Goldamycin A derivative as well as preparation and application thereof

Abstract

The invention discloses an aureomycin A derivative as well as preparation and application thereof. The structural general formula of the compound is shown as a formula I. The compound is simple in preparation method and high in yield. The aureomycin A derivative has good biological activity and excellent anti-tumor activity and antibacterial activity, and the application prospect of the aureomycin A derivative in the aspects of anti-cancer and antibacterial treatment is expanded. # imgabs0 #

Description

(I) Technical field

[0001] The invention belongs to the field of drug chemical synthesis and drug therapy, and particularly relates to a chrysomycin A derivative and a preparation method and application thereof. (II) Background technology

[0002] Chlorophycin A is a naturally occurring alkaloid that has been widely studied and applied in the fields of antibacterial and anti-tumor. However, traditional chlorophycin A has some limitations in its pharmaceutical application, such as low bioavailability and unstable efficacy.

[0003] In order to solve the above problems, it is necessary to find a derivative that can improve the properties of the drug and enhance the effect of treating antibacterial and anti-tumor diseases. (III) Summary of the invention

[0004] The purpose of the present invention is to provide a chrysogenycin A derivative and its preparation and application. The chrysogenycin A derivative has good biological activity, excellent antitumor activity and antibacterial activity, has broader application prospects in the treatment of antibacterial and antitumor diseases, provides new possibilities and opportunities for treatment and research in the medical field, and solves the limitations of traditional chrysogenycin A in clinical applications, such as low bioavailability and limited therapeutic effect.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] The present invention provides a chrysomycin A derivative represented by formula (I):

[0007]

[0008] In the formula I, the R group is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, pyridyl, benzofuranyl, benzothienyl, benzopyrrolyl, naphthyl, propenyl, dimethylamino, trimethylamino, methoxyphenyl, trifluoromethylphenyl, difluoromethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, nitrophenyl, cyanophenyl, trifluoromethoxyphenyl, biphenyl, dimethoxyphenyl, trimethoxyphenyl, difluorophenyl or trifluorophenyl.

[0009] As a preferred embodiment, the R group is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, benzofuranyl, benzothienyl, benzopyrrolyl, naphthyl, propenyl, dimethylamino, trimethylamino, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-trifluoromethoxyphenyl, 3- -trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-biphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4,5-trifluorophenyl; more preferably cyclopropyl, cyclobutyl, cyclopentyl, thienyl, furyl, pyridyl, naphthyl, 2,6-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-biphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl.

[0010] The present invention also provides a method for preparing the chrysomycin A derivative, which comprises the following steps:

[0011] In the presence of a diluent, an acid-binding agent and a catalyst, the chrysomycin A shown in formula II reacts with the compound shown in formula III at 0-50° C. for 10-40 hours, and the chrysomycin A derivative shown in formula I is obtained by purification and separation; the catalyst is 4-dimethylaminopyridine or 4-pyrrolidinylpyridine; the diluent is an inert organic solvent; and the acid-binding agent is an organic base or an inorganic base;

[0012]

[0013] In formula III, the R group is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, pyridyl, benzofuranyl, benzothienyl, benzopyrrolyl, naphthyl, propenyl, dimethylamino, trimethylamino, methoxyphenyl, trifluoromethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, nitrophenylcyanophenyl, trifluoromethoxyphenyl, biphenyl, dimethoxyphenyl, trimethoxyphenyl, difluorophenyl, and trifluorophenyl.

[0014] All of the above intermediates or target compounds can be purified by conventional separation techniques such as recrystallization or chromatography.

[0015] Further, the diluent is selected from one of the following: benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether; more preferably, the diluent is dichloromethane, benzene, toluene or tetrahydrofuran.

[0016] Furthermore, the acid binding agent is pyridine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene or diazabicycloundecene, sodium hydroxide, sodium ethoxide, trimethylamine or triethylamine; more preferably triethylamine.

[0017] Furthermore, the catalyst is 4-dimethylaminopyridine.

