CN112741831A - Application of polycyclic polyketide in preparation of novel coronavirus resistant drugs - Google Patents

Application of polycyclic polyketide in preparation of novel coronavirus resistant drugs Download PDF

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CN112741831A
CN112741831A CN202010799867.3A CN202010799867A CN112741831A CN 112741831 A CN112741831 A CN 112741831A CN 202010799867 A CN202010799867 A CN 202010799867A CN 112741831 A CN112741831 A CN 112741831A
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CN112741831B (en
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叶文才
王英
胡利军
唐维
李药兰
张冬梅
范春林
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Jinan University
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Abstract

The invention discloses an application of polycyclic polyketone compounds in preparing medicaments for resisting novel coronavirus SARS-CoV-2. The polyketide discovered by the invention has an inhibition effect on novel coronavirus SARS-CoV-2 at a cellular level, can obviously reduce the virus price of the virus in cells, inhibits cytopathic effect induced by the virus, and has concentration dependence. In addition, the polyketide has a chemical structure type different from that of Reidesvir and chloroquine phosphate, and is expected to be developed into a novel medicine for resisting novel coronavirus SARS-CoV-2. Therefore, the compounds have good application prospect in treating related diseases caused by the infection of the novel coronavirus SARS-CoV-2.

Description

Application of polycyclic polyketide in preparation of novel coronavirus resistant drugs
Technical Field
The present invention relates to a class of drugs for the treatment and prevention of viral infections. More particularly, the invention relates to application of polycyclic polyketides in preparation of medicines for resisting novel coronavirus SARS-CoV-2.
Background
2019A novel coronavirus (SARS-CoV-2) is a RNA virus with envelope and linear single-strand positive strand genome, mainly causes pneumonia and severe acute respiratory syndrome (COVID-19), and can be accompanied by renal failure and even death. SARS-CoV-2 is primarily transmitted via respiratory droplets or direct contact with secretions, and evidence also suggests that it can be transmitted via aerosol and fecal-oral routes, with rapid and widespread transmission, a serious threat to human health and life. At present, no preventive vaccine aiming at SARS-CoV-2 infection exists, and most vaccines are still in the clinical research stage. In addition, there is a clinical lack of specific anti-SARS-CoV-2 drugs. The interferon, the krestin and some traditional Chinese medicine formulas which are reported clinically have the treatment effect on the pneumonia caused by the novel coronavirus, but the antiviral effect of the medicines still needs to be further confirmed. The documents report that chloroquine phosphate, Reidcisvir and the like have the effect of resisting new coronavirus SARS-CoV-2. At present, the nucleoside analogue Reidcvir is the only approved anti-SARS-CoV-2 medicine in the world, and shows good anti-SARS-CoV-2 activity in vitro and in vivo animal models. However, the results of clinical trial studies in China show that the treatment effect on patients with severe COVID-19 is not obvious, and the WHO recommends that the therapeutic effect of Reidesciclovir should be continuously evaluated. Therefore, the research and development of new antiviral drugs for treating and preventing the infection of the novel coronavirus SARS-CoV-2 are of great significance for reducing the severe rate and the death rate of patients with COVID-19, and blocking the spread and reoccurrence of epidemic situations.
Disclosure of Invention
The invention aims to provide a polycyclic polyketone compound with the effect of resisting novel coronavirus SARS-CoV-2. The activity test result shows that the polyketides have an inhibitory effect on novel coronavirus SARS-CoV-2 at a cellular level, can obviously reduce the toxic value of the virus in cells, inhibit cell pathological changes induced by the virus, and have concentration dependence. In addition, the polyketide has a chemical structure type different from that of Reidesvir and chloroquine phosphate, and is expected to be developed into a novel medicine for resisting novel coronavirus SARS-CoV-2.
In order to achieve the purpose, the invention is realized by the following scheme:
the invention provides an application of polyketone compounds with a structure shown in a formula I or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof in preparing novel coronavirus resistant medicines:
Figure DEST_PATH_IMAGE001
in the formula:
R1is selected from C1~C6Alkyl radical, C3~C6Cycloalkyl or aryl;
R2and R3Independently selected from a hydrogen atom or-C (O) R6；
R4And R5Independently selected from hydrogen atom, C1~C6Alkyl, -C (O) R6or-S (O)mR6；
R6Selected from hydrogen atoms, substituted or unsubstituted C1~C12Alkyl, substituted or unsubstituted C3~C6Cycloalkyl or substituted or unsubstituted aryl;
m is 1 or 2;
wherein each substitution independently refers to substitution by a substituent selected from the group consisting of: halogen, hydroxy, amino, C1~C3Alkyl radical, C1~C3Alkoxy, -NH (C)1~C3Alkyl), -N (C)1~C3Alkyl) (C1~C3Alkyl), -C (= O) (C)1~C3Alkyl groups).
