CN111500467B - Marine penicillium for preparing anti-hepatitis C virus active compound leisindole A - Google Patents
Marine penicillium for preparing anti-hepatitis C virus active compound leisindole A Download PDFInfo
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- CN111500467B CN111500467B CN202010224119.2A CN202010224119A CN111500467B CN 111500467 B CN111500467 B CN 111500467B CN 202010224119 A CN202010224119 A CN 202010224119A CN 111500467 B CN111500467 B CN 111500467B
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/645—Fungi ; Processes using fungi
- C12R2001/80—Penicillium
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/14—Fungi; Culture media therefor
- C12N1/145—Fungal isolates
-
- 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
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms
Abstract
The invention belongs to the field of medical biology, and relates to a preparation method of a new-structure compound leistrickindole A obtained from marine penicillium reissum; the invention also relates to application of the compound in resisting Hepatitis C Virus (HCV) infection, and marine penicillium for preparing a hepatitis C virus resisting active compound leisindole A.
Description
The technical field is as follows:
the invention belongs to the field of medical biology, and relates to a preparation method of a new-structure compound leistrickindole A obtained from marine penicillium reissum; the invention also relates to the use of said compounds against Hepatitis C Virus (HCV) infection.
Background art:
hepatitis C Virus (HCV) poses a serious threat to human health, and it is estimated that there are about 1.7 billion HCV chronic infectors worldwide [ Lauer, et al, New England journal of medicine, 2001,345,41-51 ]. The number of people worldwide dying from HCV infection every year exceeds 39 million [ world health organization, global hepatitis report, 2017 ]. Patients with chronic hepatitis c are at high risk of developing fatal complications of liver disease, including cirrhosis and liver cancer. Among them, the incidence of liver cirrhosis reaches 20%, whereas the incidence of liver cancer reaches 4% -5% per year in patients with liver cirrhosis. In recent years, with the marketing of nucleoside/acid inhibitors such as sofosbuvir, hepatitis c treatment has been greatly advanced. However, hepatitis c therapy is still challenging due to the high cost of treatment, drug resistance and narrow viral specificity, and there is an urgent need to develop anti-HCV drugs with new mechanisms of action.
Marine microorganisms are an important source for the discovery of pharmaceutical lead compounds. The invention separates and obtains indole diketopiperazine alkaloid with a new structure from fermentation liquor of a strain of Penicillium limanii IMB17-034(Penicillium raidrickii) from sea, which is named as leistrickindolone A (English name: raidrickindole A, formula I). Relates to a chemical structure, a preparation method and anti-hepatitis C virus application of a compound shown in a formula I, and has no report so far.
The invention content is as follows:
one of the objects of the present invention is to provide a producing strain producing Raistrickindile A.
The strain is a marine fungus strain, particularly penicillium thunbergii, preferably penicillium thunbergii IMB17-034, is separated from a sea mud sample collected from a mangrove forest, is delivered to the general microbiological culture collection center of China Committee for culture Collection of microorganisms of institute of microbiology, China academy of sciences, No. 3, Ministry of sciences, Navy, in Beijing city, and facing Yang, in 2019, 22 months, and has the following suggested classification names: penicillium reissui Penicillium raistrickii, reference biological material: IMB17-034, accession number: CGMCC No. 17185.
The second purpose of the invention is to provide a compound with a new structure, namely lescentella.
The structure of the novel compound leistrickindole A found from the fermentation product of marine fungus Penicillium limanii IMB17-034(Penicillium raidrickii) is shown in formula I.
The compound has the formula C20H19N3O4 Molecular weight 365.
It is a further object of the present invention to provide a process for the preparation of the compound lesindazomethine.
The preparation method of the compound lesinundazole A comprises the following steps:
(1) inoculating activated penicillium limacinum IMB17-034 with the preservation number of CGMCC No.17185 into a fermentation culture medium of potato glucose broth (PDB) to prepare a seed solution, and then transferring the seed solution into a rice solid fermentation culture medium for culture;
(2) collecting the solid fermentation product of the strain, adding an organic solvent, and performing ultrasonic extraction to obtain an extract;
(3) separating the extract by C18 reversed phase flash column chromatography, gradient eluting with 10%, 30%, 50%, 70%, and 100% organic solvent to obtain 5 eluate fractions (F1-F5), separating 50% eluate fractions by gel column, and performing HPLC to obtain the compound containing formula I.