[0018] Further, the reaction temperature can be carried out in a wide range according to the selection of the diluent, preferably at 0-30°C for 24 hours. The ratio of the amount of the chrysomycin A shown in formula II to the compound shown in formula III is 1:1-1.5, preferably 1:1; the volume of the diluent is 1-5 mL / mmol, preferably 3 mL / mmol, based on the amount of the compound shown in formula II; the ratio of the amount of the chrysomycin A shown in formula II to the acid binding agent is 1:1-3, preferably 1:2; the ratio of the amount of the chrysomycin A shown in formula II to the catalyst is 1:0.01-0.5, preferably 1:0.2.

[0019] Furthermore, the preparation method is carried out according to the following steps: in a three-necked flask equipped with a thermometer, add chrysogenycin A shown in formula II and a diluent, stir and cool to 0°C, add an acid binding agent dropwise, and control the dropping speed to keep the temperature at 0°C; after the dropwise addition is completed, stir for 30 minutes, maintain the system temperature at 0°C, add a catalyst, and stir for 30 minutes; maintain the system temperature at 0°C, add the compound shown in formula III, and after the addition is completed, slowly warm to room temperature, react at 25°C for 18 to 24 hours, filter the reaction solution with a qualitative filter paper with a pore size of 50 microns, collect the filtrate, and dry it overnight with anhydrous magnesium sulfate; filter out the desiccant with filter paper and evaporate the solvent to obtain a light yellow solid; after the light yellow solid is dissolved in ethyl acetate, load it on a silica gel chromatography column, and use a volume ratio of 5:1 petroleum ether: acetic acid Ethyl ester is used as the eluent, the elution rate is 1 / 10 column volume per minute, 5 column volumes are eluted, petroleum ether: ethyl acetate in a volume ratio of 1:1 is used as the developing solvent for thin layer chromatography monitoring, the effluent with Rf of 0.2 is collected, and the solvent is evaporated to obtain the chrysomycin A derivative shown in formula I; the acid binding agent is triethylamine; the diluent is dichloromethane; the catalyst is 4-dimethylaminopyridine; the ratio of the amount of chrysomycin A shown in formula II to the compound shown in formula III is 1:1, the volume of the diluent is 3 mL / mmol based on the amount of chrysomycin A shown in formula II, the ratio of the amount of chrysomycin A shown in formula II to the amount of the acid binding agent is 1:2; the ratio of the amount of chrysomycin A shown in formula II to the catalyst is 1:0.2.

[0020] The present invention also provides an application of the chrysogenycin A derivative in the preparation of an anti-tumor drug, wherein the tumor includes a human breast cancer adriamycin-resistant cell line MCF-7 / ADR; and the anti-tumor drug also includes a chrysogenycin A derivative hydrochloride.

[0021] The present invention also provides an application of the chrysomycin A derivative in the preparation of an antibacterial drug, wherein the bacteria include Staphylococcus aureus, Escherichia coli, Salmonella, Enterococcus faecalis or methicillin-resistant Staphylococcus aureus. The antibacterial drug also includes chrysomycin A derivative hydrochloride.

[0022] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0023] The present invention provides a chrysogenycin A derivative, which has a simple preparation method, mild reaction conditions, high yield, and good solubility. The chrysogenycin A derivative has good biological activity, and the chrysogenycin A derivative has significant tumor cell growth inhibition activity. At a concentration of 5 μM, the growth inhibition rate of some derivatives on tumor cells (human breast cancer cell line MCF-7, human epidermal cancer cell A431) is greater than 85%, which is better than the control drug doxorubicin (the inhibition rate on MCF-7 is 72%, and the inhibition rate on A431 is 85%), and has good application prospects; the chrysogenycin A derivative has good anti-Gram-positive bacteria activity, and the growth inhibition rate of some derivatives on Gram-positive bacteria (Enterococcus faecalis, methicillin-resistant Staphylococcus aureus) is greater than 90%, which is equivalent to the activity of the control drug ciprofloxacin. It can be seen that the chrysogenycin A derivative provided by the present invention shows good growth inhibition activity on cancer cells and bacteria, expanding the application prospects of the chrysogenycin A structure in anti-tumor and anti-bacterial aspects. (IV) Description of the drawings

[0024] Figure 1 It is the hydrogen nuclear magnetic resonance spectrum of the compound represented by formula Ⅰ-1. (V) Specific implementation methods

[0025] The present invention is further explained below in conjunction with specific examples, but the specific examples do not limit the present invention in any way. Unless otherwise specified, the reagents and methods involved in the examples are all commonly used reagents and methods in the art.