In a preferred embodiment of the present invention, the compound represented by the general formula I is characterized in that R is3The polyketide is a hydrogen atom, and has a structural formula shown in a general formula II or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof:
Figure DEST_PATH_IMAGE002
；
wherein: r1、R2、R4And R5As defined in claim 1.
In a preferred embodiment of the present invention, the compounds of formula III include, but are not limited to:
Figure DEST_PATH_IMAGE003
in another preferred embodiment of the present invention, characterized in that R is2The polyketide is a hydrogen atom, and has a structural formula shown in a general formula III or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof:
Figure DEST_PATH_IMAGE004
wherein: r1、R3、R4And R5As defined in claim 1.
In a preferred embodiment of the present invention, the compounds of formula IV include, but are not limited to:
Figure DEST_PATH_IMAGE005
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE007
Figure DEST_PATH_IMAGE008
the invention relates to a pharmaceutical composition, which contains polyketone compounds shown in general formulas I, II and III or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof with therapeutically effective dose, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention relates to application of polyketone compounds shown in general formulas I, II and III, or pharmaceutically acceptable salts thereof, or stereoisomers thereof or prodrug molecules thereof containing therapeutically effective dose or a pharmaceutical composition according to claim 6 in preparing a medicament for resisting novel coronavirus SARS-CoV-2.
The invention relates to application of polyketone compounds shown in general formulas I, II and III, or pharmaceutically acceptable salts thereof, stereoisomers thereof or prodrug molecules thereof or a pharmaceutical composition according to claim 6 containing therapeutically effective dose in preparing medicaments for treating diseases such as pneumonia caused by novel coronavirus SARS-CoV-2.
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1~C6Alkyl radical "middle" C1~C6The definition of "includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. For example, "C1~C6Alkyl "specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "alkoxy" refers to a group having the structure-O-alkyl, such as-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH(CH3)2、-OCH2CH2CH2CH3、-OCH(CH3)2And the like. The term "aryl" includes, but is not limited to: imidazolyl, triazolyl, pyranylOxazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"prodrug" means a prodrug that is converted in vivo to the structure of the compounds referred to herein and pharmaceutically acceptable salts thereof.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Drawings
FIG. 1 inhibition of SARS-CoV-2 nucleic acid levels by Compound 13
FIG. 2 inhibition of SARS-CoV-2 nucleoprotein expression level by Compound 13
Detailed Description
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. The NMR was measured by using a Bruker AVANCE-300, Bruker AVANCE-400, Bruker AVANCE-500 or Bruker AVANCE-600 nuclear magnetic spectrometer with deuterated dimethyl sulfoxide (DMSO-d 6 ) Deuterated chloroform (CDCl)3) Deuterated methanol(CD3OD), internal standard Tetramethylsilane (TMS).
MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), carbofuran, Annage, Darrill Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the embodiment, no special description is provided, and the reaction temperature is room temperature and is 20-30 ℃.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for separation and purification of compounds, and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane system, G: ethyl acetate/dichloromethane/n-hexane, H: ethyl acetate/dichloromethane/acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
Specific compounds prepared in the following examples include, but are not limited to, those shown in tables 1-25 above.
Example 1
Preparation of 6, 8-hydroxy-5- (3-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (1)
Figure DEST_PATH_IMAGE009
First step of
Phloroglucinol 26a (2.5 g, 20 mmol) was dissolved in nitromethane solution at room temperature, anhydrous aluminum trichloride (10.7 g, 80 mmol) and isobutyryl chloride (2.3 g, 22 mmol) were added successively, and the temperature was raised to reflux. After 12 hours of reaction, the reaction mixture was slowly poured into ice water, and a saturated sodium potassium tartrate solution (100 mL) was added thereto and stirred vigorously. The reaction mixture was extracted 3 times with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The crude product was isolated and purified by silica gel column chromatography to give compound 26c (3.6 g, 85% yield).
Second step of
Compound 26c (2.1 g, 10 mmol) was dissolved in MeOH (30 mL) at room temperature and NaOMe (5 mmol/mL, 9 mL, 45 mmol) in MeOH was added. After reacting at room temperature for 10min, adding methyl iodide (3.1 mL, 50 mmol) into the reaction system, heating to 55 ℃, reacting for 15 min, cooling to 0 ℃, and acidifying with 1N HCl. The reaction solution was extracted three times with ethyl acetate (3X 10 mL), and the organic phases were combined and washed with saturated NaCl solution (5 mL). After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The crude product was isolated and purified by silica gel column chromatography to give 26d (2.4 g, 91% yield) as a yellow oil.