Preferably, the preparation method of the compound rasindole A comprises the following steps:
(1) inoculating activated penicillium limacinum IMB17-034 with the preservation number of CGMCC No.17185 into a fermentation culture medium of potato glucose broth (PDB), shaking and culturing at 28 ℃ for 3-5 days to prepare a seed solution, transferring the seed solution into a rice solid fermentation culture medium, and standing and culturing at 28 ℃ for 30 days;
(2) collecting the solid fermentation product of the strain, adding an organic solvent, and performing ultrasonic extraction to obtain an extract;
(3) separating the ethyl acetate fraction extract by C18 reversed phase flash column chromatography, sequentially eluting with 10%, 30%, 50%, 70%, and 100% organic solvent to obtain 5 eluate fractions (F1-F5), separating 50% eluate fractions by gel column, and preparing by HPLC to obtain the compound containing formula I.
Wherein, in the step (1), the solid culture medium is selected from: including but not limited to rice or solid media based on rice.
Wherein, in the step (2), the organic solvent is selected from: alcohols with carbon chain less than or equal to 4 such as chloroform, dichloromethane, ethyl acetate, methanol, acetic acid, etc., acetone, butanone or the mixed solution of the above solvents. Preferably, ethyl acetate.
Wherein, in the step (3), the fractions F1-F5 are obtained by sequentially eluting 10%, 30%, 50%, 70% and 100% of organic solvents;
wherein the solvent is selected from: including but not limited to one or more of acetone aqueous solution, alcohol solution with carbon chain less than or equal to 4, acetonitrile aqueous solution, or methanol.
The HPLC separation and purification process of the compound shown in the formula I is as follows:
the solvent is selected from: acetone water solution, alcohol solution with carbon chain not more than 4 and acetonitrile water solution.
The chromatographic column is selected from: including but not limited to C18, C8, C3, phenyl-bonded columns.
Preferably: c-18 column, 10mm X250 mm, 30% MeCN,4 mL/min.
Further preferably, the preparation method of the compound rasindole A comprises the following steps:
(1) fermentation of the fungus IMB17-034(Penicillium raidrickii):
inoculating activated penicillium limacinum IMB17-034 with preservation number of CGMCC No.17185 on potato glucose agar (PDA) plate, culturing in 28 deg.C incubator for 7-14 days, and taking 1cm with sterile iron shovel2Inoculating the bacterium-containing agar block into 100mL liquid potato glucose broth (PDB) fermentation medium, and performing shake culture at 28 deg.C for 5d in 500mL triangular flask to obtain seed solution; then, the seed liquid is inoculated according to the amount of 10 percent and transferredInoculating to rice solid fermentation medium, standing at 28 deg.C for 30 days in 30 bottles;
(2) extracting a fermentation product and obtaining an extract:
collecting solid fermentation product of strain IMB17-034, adding equal volume of ethyl acetate, performing ultrasonic extraction for 3 times (each time for 60 min), and recovering solvent under reduced pressure to obtain ethyl acetate extract;
(3) isolation of the Compound of formula I
Separating ethyl acetate fraction by C18 reverse phase flash column chromatography, sequentially gradient-eluting with 10%, 30%, 50%, 70%, and 100% methanol-water solution to obtain 5 eluate fractions (F1-F5), separating F3 fraction eluted with 50% methanol by gel column chromatography, eluting with 80% methanol to obtain 16 fractions (F1-F5)3-1-F3-16) Fraction E3-11Separating and purifying by HPLC chromatography (Capcell MGII 5 μm, 10mm × 250mm, 30% MeCN,4 mL/min).
The fourth purpose of the invention is to provide the application of the compound shown in the formula I or the pharmaceutical composition taking the compound as the active ingredient in the drugs for treating Hepatitis C Virus (HCV).