[0026] The room temperature described in the present invention refers to 25-30°C.

[0027] Example 1. Preparation of Compound Ⅰ-1

[0028]

[0029] Add 7.5mmol chrysotoxomycin A (Ⅱ) and 22.5mL dichloromethane to a 50mL three-necked flask equipped with a thermometer, stir and cool to 0℃, add 15mmol triethylamine dropwise, and control the dropping speed to keep the temperature at 0℃. After the addition is completed, stir for 30min, maintain the system temperature at 0℃, add 1.5mmol 4-dimethylaminopyridine, and stir for 30min; maintain the system temperature at 0℃, add 7.5mmol benzoyl chloride (Ⅲ-1), add dropwise, slowly warm to room temperature, and react at 25℃ for 20h. Filter the reaction solution with qualitative filter paper with a pore size of 50 microns, collect the filtrate, and dry it overnight with anhydrous magnesium sulfate. After filtering out the desiccant, evaporate the solvent to obtain a light yellow solid. All the light yellow solids were dissolved with 0.1 mL of ethyl acetate and then loaded onto a silica gel chromatography column (silica gel 200-300 mesh, column height 10 cm, diameter 2 cm), with petroleum ether: ethyl acetate in a volume ratio of 5:1 as the eluent, the elution rate was 1 / 10 of the column volume per minute, the elution volume was 5 column volumes, and V petroleum ether / V ethyl acetate = 1 / 1 was used as the developing solvent for thin layer chromatography monitoring, and the effluent with Rf of 0.2 was collected. After the solvent was evaporated at 80°C, 7.4 mmol of the target compound Ⅰ-1 was obtained. The hydrogen nuclear magnetic resonance spectrum is attached Figure 1 .

[0030] According to the similar method of Example 1, R in the compound shown in III is replaced as shown in Table 1 to obtain the corresponding compound shown in Formula I. The appearance, yield and high-resolution mass spectrum data of the above compounds are listed in Table 1, and the nuclear magnetic hydrogen spectrum results are listed in Table 2. It can be seen from the above that the structures of the above compounds are correct and they are all compounds shown in Formula I.

[0031] Table 1 Physicochemical constants and high resolution mass spectrometry data of the compounds represented by formula I

[0032] serial number R Appearance Yield (%) <![CDATA[MS / ESI([M+Na] + )]]> Ⅰ-1 Cyclopropyl Yellow solid 73 599.1884 Ⅰ-2 Cyclobutyl Yellow solid 82 613.2043 Ⅰ-3 Cyclopentyl Yellow solid 66 627.2202 Ⅰ-4 Thienyl Yellow solid 71 641.1455 Ⅰ-5 Furanyl Yellow solid 69 625.1684 Ⅰ-6 Pyridyl Yellow solid 72 636.1842 Ⅰ-7 Naphthyl Yellow solid 75 685.2040 Ⅰ-8 2,6-Difluorophenyl Yellow solid 79 671.1700 Ⅰ-9 2-Fluorophenyl Yellow solid 74 653.1791 Ⅰ-10 3-Fluorophenyl Yellow solid 69 653.1793 Ⅰ-11 4-Fluorophenyl Yellow solid 70 653.1811 Ⅰ-12 2-Chlorophenyl Yellow solid 68 669.1513 Ⅰ-13 3-Chlorophenyl Yellow solid 73 669.1509 Ⅰ-14 4-Chlorophenyl Yellow solid 71 669.1514 Ⅰ-15 4-Iodophenyl Yellow solid 75 761.0853 Ⅰ-16 4-Biphenyl Yellow solid 80 711.2200 Ⅰ-17 2-Methoxyphenyl Yellow solid 82 665.1991 Ⅰ-18 3-Methoxyphenyl Yellow solid 73 665.1993 Ⅰ-19 4-Methoxyphenyl Yellow solid 76 665.1989 Ⅰ-20 4-Trifluoromethylphenyl Yellow solid 75 703.1762

