CN112843026B - Application of diphenyl ether compound in preparation of acetylcholinesterase inhibitor or medicament for treating Alzheimer disease - Google Patents
Application of diphenyl ether compound in preparation of acetylcholinesterase inhibitor or medicament for treating Alzheimer disease Download PDFInfo
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- CN112843026B CN112843026B CN202110090090.8A CN202110090090A CN112843026B CN 112843026 B CN112843026 B CN 112843026B CN 202110090090 A CN202110090090 A CN 202110090090A CN 112843026 B CN112843026 B CN 112843026B
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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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
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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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/36—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
- C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic
Abstract
The invention discloses an application of a diphenyl ether compound in preparing an acetylcholinesterase inhibitor or a medicament for treating Alzheimer disease. The invention separates the compounds expansol F (1), expansol C (2), expansol D (3) and corditol C (4) shown in formula (I) from the fermentation culture of marine fungus Aspergillus sp.BH4-11. The marine fungus Aspergillus sp.BH4-11 is preserved in Guangdong province microorganism culture Collection (GDMCC) at 11/3 of 2020, and the preservation number is as follows: GDMCC No:61265. the four compounds have obvious inhibitory activity to acetylcholinesterase, provide alternative compounds for developing new acetylcholinesterase inhibitors, and have important significance for developing marine drug resources in China.
Description
The technical field is as follows:
the invention belongs to the field of natural products, and particularly relates to four diphenyl ether compounds and application thereof in preparation of acetylcholinesterase inhibitors or medicines for treating Alzheimer's disease.
Background art:
senile dementia, which is Alzheimer's Disease (AD), is a brain degenerative disease characterized by progressive dementia, and is the most common age-related neurodegenerative disease that seriously affects the cognitive function, memory function, visual function, social life ability, personal ability to live, emotional personality, etc. with the rapid growth of the world's elderly population, the number of AD episodes also increases year by year, and at present, about 4600 ten thousand AD patients exist throughout the world. The number of AD patients in China is over 600 thousands, and the AD becomes the third killer threatening the health of human beings after cardiovascular and cerebrovascular diseases and malignant tumors. The currently believed most effective treatment for alzheimer's disease is to enhance cholinergic neurotransmission in the brain and reduce acetylcholine (ACh) hydrolysis. The acetylcholinesterase inhibitor can enable ACh to be accumulated and increased in content at synapses, ensures normal transmission of nerve signals in vivo, thereby improving functions of learning, memory and the like, and is a treatment medicament which is most widely clinically applied at present and achieves the purpose of relieving AD symptoms by improving the content of acetylcholine. However, the existing acetylcholinesterase inhibitor drugs have large side effects and are not beneficial to long-term administration of patients. Therefore, the search for a novel acetylcholinesterase inhibitor with more obvious activity, high selectivity and small toxic and side effects is particularly urgent. Biological resources in the special marine ecological environment become a new space for expanding natural medicinal resources, and are also the new fields which are most abundant in resources, most complete in storage and most potential in developing new drugs at present. The marine natural products are more and more regarded as important and have become the main source for finding important lead drugs and the basis for developing new drugs. Therefore, natural products with acetylcholinesterase inhibition activity are screened and found in marine microorganisms, and the natural products have important significance for developing acetylcholinesterase inhibitors.
The invention content is as follows:
the invention aims to provide application of a diphenyl ether compound in preparing acetylcholinesterase inhibitors or medicaments for treating Alzheimer's disease.
The diphenyl ether compound is a compound expansol F (1), expansol C (2), expansol D (3) or cordiyol C (4) shown in a formula (I).
The second object of the present invention is to provide an acetylcholinesterase inhibitor or a drug for treating alzheimer's disease, which comprises an effective amount of a diphenyl ether compound or a pharmaceutically acceptable salt thereof as an active ingredient. Preferably, a pharmaceutically acceptable carrier is also included.
Preferably, the diphenyl ether compound is a compound expansol F (1), expansol C (2), expansol D (3) or corditol C (4) shown in formula (I).