The present invention tests the inhibitory activity of said lesindolone A against HCV virus. The experimental result shows that the compound has better inhibitory activity to the tested HCV virus. The compounds are indicated to be useful for the preparation of anti-HCV drugs. The compound is used as an active ingredient and is compatible with one or more pharmaceutically acceptable carriers, excipients or auxiliary materials to prepare the anti-HCV pharmaceutical composition. The medicine and the medicine composition can be used for clinical treatment of hepatitis C. The compound can also be combined with known medicaments to form a compound preparation for treating the hepatitis C.
The method for preparing the rasindole A shown in the formula I by microbial fermentation in the invention can be applied to any other microorganisms capable of producing the compounds.
The derivatives are used as active ingredients and are compatible with one or more pharmaceutically acceptable carriers, excipients or auxiliary materials to prepare the anti-HCV pharmaceutical composition. The medicine and the medicine composition can be used for clinical treatment of HCV infection. The compound can also be combined with known medicaments to form a compound preparation for treating the hepatitis C.
The fifth object of the present invention is to provide a pharmaceutical composition comprising the compound represented by formula I as an active ingredient.
The pharmaceutical composition comprises lescentella and a pharmaceutically acceptable carrier.
Wherein the pharmaceutically acceptable carrier is 0.1-99.9% by weight of the total weight of the pharmaceutical composition.
Wherein the pharmaceutically acceptable carrier comprises mannitol, sorbitol, sorbic acid or potassium salt, sodium pyrosulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin A, vitamin C, vitamin E, vitamin D, azone, disodium EDTA, calcium sodium EDTA, carbonate, acetate, phosphate or its aqueous solution of monovalent alkali metal, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerol, propylene glycol, ethanol, Tween 60-80, span-80, beeswax, lanolin, liquid paraffin, cetyl alcohol, gallic acid esters, One or more of agar, triethanolamine, basic amino acid, urea, allantoin, calcium carbonate, calcium bicarbonate, surfactant, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid material, kaolin, pulvis Talci, calcium stearate, magnesium stearate, and microcrystalline; preferably, the carrier is one or more of microcrystalline cellulose, lactose, starch, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and talcum powder.
The pharmaceutical composition can be prepared into any dosage form to be used. The preparation is any one of tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquid, buccal agents, granules, pills, powder, ointment, pellets, suspensions, solutions, injections, suppositories, ointments, plasters, creams, sprays and patches; preferably, the preparation is capsule, granule or tablet.
The anti-Hepatitis C Virus (HCV) activity of lesindolone in the present invention is comparable to that of natural products with anti-HCV) activity reported in the literature [ Jardim, a.c. et al.virol.j.2018,15,34 ]; nishikori, s.et al.j.nat.prod.2016,79,442-6; or more preferably [ Li, b.et al.bioorg.med.chem.2019,27, 560-. Although the activity intensity is lower than that of sofosbuvir (sofosbuvir), which is a newly marketed anti-HCV drug, the latter is expensive, causing a serious economic burden to patients. Leisindoline is an anti-HCV compound with a brand-new structural framework structure, possibly has a new action mechanism, and therefore can be used for treating drug-resistant HCV infection. In addition, the rasindole A is a natural product obtained by microbial fermentation, and raw materials are easy to obtain, so that the rasindole A can be used as a lead compound for resisting HCV to perform structure optimization so as to develop an anti-HCV medicament with better activity.
Description of the drawings:
FIG. 1: high resolution electrospray mass spectrometry of a compound of formula I
FIG. 2: process for preparing compounds of formula I1H NMR spectrum
FIG. 3: process for preparing compounds of formula I13C NMR spectra
The specific implementation mode is as follows:
embodiments of the present invention are applicable to the preparation of raistrickindole a and its derivatives from any microorganism, but are not limited to, the fermentation products of penicillium thunbergii. The following examples are set forth to aid those skilled in the art in a better understanding of the present invention and are not intended to limit the invention in any way.