[0033] Table 2 H NMR data of the compound represented by formula I

[0034]

[0035]

[0036]

[0037] Example 2 Anticancer activity of chrysogenycin A derivatives represented by formula I

[0038] Cell lines: human breast cancer cell line MCF-7, human epidermal carcinoma cell line A431.

[0039] Test compound testing concentration: 5 μM.

[0040] Positive control drug: doxorubicin.

[0041] Experimental method: The cell proliferation activity of the compounds was tested using the MTT (methyl thiazolyl tetrazolium) method.

[0042] MCF-7 or A431 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2 saturated humidity. Cells in the logarithmic growth phase were taken and cultured at 1×10 5 / mL density was inoculated in a 96-well culture plate, 100μL per well, and cultured at 37℃, 5% CO2 saturated humidity, and divided into blank control group, test compound group, and positive control drug group. The test compound and positive control drug were prepared into a 10mM solution with dimethyl sulfoxide (DMSO) for standby use. Different test compound solutions were added to the test compound group and diluted with RPMI 1640 medium containing 10% fetal bovine serum, and the final concentration was 5μmol / L; the positive control drug group was added with positive control drug solution, diluted with RPMI 1640 medium containing 10% fetal bovine serum, and the final concentration was 5μmol / L; the blank control group was given an equal volume of PBS. After 48 hours of culture, MTT working solution was added, and the culture solution was removed after 4 hours. 100μL DMSO was added to each well to dissolve, and then the absorbance was read at a wavelength of 570nm on an ELISA reader to calculate the effect of the compound on cell survival rate.

[0043] Cell survival rate = (average OD value of experimental group / average OD value of control group) × 100%

[0044] The cytotoxicity of the test compounds on MCF-7 or A431 cells was determined by MTT method, and the results are shown in Table 3. The data show that the chrysogenycin A derivatives shown in Formula I have significant tumor cell growth inhibitory activity, and most of the derivatives are superior to the control drug doxorubicin, and have good application prospects.

[0045] Table 3 Growth inhibition rate of MCF-7 and A431 cells at 5 μM test concentration of the compounds of formula I

[0046]

[0047]

[0048] Example 3 Antibacterial activity of the chrysomycin A derivatives represented by formula I.

[0049] Test strains: Enterococcus faecalis (CICC20419), Escherichia coli (ATCC43896), methicillin-resistant Staphylococcus aureus (ATCC29213), Salmonella (ATCC36400), and Staphylococcus argenteus (DSM28299).

[0050] Sample test concentration: 10 μM.

[0051] Positive control drug: ciprofloxacin.

[0052] Experimental method: The antibacterial activity of the compounds was tested using the enzyme marker method.

[0053] 1. Preparation before the experiment:

[0054] (1) Cleaning of instruments: Clean and wrap test tubes, watch glasses, conical flasks, pipette tips and other experimental instruments, sterilize them by high pressure sterilization at 121°C for 20 min, and dry them in an oven for later use.

[0055] (2) Preparation of MHⅡ solid culture medium: Weigh 0.4g beef extract and 3.4g LB agar into a 250mL conical flask, and add 200mL pure water to dissolve. Then add 3.5g acid-hydrolyzed casein and 0.3g soluble starch and continue to dissolve. Add 1.2g yeast extract and dissolve with ultrasound. Autoclave the culture medium at 121℃ for 20 minutes. After the agar cools slightly, pour it into a plate (15-20mL per plate) in the clean bench. After solidification, put it in a 37℃ constant temperature incubator overnight for sterility inspection. If it passes the test, put it in the clean bench for use.