The third purpose of the invention is to provide a preparation method of diphenyl ether compounds, which is characterized in that the diphenyl ether compounds are obtained by separating from fermentation cultures of marine fungi Aspergillus sp.BH4-11, the diphenyl ether compounds are compounds expansol F, expansol C, expansol D and/or cordiyol C shown in formula (I), the marine fungi Aspergillus sp.BH4-11 has a collection number of GDMCC No:61265.
preferably, the method comprises the following steps:
extracting a fermentation culture of the marine fungus Aspergillus sp.BH4-11 with acetone, extracting with ethyl acetate, concentrating the extract to obtain a crude extract, separating the crude extract by medium-pressure silica gel column chromatography, and performing separation by using petroleum ether: gradient eluting ethyl acetate from volume ratio of 100: 0 to 1: 1, gradient eluting with petroleum ether, ethyl acetate and methanol from volume ratio of 20: 1 to 0: 100, and identifying and mixing the same fractions by thin layer chromatography; collecting petroleum ether/ethyl acetate at volume ratio of 85: 15, subjecting to reverse phase medium pressure chromatography at position Fr.4, wherein the mobile phase is methanol/water, gradient eluting from volume ratio of 20: 80 to 100: 0, collecting position Fr.4-8 eluted at methanol/water volume ratio of 60: 40, purifying by HPLC to obtain compound expansol F, collecting position Fr.4-9 eluted at methanol/water volume ratio of 70: 30, and purifying by HPLC to obtain compound expansol C and compound expansol D; collecting petroleum ether/ethyl acetate at volume ratio of 75: 25, subjecting to reverse phase medium pressure chromatography at a mobile phase of methanol/water, gradient eluting from volume ratio of 20: 80 to 100: 0, collecting methanol/water at volume ratio of 50:50, and purifying by HPLC at a position Fr.5-3 to obtain compound cordyol C.
Preferably, the fermentation culture of the marine fungus Aspergillus sp.BH4-11 is prepared by the following method: inoculating Aspergillus sp.BH4-11 into MB culture medium, culturing at 27 deg.C and 200rpm for 72 hr to obtain seed liquid, inoculating the seed liquid into rice culture medium, and culturing at 27 deg.C and standing for 70 days to obtain fermentation culture of Aspergillus sp.BH4-11.
A fourth object of the present invention is to provide the use of the marine fungus Aspergillus sp.bh4-11 for the preparation of diphenyl ether compounds, such as compounds expansol D, expansol E, expansol F and/or cordidyl C according to formula (i), wherein the marine fungus Aspergillus sp.bh4-11 has the accession number GDMCC No:61265.
the compounds expansol F (1), expansol C (2), expansol D (3) and corditol C (4) are isolated from the fermentation culture of the marine fungus Aspergillus sp.BH4-11. The four compounds have obvious inhibitory activity to acetylcholinesterase, provide alternative compounds for developing new acetylcholinesterase inhibitors, and have important significance for developing marine drug resources in China.
The marine fungus Aspergillus sp.BH4-11 of the invention is deposited in Guangdong province microorganism culture Collection (GDMCC) at 11/3 of 2020, address: the preservation number of the Guangzhou city, jielizhou 100 college No. 59 building 5, guangdong province microbiological research institute: GDMCC No:61265.
description of the drawings:
FIG. 1 shows molecular docking analysis of expansol F with recombinant human acetylcholinesterase (PDB ID:4EY 7).
FIG. 2 shows molecular docking analysis of expansol C with recombinant human acetylcholinesterase (PDB ID:4EY 7).
FIG. 3 shows molecular docking analysis of expansol D with recombinant human acetylcholinesterase (PDB ID:4EY 7).
FIG. 4 shows molecular docking analysis of corditol C with recombinant human acetylcholinesterase (PDB ID:4EY 7).
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1: preparation and structural characterization of expansol F, expansol C, expansol D and corditol C
1. Preparation of expansol F (1), expansol C (2), expansol D (3) and corditol C (4) of formula (I)
1. And (3) microorganism culture conditions:
inoculating Aspergillus sp.BH4-11 into a 100mL triangular flask, culturing at the temperature of 27 ℃ and 200rpm for 72 hours to obtain a seed solution, inoculating the seed solution into a 1000mL triangular flask containing a rice culture medium, culturing for 30 bottles together, and culturing at the temperature of 27 ℃ and under a standing condition for 70 days to obtain a rice culture product of the Aspergillus sp.BH4-11 (namely a fermentation culture of the Aspergillus sp.BH4-11). The seed culture medium is MB culture medium: malt extract 15g, refined sea salt 10g, distilled water 1000mL, its preparation method is to mix each component evenly, adjust pH 7.0, subpackage to 100mL triangular flask, each flask 20mL, autoclave sterilization for 30min at 121 ℃. The preparation method of the rice culture medium comprises the following steps: every 1000mL of triangular flask is filled with 200g of rice, 2g of refined sea salt and 200mL of distilled water, and is sterilized at 121 ℃ for 30min under high pressure.