< example 1> identification of the fungus IMB17-034(Penicillium raidrickii)
a) The strain source is as follows: the fungus IMB17-034(Penicillium raidrickii) was isolated from a sample of sea mud (18 ℃ 24 '09.00 "N, 109 ℃ 51' 08.00" E) collected from the mangrove forest in this laboratory.
b) And (3) strain identification: the fungus IMB17-034(Penicillium raidrickii) was identified on the basis of the conservation of the DNA sequence of the ITS, 18S region in microbial species. The genome of fungus IMB17-034(Penicillium raidrickii) is extracted, ITS and 18S rRNA genes are amplified by PCR and sequenced, and the genes are submitted to NCBI GenBank database to obtain accession numbers MK027053 and MK204575, the sequences of which are shown as SEQ ID NO.1 and SEQ ID NO. 2.
SEQ ID NO.1
SEQ ID NO.2
The strain is shown to be one of Penicillium of aspergillus, is named as Penicillium reissue (Penicillium raidrickii) IMB17-034, is preserved in the general microorganism center of China general microbiological culture Collection center in 2019, and has the preservation number of CGMCC No. 17185.
< example 2> fermentation of the fungus IMB17-034(Penicillium raidrickii)
Inoculating the strain spore liquid to a PDA culture medium plate (formula is as follows: 2.0g of glucose, 0.3g of potato extract powder, 18g of agar powder and 100mL of deionized water]Culturing in 28 deg.C constant temperature incubator for 7-14 days, and taking 1cm with sterile iron shovel2The bacteria-containing agar block was inoculated in 100mL of liquid PDB fermentation medium [ formula: 2.0g of glucose, 0.3g of potato extract powder and 100mL of deionized water]Seed solutions were prepared in 500mL Erlenmeyer flasks at 28 ℃ and 200r/min for 5 days of shake culture. Then, the seed solution was inoculated to a rice solid fermentation medium (formula: 100g of rice, 0.3g of peptone and 3.0g of artificial sea salt, and 100mL of deionized water]30 bottles in total, and 30 days of static culture at 28 ℃.
< example 3> extraction of fermentation product and obtaining of extract
Collecting solid fermentation product of strain IMB17-034, adding equal volume of ethyl acetate, ultrasonic extracting for 3 times (each time for 60 min), and recovering solvent under reduced pressure to obtain ethyl acetate extract.
< example 4> isolation, preparation and structural identification of the Compound of formula I
The ethyl acetate fraction was chromatographed on a C18 reverse phase flash column (55 mm. times.400 mm) using a gradient of 10%, 30%, 50%, 70%, 100% methanol in water to give 5 fractions (F1-F5). Separating F3 fraction with 50% methanol by Toyopearl HW-40 gel column chromatography, eluting with 80% methanol to obtain 16 fractions (F)3-1-F3-16). Fraction E3-11HPLC chromatographic separation and purification (Capcell MGII 5 μm, 10 mm. times.250 mm, 30% MeCN,4mL/min) and collection of HRESIMS excimer peak m/z 366.1444 gave lescentex indole A.
A compound of formula I: structural identification of lesinusoindole
White powder, and is easily dissolved in methanol and DMSO. High resolution electrospray mass spectrometry (HRESIMS) showed an excimer peak M/z 366.1444[ M + H ]]+(FIG. 1), nuclear magnetic resonance spectroscopy (NMR) data was combined to determine the molecular formula C20H20O4N3The unsaturation degree was 13. The UV spectrum of the compound of formula I shows maximum absorption peaks at 240, 295nm, revealing the presence of unsaturated structural units in the compound. IR spectra of the compounds were 3353, 1677, 1615cm-1The characteristic absorption peaks of hydroxyl, carbonyl and benzene rings are shown. Process for preparing compounds of formula I1H NMR Spectroscopy (CD)3OD, FIG. 2) shows a set of ortho-disubstituted aromatic conjugated system proton signals delta at low field respectivelyH6.71(d, H-7),7.15(ddd, H-8),6.75(ddd, H-9),7.05(dd, H-10) and a group of mono-substituted benzene ring proton signals deltaH7.07(2H, dd, H-20,24),7.00(2H, t, H-21,23),6.84(tt, H-22), one vicinal oxymethylene proton deltaH5.27(s, H-4). Two amino acids alpha-carbon proton delta are shown in the high field regionH4.38(ddd, H-14) and 4.32(td, H-17) and two sets of methylene signals deltaH2.13(dd, H-13a),1.22(dd, H-13 b); 2.97(dd, H-18a),2.84(dd, H-18 b). In addition, in DMSO-d6Of (2) determination1H NMR can observe 3 active proton signals deltaH5.79(s, OH-12),8.03(s, NH-16) and 6.64(d, NH-5). Process for preparing compounds of formula I13The C NMR spectrum (FIG. 3) and HSQC spectrum show 20 carbon signals, including 2 carbonyl carbons, deltaC 1680(C-15) and 163.4(C-1), 3 being sp2Hybrid quaternary carbon, 1 quaternary carbon with oxygen linkage deltaC76.0(C-12), 12 methine carbons (9 of which are sp2Hybridization, 2 nitrogen-containing methine groups) and 2 methylene carbon signals.