The third step
The compound 26d (2.4 g, 9.1 mmol) was dissolved in tetrahydrofuran solution and after dropping to-78 ℃, diisopropylaluminum hydride was added dropwise. After 2 hours of reaction, the reaction was quenched by addition of saturated aqueous sodium potassium tartrate solution (100 mL). After stirring at room temperature for 3 hours, the reaction mixture was extracted with ethyl acetate 3 times (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography to give compound 26e (2.0 g, yield 89%).
The fourth step
Compound 26c (1.0 g, 5 mmol) was dissolved in tetrahydrofuran at room temperature and added to compound 26e (1.8 g, 7.5 mmol). After 4 hours of reaction, p-toluenesulfonic acid monohydrate (2.9 g, 15 mmol) was added and the temperature was raised to reflux. After 2 hours of reaction, the temperature was lowered to room temperature, and the reaction was quenched by adding saturated aqueous sodium bicarbonate (100 mL), and the reaction solution was extracted 3 times with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography to give compound 1 (896 mg, yield 50%).
1H NMR (500 MHz, CDCl3) δ 13.29 (s, 1H), 7.29 (d, J = 7.2 Hz, 3H), 7.24 (d, J = 7.8 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 5.27 (s, 1H), 3.95 (h, J= 6.6 Hz, 1H), 1.85 (tt, J = 14.3, 7.3 Hz, 2H), 1.69–1.65 (m, 1H), 1.63 (s, 3H), 1.51 (s, 3H), 1.35 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H), 1.12 (s, 3H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 212.1, 204.1, 199.0, 167.7, 164.3, 160.5, 153.1, 114.8, 106.3, 105.4, 100.2, 56.2, 53.4, 47.4, 46.9, 25.5, 25.1, 24.9, 24.8, 24.6, 24.4, 23.5, 23.2, 23.0, 22.7; HR-ESI-MSm/z443.2432 [M+H]+。
Example 2
Preparation of 6, 8-dihydroxy-5- (2-diylbutyryl) -9-isopropyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (2)
Figure DEST_PATH_IMAGE010
Compound 27b (1.0 g, 5 mmol) was dissolved in tetrahydrofuran at room temperature and added to compound 27a (1.8 g, 7.5 mmol). After 4 hours of reaction, p-toluenesulfonic acid monohydrate (2.9 g, 15 mmol) was added and the temperature was raised to reflux. After 2 hours of reaction, the temperature was lowered to room temperature, and the reaction was quenched by adding saturated aqueous sodium bicarbonate (100 mL), and the reaction solution was extracted 3 times with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography to give Compound 2 (964 mg, yield 45%).
1H NMR (500 MHz, CDCl3) δ 13.32 (s, 1H), 6.29 (s, 1H), 4.30 (d, J = 3.5 Hz, 1H), 3.90 (dt, J = 13.7, 6.8 Hz, 1H), 1.94–1.85 (m, 1H), 1.61 (s, 3H), 1.44 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H), 1.23 (s, 2H), 0.82 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 212.0, 209.1, 198.1, 167.8, 164.9, 159.6, 153.6, 112.2, 104.0, 103.7, 100.7, 56.3, 47.4, 39.8, 34.9, 31.7, 29.8, 25.3, 25.1, 24.9, 24.3, 21.0, 19.0, 18.9, 17.8; HR-ESI-MSm/z 429.2279 [M+H]+。
Example 3
Preparation of 6, 8-dihydroxy-5- (2-methylbutyryl) -9-phenyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (3)
Figure DEST_PATH_IMAGE011
Compound 27b (1.0 g, 5 mmol) was dissolved in tetrahydrofuran at room temperature and added to compound 28a (2.0 g, 7.5 mmol). After 4 hours of reaction, p-toluenesulfonic acid monohydrate (2.9 g, 15 mmol) was added and the temperature was raised to reflux. After 2 hours of reaction, the temperature was lowered to room temperature, and the reaction was quenched by adding saturated aqueous sodium bicarbonate (100 mL), and the reaction solution was extracted 3 times with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography to give Compound 3 (994 mg, yield 43%).