2. Extraction and separation:
soaking a rice culture product of Aspergillus sp.BH4-11 marine fungi in acetone with a volume twice that of the rice culture product for 2 days, mashing the rice, carrying out ultrasonic treatment at an ultrasonic frequency of 40KHZ and an ultrasonic power of 360w for 15 minutes, and carrying out reduced pressure filtration by using 8 layers of gauze. The filtrate is decompressed and concentrated to remove acetone, then ethyl acetate with twice volume is used for extraction for 3 times, and ethyl acetate phase crude extract is obtained after the extract liquid is concentrated. Extracting the filter residue with ethyl acetate for 3 times, concentrating the extract, mixing the ethyl acetate phase crude extract to obtain total crude extract (120 g), dissolving the total crude extract with 250mL of methanol, mixing with 100-200 mesh silica gel, separating by medium pressure silica gel column chromatography, wherein the mobile phase is petroleum ether and ethyl acetate, and the volume ratio is 100: 0 to 1: 1 (flow rate 50mL min.) -1 ) Gradient eluting to obtain first fraction, and eluting with petroleum ether, ethyl acetate and methanol at a volume ratio of 20: 1 to 0: 100 (flow rate of 50mL min) -1 ) Gradient elution provided a second fraction. The first fraction and the second fraction were identified by Thin Layer Chromatography (TLC) and the same fractions gave 7 elution sites Fr.1-7. Wherein Fr.4 (petroleum ether: ethyl acetate elution part with volume ratio of 85: 15) is subjected to reverse phase medium pressure chromatography (ODS), the mobile phase is methanol/water, 10 sub-elution parts Fr.4-1-Fr.4-10, fr.4-8 (methanol/water elution part with volume ratio of 60: 40) are subjected to semi-preparative High Performance Liquid Chromatography (HPLC) purification, YMC semi-preparative column (ODS-A, 12nm, S-50 μm) is selected, the column temperature is 27 deg.C, the mobile phase is methanol/water volume ratio of 55: 45, the flow rate is 3mL/min, fraction with retention time of 48min is collected to obtain compound 1 (2.1 mg), fr.4-9 (methanol/water volume ratio of 70: 30) is subjected to semi-preparative HPLC purification, the YMC semi-preparative column (ODS-A, 2nm, S-50 μm), the column temperature is 27 deg.40, the flow rate is 60: 30, the fraction is collected for 3min, the fraction is collected for 3.33 mg, and the fraction is collected for 3.3 min. Fr.5 (petroleum ether: ethyl acetate 75: 25 by volume ratio elution part) by reverse phase medium pressure chromatography (ODS), mobile phase is methanol/water, and gradient elution is performed from 20: 80 to 100: 0 by volume ratio to obtain 8 eluatesThe fraction Fr.5-1-Fr.5-8, fr.5-3 (the fraction eluted with methanol/water volume ratio of 50: 50) was purified by semi-preparative high performance liquid chromatography using YMC semi-preparative column (ODS-A, 12nm, S-50 μm), column temperature 27 deg.C, mobile phase methanol/water volume ratio of 50, flow rate 3mL/min, and fraction retention time 37min was collected to give compound 4 (18.5 mg).
2. Structural characterization of Compound 1, compound 2, compound 3 and Compound 4
Compound 1: a light brown oil which is a white oil, 1 H-NMR、 13 C-NMR (Table 1) and reported expansol F data are in agreement, and low resolution mass spectrometry (LR-ESIMS) gives the excimer ion peak M/z 447.2 ([ M + H ] s] + ) This data is consistent with the molecular weight 288.1 of expansol F and is therefore identified as expansol F.
Compound 2: a light brown oil which is a white oil, 1 H-NMR、 13 C-NMR (Table 1) and reported expansol C data alignment, low resolution mass spectrometry (LR-ESIMS) gave the excimer ion peak M/z 447.2 ([ M + H ]] + ) This data is consistent with the molecular weight of expansol C288.1 and is therefore identified as expansol C.