1H-1H COSY spectrum proves that 1 single substituted benzene ring, 1 ortho-disubstituted benzene ring and 2-CHCH exist in the compound shown in the formula I2-4 spin coupling systems (fig. 3). In HMBC spectra, H-7 was observed to be associated with C-9, C-11, H-10 with C-6, C-8, C-12, and H-4 with C-6, C-11, C-12, in combination with the chemical shifts of these carbons, suggesting the presence of an indole unit in the structure. According to C-12 (delta)C76.0), indicating it is an oxygen-linked carbon, presumably linked to a free hydroxyl group. In DMSO-d6OH proton (. delta.) in the HMBC spectra measured in (1)H5.79) have a correlation peak with C-11, C-12, C-13, C-4, demonstrating that OH is attached at C-12. H-18a, H-18b are both related to C-1, C-17 (. delta.)C56.5), C-19, C-20, C-24, indicating the presence of an alpha-phenylalanine residue in the structure. In addition, the alpha-proton H-17 (. delta.) in phenylalanine was also observed in the HMBC spectraH4.32) and another nitrogen-containing methine proton H-14 (. delta.))H4.38) are each respectively associated with C-1 and C-15 (. delta.) (C168.0) and determining that the structure contains a diketopiperazine ring structural unit. H-13a, H-13b are related to HMBC at C-11, C-12, C-14, C-15 and C-4, and the C-14 of the diketopiperazine unit is determined to be connected with the C-12 position of the indole ring through methylene C-13. All the structural units comprise 1 benzene ring, 1 indole ring and 1 diketopiperazine ring which form 12 unsaturations. According to the methine carbon C-4 (. delta.)C101.3), which is presumed to be an azaacetal carbon. According to the molecular formula containing 13 unsaturations and molecular composition, C-4 and N-2 are connected through oxygen atoms to form an oxazine ring, so that the determination of the planar structure of the compound shown in the formula I is completed.
The relative configuration of the compound of formula I was determined by analyzing its ROESY spectrum and 1D NOE spectrum. In the ROESY spectra, correlation peaks were observed for OH-12/H-4, OH-12/H-14, H-4/H-13a, H-14/H-13a, indicating that these protons are located on the same side of the oxazine ring (FIG. 3). In addition, a strong correlation signal was observed for H-10 and H-13b in the ROESY spectra, suggesting that both H-10 and H-13b are located on the other side of the oxazine ring plane. In the 1D NOE spectrum, H-4 and H-17 showed gains when irradiated with H-14, further confirming that H-4, H-14 and H-17 are all on the same side of the plane of the ring. The absolute configuration of the compounds of formula I was determined using the advanced Marfey's reaction. The retention times of the L-FDLA derivatives of the acid hydrolysis products were: phe (m/z 460,37.3 min); the D-FDLA derivative has a respective retention time of Phe (m/z 460,48.4min), indicating that the phenylalanine residue in the compound of formula I is in the L configuration. Accordingly, the absolute configuration of the compound of formula I is identified as 4R,12S,14S, 17S. The compound shown as the formula I has a new structure and is named as Raistrickindiole A.