[0056] (3) Preparation of MHⅡ liquid culture medium: Weigh 0.4g beef extract powder and 3.5g acid-lysed casein into a 250mL conical flask, add 200mL pure water to dissolve, then add 0.3g soluble starch and continue to dissolve. Add 1.2g yeast extract and dissolve with ultrasound. Prepare two bottles of 250mL liquid culture medium in this way and divide them into four 250mL conical flasks, 100mL in each conical flask. Sterilize the prepared culture medium in an autoclave at 121℃ for 20min. Let it cool slightly and place it on a clean bench for use.

[0057] (4) Preparation and storage of drug stock solution: The chrysomycin A derivative represented by formula I and ciprofloxacin prepared in Example 1 were diluted to a concentration of 10 mM using DMSO.

[0058] (5) Preparation of bacterial solution: Select the test strains (Enterococcus faecalis, Escherichia coli, methicillin-resistant Staphylococcus aureus, Salmonella, and Staphylococcus aureus), streak and culture on MHⅡ solid agar plates for 16 to 24 h. The next day, select a single colony and inoculate it into LB liquid culture medium. Culture it in a shaking incubator at 37°C for 16 to 24 h to prepare the test bacterial solution.

[0059] 2. Determination of antibacterial rate:

[0060] (1) Dilution of bacterial solution: Use a pipette to draw 1 μL of bacterial solution from the shaker culture and add it to 100 mL of sterilized LB liquid medium and shake well to obtain a 100,000-fold diluted bacterial solution.

[0061] (2) Add 1 μL of ciprofloxacin stock solution to B2, C2, and D2 of a 96-well plate (row numbers 1-12, column numbers A, B, C, D, E, and F), add 1 μL of the stock solution of the chrysotoxomycin A derivative of formula Ⅰ-1 to B3, C3, and D3 of the 96-well plate, and so on, add 1 μL of the stock solution of the chrysotoxomycin A derivative of formula Ⅰ-2 to Ⅰ-20 to the remaining wells of the 96-well plate, and set up three parallel controls. Then, use a pipette to draw 199 μL of the diluted bacterial solution and add it to the 2-11 columns of the B, C, and D rows of the 96-well plate. Shake slightly and incubate in a 37°C incubator for 16-24 hours.

[0062] (3) Take out the 96-well plate, turn on the microplate reader, and measure the OD 600 , calculate the antibacterial rate (Note: 3 parallel groups were made for each sample). The results are shown in Table 4.

[0063] Inhibition rate calculation formula = (OD 600 control-OD 600 ) / OD 600 control×100%.

[0064] Table 4 Inhibitory activity of the compound represented by formula I at a concentration of 10 μM against Salmonella, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus

[0065]

[0066] As can be seen from Table 4, the compounds of Formula I generally have good anti-Gram-positive bacteria activity, and some derivatives have a growth inhibition rate of more than 90% on Gram-positive bacteria (Enterococcus faecalis, methicillin-resistant Staphylococcus aureus), which is equivalent to the activity of the control drug ciprofloxacin, and has good application prospects.

Claims

1. A chrysomycin A derivative represented by formula I, In the formula I, the R group is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, pyridyl, benzofuranyl, benzothienyl, benzopyrrolyl, naphthyl, propenyl, dimethylamino, trimethylamino, methoxyphenyl, trifluoromethylphenyl, difluoromethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, nitrophenyl, cyanophenyl, trifluoromethoxyphenyl, biphenyl, dimethoxyphenyl, trimethoxyphenyl, difluorophenyl or trifluorophenyl.

2. The phenylnaphthalene compound according to claim 1, characterized in that: The R group is cyclopropyl, cyclobutyl, cyclopentyl, thienyl, furyl, pyridyl, naphthyl, 2,6-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-biphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl.