Compound 3: a light brown oil which is a white oil, 1 H-NMR、 13 C-NMR (Table 1) and reported expansol D data are in agreement, and low resolution mass spectrometry (LR-ESIMS) gives the excimer ion peak M/z 447.2 ([ M + H ] S] + ) This data is consistent with the molecular weight 288.1 of expansol D and is therefore identified as expansol D.
Compound 4: a light brown oil which is a white oil, 1 H-NMR、 13 C-NMR (Table 2) was in agreement with the reported cordyol C data, and low resolution mass spectrometry (LR-ESIMS) gave the excimer ion peak M/z 247.1 ([ M + H ]] + ) This data is consistent with cordyol C molecular weight 288.1 and is therefore identified as cordyol C.
TABLE 1 preparation of Compounds 1 to 3 1 H NMR and 13 c NMR data
TABLE 2 preparation of Compound 4 1 H NMR and 13 c NMR data
Example 2: determination of acetylcholinesterase inhibitory Activity of Compound 1, compound 2, compound 3 and Compound 4 first, computer molecular docking of Compound 1, compound 2, compound 3 and Compound 4, as shown in formula (I)
Use of
The software screens a number of diphenyl Ether natural products by high performance computerized molecular docking analysis, operating as described in the literature (Dai, Y.; li, K.; she, J.; zeng, Y.; wang, H.; liao, S.; lin, X.; yang, B.; wang, J.; tao, H.; dai, H.; zhou, X.; liu Y. Lipopeptide injectors and a peptide Glycerol Ether with AChE inhibition 8978. zxft 8978.). Compounds 1-4 were docked with the acetylcholinesterase target (PDB ID:4EY 7) and their interactions assessed, and the molecular interactions between the ligand binding domain and the compounds were analyzed and the results are shown in Table 3 and FIGS. 1-4. It can be seen that the screened compounds 1-4 all produce better interaction with the target protein, which indicates that the compounds have significant acetylcholinesterase inhibitory activity, wherein the compound 3 has the best binding score (the more negative the score is, the better the binding is), shows higher binding energy, and is similar to the original score of the small molecular ligand E20 in the crystal complex.
TABLE 3 evaluation of Compounds 1-4 by computer molecular docking with the acetylcholinesterase target (PDB ID:4EY 7)
2. Determination of acetylcholinesterase inhibitory Activity of Compound 1, compound 2, compound 3 and Compound 4 represented by formula (I)
The acetylcholinesterase Inhibitory activity of compounds 1-4 was further evaluated using the Ellman method, as described in the literature (Dai, Y.; li, K.; she, J.; zeng, Y.; wang, H.; liao, S.; lin, X.; yang, B.; wang, J.; tao, H.; dai, H.; zhou, X.; liu, U.Y.Lipopeptin animals and a peptide Glycerol Ether with AChE inhibition activity from the Marine-degraded Fungus coli Luchob Lunatus SCSIO41401.Marine drugs 2020,18.). The results show that compounds 1-4 have significant inhibitory activity against acetylcholinesterase, the activity results are shown in table 4, and tacrine is a positive control.
TABLE 4 Compounds 1-4 have significant inhibitory Activity on acetylcholinesterase
| Compound (I) | 1 | 2 | 3 | 4 | Tacrine |
| IC 50 (μg/ml) | 5.15 | 15.08 | 1.74 | 4.87 | 0.05455 |
Claims (1)
1. The application of diphenyl ether compounds or medicinal salts thereof in preparing medicaments for treating Alzheimer disease;
the diphenyl ether compound is a compound expansol F, expansol D or corditol C;
the structural formula of the compound expansol F is shown as 1, the structural formula of the compound expansol D is shown as 3, and the structural formula of the compound cordiol C is shown as 4;
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| Phenolic bisabolanes from the sponge-derived fungus Aspergillus sp.;Shuai Liu et al.;《Phytochemistry Letters》;20161018;第18卷;第187-191页 * |
| 中国南海六种珊瑚次级代谢产物及其化学防御作用;孙玲玲;《中国优秀博硕士学位论文全文数据库(博士) 医药卫生科技辑》;20130115(第01期);E057-12 * |
| 孙玲玲.中国南海六种珊瑚次级代谢产物及其化学防御作用.《中国优秀博硕士学位论文全文数据库(博士) 医药卫生科技辑》.2013,(第01期),E057-12. * |
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