The physical and chemical data of the rasindole A (1) are white powder, and the rasindole A is easily dissolved in methanol and DMSO. [ alpha ] to]20 D+3.3(c 0.12,MeOH)；UV(MeOH)λmax(logε)240(3.12),295(2.62)nm；ECD(c2.74×10-3M)λmax(△ε)248(+1.21),301(+0.11)nm；IR vmax 3353,2920,1677,1615,1469,1452,and 1070cm-1；1H-NMR(CD3OD,600MHz) and13C NMR(CD3OD,125MHz) data are shown in table 1. HRES-MS M/z 366.1444[ M + H ]]+(C20H20O4N3Theoretical value 366.1448).
TABLE 1 preparation of Raistrickindole A1H and13c NMR data (CD)3OD)
< example 5> test for anti-Hepatitis C Virus (HCV) Activity of Raistrickindole A
1. Experimental Material
Detecting cell strains: huh7.5 human liver cells
Required reagents: eagle's medium (DMEM, Invitrogen, CA, USA), fetal bovine serum, streptomycin qing; RNeasy Mini Kit, VX 95.
2. Experimental methods
(1) The positive drugs and the samples to be tested were diluted as follows:
for HCV assay, 20mM drug stock was diluted to 100. mu.M in DMEM and then serially diluted three times with a minimum concentration of 0.04. mu.M for a total of eight concentration gradients, with three duplicate wells per drug concentration. The highest concentration of the cytotoxicity determination is 200 mu M, the dilution is carried out according to five-fold gradient, the lowest concentration is 0.00256 mu M, the total concentration is eight concentration gradients, and three multiple wells are arranged at each medicine concentration.
anti-HCV activity assay: huh7.5 cells at 3X 104Per cm2Was seeded into 96-well plates. After culturing for 24h, infecting normal Huh7.5 cells with HCV virus supernatant at a virus infection amount of 45 IU/cell, and simultaneously adding corresponding drugs or positive drug control treatment. After 72h of culture, the culture supernatant was aspirated and total cellular RNA was extracted using RNeasy Mini Kit and cellular HCV RNA levels were determined by qRT-PCR. By Reed&The Muench method calculates the median effective concentration (EC 50).
The cytotoxicity detection method comprises the following steps: huh7.5 cells at 3X 104Per cm2The density seeds were cultured in 96-well plates. After 24h of incubation, the culture medium was aspirated, and the cells were treated with 100 μ L of different concentrations of drug solutions and solvent controls. After 72 hours of treatment, 10. mu.L of MTT solution at a concentration of 5. mu.g/mL was added to each well, and culture was continued after gentle shaking. After 4h, the culture medium was aspirated, and 100. mu.L of DMSO was added to each well, followed by shaking for 10 minutes to sufficiently dissolve formazan crystals. The absorbance at 570nm was then measured at a reference wavelength of 630 nm. Calculate half the Cytotoxic Concentration (CC)50)。
3. Results of the experiment
anti-HCV activity of rassin indole a (raidrickindole a) is shown in table 2. At present, most of the anti-HCV active compounds found in natural products have EC50 values at micromolar levels. Although the inhibitory activity of the leisindole A against HCV is lower than that of the positive drug VX-950, it is comparable to that of Penicillium herquei Penicillium peniciherquamide C [ Nishikori, et al.J.Nat.Prod.2016,79(2), 442-. Because the rasindole A is derived from a microbial fermentation natural product, is easy to obtain, environment-friendly and low in pollution compared with a synthetic product, and can act on a new target, the rasindole A has an application prospect of being developed into an anti-HCV medicament.