1H NMR (400 MHz, CDCl3) δ 13.50 (s, 1H), 6.31 (s, 1H), 4.31 (t, J = 5.5 Hz, 1H), 3.19 (dd, J = 17.0, 7.2 Hz, 1H), 2.94 (dd, J = 17.1, 5.9 Hz, 1H), 2.34 (dt, J = 13.0, 6.5 Hz, 1H), 1.63 (s, 3H), 1.47 (s, 3H), 1.42 (s, 4H), 1.39 (s, 5H), 1.00 (dd, J = 11.2, 6.6 Hz, 6H), 0.90–0.75 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 211.3, 209.5, 197.5, 165.0, 164.9, 159.6, 151.5, 143.9, 128.7, 128.2, 127.1, 113.2, 105.2, 104.7, 101.0, 56.5, 47.3, 45.8, 33.2, 28.1, 25.1, 24.9, 24.5, 23.3, 16.5, 11.4; HR-ESI-MSm/z 463.2112 [M+H]+。
Example 4
Preparation of 6, 8-dihydroxy-5- (2-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (4)
Compound 27b (1.0 g, 5 mmol) was dissolved in tetrahydrofuran at room temperature and added to compound 26e (1.8 g, 7.5 mmol). After 4 hours of reaction, p-toluenesulfonic acid monohydrate (2.9 g, 15 mmol) was added and the temperature was raised to reflux. After 2 hours of reaction, the temperature was lowered to room temperature, and the reaction was quenched by adding saturated aqueous sodium bicarbonate (100 mL), and the reaction solution was extracted 3 times with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography to give Compound 4 (1.2 g, yield 52%).
1H NMR (600 MHz, CDCl3) δ 13.21 (s, 1H), 6.26 (s, 1H), 4.31 (t, J = 5.9 Hz, 1H), 3.89 (q, J = 6.6 Hz, 1H), 1.76 (dt, J = 13.8, 6.6 Hz, 1H), 1.60 (s, 3H), 1.57 (d, J = 7.0 Hz, 1H), 1.51–1.47 (m, 1H), 1.43 (d, J = 1.0 Hz, 8H), 1.39 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H), 0.87 (ddd, J = 11.7, 6.4, 4.4 Hz, 12H); 13C NMR (150 MHz, CDCl3) δ 211.9, 209.4, 198.7, 167.5, 164.3, 159.6, 153.0, 114.5, 106.1, 105.4, 100.5, 56.3, 47.4, 46.5, 45.6, 28.5, 25.2, 25.1, 25.0, 24.9, 24.8, 24.3, 23.7, 23.4, 16.0, 11.3; HR-ESI-MSm/z 443.2430 [M+H]+。
Example 5
Preparation of 6, 8-dihydroxy-9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione intermediate (26)
Compound 26a (630 mg, 5 mmol) was dissolved in tetrahydrofuran at room temperature and added to compound 26e (1.8 g, 7.5 mmol). After 4 hours of reaction, p-toluenesulfonic acid monohydrate (2.9 g, 15 mmol) was added and the temperature was raised to reflux. After 2 hours of reaction, the temperature was lowered to room temperature, and the reaction was quenched by adding saturated aqueous sodium bicarbonate (100 mL), and the reaction solution was extracted 3 times with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography to give compound 26 (896 mg, yield 50%).
1H NMR (600 MHz, CD3OD) δ 6.17 (d, J = 2.3 Hz, 1H), 6.10 (d, J = 2.3 Hz, 1H), 4.18 (t, J = 5.7 Hz, 1H), 3.33 (dt, J = 3.3, 1.6 Hz, 1H), 1.54 (s, 3H), 1.49 (m, 2H), 1.45 (s, 3H), 1.39 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H), 0.85 (d, J = 6.5 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H); 13C NMR (150 MHz, CD3OD) δ 212.4, 198.2, 168.5, 156.8, 155.7, 152.4, 113.5, 104.6, 98.8, 94.0, 55.4, 47.0, 45.6, 25.5, 24.7, 23.9, 23.8, 23.6, 23.3, 22.9, 22.3; HR-ESI-MSm/z359.1847 [M+H]+。
Example 6
Preparation of 6, 8-dihydroxy-9-cyclobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione intermediate (29)
Figure DEST_PATH_IMAGE012
First step of
Phloroglucinol 26a (2.5 g, 20 mmol) was dissolved in nitromethane solution at room temperature, and anhydrous aluminum trichloride (10.7 g, 80 mmol) and cyclobutyryl chloride (2.6 g, 22 mmol) were added successively, and the temperature was raised to reflux. After 12 hours of reaction, the reaction mixture was slowly poured into ice water, and a saturated sodium potassium tartrate solution (100 mL) was added thereto and stirred vigorously. The reaction mixture was extracted 3 times with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography to give compound 29c (3.4 g, yield 83%).