3. A method for preparing the chrysomycin A derivative according to claim 1, characterized in that: The method comprises the following steps: In the presence of a diluent, an acid-binding agent and a catalyst, the chrysomycin A shown in formula II reacts with the compound shown in formula III at 0-50° C. for 10-40 hours, and the chrysomycin A derivative shown in formula I is obtained by purification and separation; the catalyst is 4-dimethylaminopyridine or 4-pyrrolidinylpyridine; the diluent is an inert organic solvent; and the acid-binding agent is an organic base or an inorganic base; In formula III, the R group is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, pyridyl, benzofuranyl, benzothienyl, benzopyrrolyl, naphthyl, propenyl, dimethylamino, trimethylamino, methoxyphenyl, trifluoromethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, nitrophenylcyanophenyl, trifluoromethoxyphenyl, biphenyl, dimethoxyphenyl, trimethoxyphenyl, difluorophenyl, and trifluorophenyl.

4. The preparation method according to claim 3, characterized in that: The diluent is selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether; The acid binding agent is pyridine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene, diazabicycloundecene, sodium hydroxide, sodium ethoxide, trimethylamine or triethylamine.

5. The preparation method according to claim 3, characterized in that: The ratio of the amount of chrysocycline A shown in formula II to the amount of the compound shown in formula III is 1:1-1.5, the volume of the diluent is 1-5mL / mmol based on the amount of the compound shown in formula II, the ratio of the amount of chrysocycline A shown in formula II to the amount of the acid binding agent is 1:1-3, and the ratio of the amount of the compound shown in formula II to the amount of the catalyst is 1:0.01-0.

5.

6. The preparation method according to claim 3, characterized in that: The method is carried out according to the following steps: adding chrysomycin A shown in formula II and a diluent to a three-necked flask equipped with a thermometer, stirring and cooling to 0°C, dripping an acid-binding agent, and controlling the dripping speed to keep the temperature at 0°C; stirring for 30 minutes after the dripping is completed, maintaining the system temperature at 0°C, adding a catalyst, and stirring for 30 minutes; maintaining the system temperature at 0°C, adding the compound shown in formula III, and after the addition is completed, slowly warming to room temperature, reacting at 25°C for 18 to 24 hours, filtering the reaction solution with a qualitative filter paper with a pore size of 50 microns, collecting the filtrate, and drying it overnight with anhydrous magnesium sulfate; filtering with a filter paper After filtering out the desiccant with paper, the solvent was evaporated to obtain a light yellow solid; the light yellow solid was dissolved with ethyl acetate and loaded onto a silica gel chromatography column, and petroleum ether:ethyl acetate in a volume ratio of 5:1 was used as the eluent, and the elution rate was 1 / 10 of the column volume per minute, and 5 column volumes were eluted, and thin layer chromatography monitoring was performed with petroleum ether:ethyl acetate in a volume ratio of 1:1 as the developing solvent, and the effluent with Rf of 0.2 was collected, and the solvent was evaporated to obtain the chrysogenycin A derivative shown in formula I; the acid binding agent is triethylamine; the diluent is dichloromethane; and the catalyst is 4-dimethylaminopyridine; The ratio of the amount of chrysomecin A shown in formula II to the compound shown in formula III is 1:1, the volume of the diluent is 3 mL / mmol based on the amount of chrysomecin A shown in formula II, the ratio of the amount of chrysomecin A shown in formula II to the amount of the acid binding agent is 1:2; the ratio of the amount of chrysomecin A shown in formula II to the amount of the catalyst is 1:0.

2.

7. Use of the chrysomycin A derivative according to claim 1 in the preparation of anti-tumor drugs.

8. The use according to claim 7, characterized in that The tumors include human breast cancer cell line MCF-7 and human epidermal cancer cell line A431.

9. Use of the chrysomycin A derivative according to claim 1 in the preparation of antibacterial drugs.

10. The use according to claim 9, characterized in that The bacteria include Staphylococcus aureus, Escherichia coli, Salmonella, Enterococcus faecalis or methicillin-resistant Staphylococcus aureus.

Images