TABLE 2 Res indole (raidrickindole A) anti-HCV viral Activity
Sequence listing
<110> institute of medical and Biotechnology of Chinese academy of medical sciences
<120> marine penicillium for preparing anti-hepatitis C virus active compound lesindolone
<140>
<141>
<160> 2
<210> 1
<211> 600
<212> DNA
<213> Penicillium raistrickii IMB17-034
<220>
<223> ITS
<400> 1
aatttctgat ttcgtagtga cctgcggaag gatcattacc gagtgagggc cctctgggtc 60
caacctccca cccgtgttta ttataccttg ttgcttcggc gggcccgccg tatggccgcc 120
ggggggcttc tgcccccggg cccgcgcccg ccgaagacat ctcgaactct gtctgaagat 180
tgtagtctga gtaaaaatat aaattattta aaactttcaa caacggatct cttggttccg 240
gcatcgatga agaacgcagc gaaatgcgat acgtaatgtg aattgcagaa ttcagtgaat 300
catcgagtct ttgaacgcac attgcgccct ctggtattcc ggagggcatg cctgtccgag 360
cgtcattgct gccctcaagc acggcttgtg tgttgggccc cgtcctccga tcccggggga 420
cgggcccgaa aggcagcggc ggcaccgcgt ccggtcctcg agcgtatggg gctttgtcac 480
ccgctctgta ggcccggccg gcgcttgccg atcaaccaaa tttttatcca ggttgacctc 540
ggatcaggta gggatacccg ctgaacttaa gcatatcaat aaaagcccgg aggaatctaa 600
<210> 2
<211> 561
<212> DNA
<213> Penicillium raistrickii IMB17-034
<220>
<223> 18S rDNA
<400> 2
tttgtagtta caaaaagtgt ctcaaagatt aagccatgca tgtctaagta taagcaactt 60
gtactgtgaa actgcgaatg gctcattaaa tcagttatcg tttatttgat agtaccttac 120
tacatggata cctgtggtaa ttctagagct aatacatgct aaaaaccccg acttcaggaa 180
ggggtgtatt tattagataa aaaaccaacg cccttcgggg ctccttggtg aatcataata 240
acttaacgaa tcgcatggcc ttgcgccggc gatggttcat tcaaatttct gccctatcaa 300
ctttcgatgg taggatagtg gcctaccatg gtggcaacgg gtaacgggga attagggttc 360
gattccggag agggagcctg agaaacggct accacatcca aggaaggcag caggcgcgca 420
aattacccaa tcccgatacg gggaggtagt gacaataaat actgatacgg ggctcttttg 480
ggtctcgtaa ttggaatgag aacaatttaa atcccttaac gaggaacaat tggagggcaa 540
gtctgggccc agccagccaa a 561
Claims (1)
1. A marine fungus strain for preparing the compound shown in the formula I is characterized in that the strain is penicillium limacinum IMB17-034 with the preservation number of CGMCC No.17185,
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| CN102030753A (en) * | 2010-11-23 | 2011-04-27 | 沈阳药科大学 | Prenylated indole alkaloids and preparation method and application thereof |
| CN103288847A (en) * | 2013-06-09 | 2013-09-11 | 滨州医学院 | Preparation method and use of compound comprising benzo spiroketal and benzo bridged cycloketal |
| KR20130139199A (en) * | 2012-06-12 | 2013-12-20 | 동국대학교 산학협력단 | Indole compound with selective inhibitory activity of genome replication of hcv, method for preparing the same, and pharmaceutical composition comprising the same for preventing or treating hepatitis c |
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| CN103145617B (en) * | 2013-03-01 | 2016-04-06 | 中国科学院昆明植物研究所 | Phenanthridines analog derivative and pharmaceutical composition thereof and its preparation method and application |
| WO2017136739A1 (en) * | 2016-02-04 | 2017-08-10 | The Johns Hopkins University | Glucose conjugates of triptolide, analogs and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102030753A (en) * | 2010-11-23 | 2011-04-27 | 沈阳药科大学 | Prenylated indole alkaloids and preparation method and application thereof |
| KR20130139199A (en) * | 2012-06-12 | 2013-12-20 | 동국대학교 산학협력단 | Indole compound with selective inhibitory activity of genome replication of hcv, method for preparing the same, and pharmaceutical composition comprising the same for preventing or treating hepatitis c |
| CN103288847A (en) * | 2013-06-09 | 2013-09-11 | 滨州医学院 | Preparation method and use of compound comprising benzo spiroketal and benzo bridged cycloketal |
Non-Patent Citations (2)
| Title |
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| Raistrickindole A, an Anti-HCV Oxazinoindole Alkaloid from Penicillium raistrickii IMB17-034;Jiao Li等;《J Nat Prod》;20190423;第82卷(第5期);第1391-1395页 * |
| 微生物转化法合成3-氧代齐墩果酸及其条件优化;刘婷等;《化学与生物工程》;20100325;第27卷(第3期);第55-59页 * |
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