishes an inflammation model of copper sulfate stimulated fluorescence transgenic zebra fish (Tg: zlyz-EGFP), counts the migration quantity of macrophages, carries out anti-inflammatory activity screening of hexahydrophenanthridine alkaloid compounds with a general formula (I), and observes whether compounds separated from the Ningpo dactylicapnos have anti-inflammatory potential.
Anti-inflammatory Activity assay:
the activity test method is as follows:
healthy inflammatory cell fluorescence at fertilization of 72hpfTransgenic zebra fish are used as experimental animals and randomly divided into 5, 10 and 25 mu M sample treatment groups to be detected, a model group, a blank control group and a positive control group (20 mu M ibuprofen), wherein 10 embryos are arranged in each group, 2 compound holes are arranged at the same time, and each concentration is repeated three times. Each of the above groups was placed in a constant temperature incubator at 28.5℃for co-cultivation for 2 hours. Then use 20 mu M CuSO 4 Zebra fish of each sample group and positive control group were treated for 1h, respectively. After the treatment, the zebra fish is washed, inflammatory reaction is observed under a fluorescence microscope, the number of inflammatory cells migrating to the zebra fish line is calculated, and each group of data is statistically analyzed by GraphPad software.
The activity measurement results are shown in figure 8.
The anti-inflammatory activity of compound 2 in the alkaloid is best; the number of the methylene and methoxy groups of the Pr Luo Huanyang and the position of the methoxy group influence the activity, and the methoxy group at the 4-position weakens the activity; the order of magnitude of anti-inflammatory activity at 25. Mu.M of benzophenanthridines is as follows: 2>1 it can be initially obtained that hexahydrophenanthridine has a strong anti-inflammatory effect.
Experimental example 2:
the experiment establishes a thrombus model of the wild zebra fish (AB) stimulated by arachidonic acid, counts the red dyeing area of the heart, carries out antithrombotic activity screening of hexahydrophenanthridine alkaloid compounds with a general formula (I), and observes whether compounds separated from the Niuzuo dactylon have antithrombotic potential.
Antithrombotic Activity assay:
the activity test method is as follows:
72hpf wild zebra fish embryos are selected in a culture dish under a stereoscopic microscope, and the embryos which are normal in development are transferred into 24-hole culture plates, 10 embryos are transferred into each hole, and 2 compound holes are formed at each concentration. Setting an experimental group, namely a solvent control group and a model group: adding 0.4% DMSO solution, and changing into 80 μm AA solution after 6 hr; positive control group: ASP solution is added to make the final concentration be 22.5 mug/mL, and the mixture is put into a 28 ℃ incubator for 6 hours and then is changed into AA solution with the final concentration of 80 mu M; drug intervention group: the drug stock solution was added to give final concentrations of 5, 10 and 50. Mu.M, and the mixture was placed in an incubator at 28℃for 6 hours, followed by a change to 80. Mu.M AA solution. After that, the mixture was placed in an incubator at 28℃for 1.5 hours. Taken out and stained with 1mg/mL o-dianisidine staining solution in the dark for 10min. The fish is washed 3 times, observed and photographed.
The activity measurement results are shown in figure 9.
As seen from Table 1, the positive control group (aspirin) had a thrombus-preventing rate of 67.4%; the antithrombotic activity of compounds 1 and 2 showed a concentration dependence, and the rate of thrombus prevention at 10. Mu.M was 76.5% for compound 2.
Table 1 thrombosis prevention rates of Compounds 1 and 2
Experimental example 3: experiment of the protective action of the benzophenanthridine alkaloid compound with the general formula (I) on dopamine neurons
1) Preparation of zebra fish embryos: when eggs are collected, firstly, selectively matured zebra fish are put into an oviposition cylinder with a baffle plate at 5-6 pm according to the proportion of male to female of 1:1; 8 am the next day: 30, extracting the partition plate, collecting fertilized eggs after 2 hours, repeatedly flushing the fertilized eggs with fresh fish culture water for 3 times, transferring the fertilized eggs into fresh culture water containing 2mg/L methylene blue, and then placing the fertilized eggs in a 28 ℃ incubator for hatching.
2) Experimental grouping and processing: firstly, the transgenic zebra fish Vmat of 1dpf after fertilization, GFP and wild zebra fish AB embryo are subjected to demoulding treatment by using 1mg/mL Pronase E 131 Then, the fish is washed 3 times with fresh fish-raising water and placed in 6-hole plates, 30 young fish are placed in each hole, and the following experimental groups are established: 5mL of fresh fish-farming water treated control group, 5mL of MPTP treated group with a concentration of 50. Mu.M, 5mL of MPTP co-treated group with different concentrations (5. Mu.M, 10. Mu.M, 50. Mu.M) of the compounds in Table 4.2 and 50. Mu.M (the compounds and MPTP were added simultaneously to fresh fish-farming water to reach working concentrations respectively). Transgenic zebra fish Vmat GFP was dosed with fresh fish water containing 0.03mg/mL PTU to inhibit melanin production and facilitate the observation of DA neurons. Adding the medicine, culturing in a 28 ℃ incubator, and changing the medicine every 24 hours.
3) DA neuron observation: at 4dpf, 8 juvenile fishes are randomly selected from different experimental groups of the transgenic zebra fish Vmat, GFP, DA neuron conditions of the juvenile fishes are observed by a Zeiss stereoscopic fluorescent microscope respectively, and the record is photographed.
4) Behavioural experiments: at 5dpf, 8 juvenile fishes are randomly selected from different experimental groups of the wild zebra fish AB, the juvenile fishes are placed into 48 pore plates, each pore plate is placed with 1mL of fresh fish raising water, then the 48 pore plates are placed into a camera bellows of a Zebra zebra fish behavior analyzer for 15min, and after the juvenile fishes adapt to the environment, the behavioral detection is started. And (5) acquiring the motion trail of the zebra fish within 20 minutes by using Zeblab software, deriving data by using the software, and calculating the total distance.
The ratio of DA neuronal area length to control at 10. Mu.M for the positive drug was 1.29, and the ratio of 1 (5. Mu.M) 1 (10. Mu.M) 2 (10. Mu.M) was 1.41,1.28 and 1.21, respectively. Of these, novel compound 1 (5. Mu.M) was the most potent in DA protection.
Finally, it should be noted that the above-mentioned embodiments are only preferred embodiments of the present application, and the present application is not limited to the above-mentioned embodiments, but may be modified or substituted for some of them by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application. While the foregoing describes the embodiments of the present application, it should be understood that the present application is not limited to the embodiments, and that various modifications and changes can be made by those skilled in the art without any inventive effort.
Claims (1)
1. The application of the compound 4-methoxycylinine in preparing medicaments for treating Parkinson; the structural formula of the compound 4-methoxycylinine is as follows:
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