Second step of
Compound 29c (2.1 g, 10 mmol) was dissolved in MeOH (30 mL) at room temperature and NaOMe (5 mmol/mL, 9 mL, 45 mmol) in MeOH was added. After reacting for 10 minutes at room temperature, adding iodomethane (3.1 mL, 50 mmol) into the reaction system, heating to 55 ℃, reacting for 15 minutes, cooling to 0 ℃, and acidifying with 1N HCl. The reaction solution was extracted three times with ethyl acetate (3X 10 mL), and the organic phases were combined and washed with saturated NaCl solution (5 mL). After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The crude product was isolated and purified by silica gel column chromatography to give compound 29d (2.4 g, 90% yield) as a yellow solid.
The third step
The compound 29d (2.4 g, 9.0 mmol) was dissolved in tetrahydrofuran solution and after dropping to-78 ℃, diisopropylaluminum hydride was added dropwise. After 2 hours of reaction, the reaction was quenched by addition of saturated aqueous sodium potassium tartrate solution (100 mL). After stirring at room temperature for 3 hours, the reaction mixture was extracted with ethyl acetate 3 times (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The crude product was isolated and purified by silica gel column chromatography to give compound 29e (1.9 g, 85% yield).
The fourth step
Compound 26a (630 mg, 5 mmol) was dissolved in tetrahydrofuran at room temperature and added to compound 29e (1.8 g, 7.5 mmol). After 4 hours of reaction, p-toluenesulfonic acid monohydrate (2.9 g, 15 mmol) was added and the temperature was raised to reflux. After 2 hours of reaction, the temperature was lowered to room temperature, and the reaction was quenched by adding saturated aqueous sodium bicarbonate (100 mL), and the reaction solution was extracted 3 times with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated NaCl solution. After drying over anhydrous sodium sulfate and filtration, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography to give compound 29 (927 mg, yield 52%).
1H NMR (300 MHz, CD3OD) δ 6.19 (d, J = 2.2 Hz, 1H), 6.12 (d, J = 2.2 Hz, 1H), 4.12 (d, J = 5.7 Hz, 1H), 2.59 (dt, J = 9.0, 6.8 Hz, 1H), 1.65 (m, 5H), 1.53 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.31 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 212.4, 198.5, 169.2, 156.8, 155.8, 152.8, 111.1, 102.3, 98.9, 94.0, 55.5, 41.9, 29.6, 24.7, 24.2, 23.9, 23.6, 23.5, 17.2; HR-ESI-MSm/z 357.1693 [M+H]+。
Example 7
Preparation of 6, 8-dihydroxy-7- (3-methylbutyryl) -9-isobutyl-2, 2,4, 4-dimethyl-4, 9-hydro-1H-xanthene-1, 3(2H) -dione (6)
Titanium tetrachloride (0.4 mmol, 1.0M in CH) was added at room temperature2Cl2) And 3-methylbutyryl chloride (0.11 mmol) were added to a solution of compound 26 (0.1 mmol) in dichloromethane, respectively, and stirred at ordinary temperature. After 24 hours of reaction, the reaction was quenched by addition of 1N aqueous hydrochloric acid solution and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography to give the corresponding product 6 (15.5 mg, 35% yield).
1H NMR(500 MHz, CDCl3) δ 13.05 (s, 1H), 7.58 (s, 1H), 6.13 (s, 1H), 4.29 (t, J = 5.3 Hz, 1H), 3.01 (m, 2H), 2.29 (m, 1H), 1.73 (s, 3H), 1.57 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H), 1.42 (m, 3H), 1.39 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H), 0.89 (d, J = 5.8 Hz, 3H), 0.85 (d, J = 5.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 212.2, 206.5, 197.9, 167.1, 162.6, 158.5, 155.6, 114.2, 107.6, 106.6, 94.8, 56.1, 53.2, 47.2, 45.9, 25.2, 25.1, 24.7, 24.6, 24.6, 24.2, 23.5, 23.2, 22.8, 22.8; HR-ESI-MSm/z 443.2432 [M+H]+。
Example 8
Preparation of 6, 8-dihydroxy-7- (3-methylbutyryl) -9-phenyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (8)
Figure DEST_PATH_IMAGE013
Titanium tetrachloride (0.4 mmol, 1.0M in CH) was added at room temperature2Cl2) And 3-methylbutyryl chloride (0.11 mmol) were added to a solution of compound 30 (0.1 mmol) in methylene chloride, respectively, and stirred at ordinary temperature. After 24 hours of reaction, the reaction was quenched by addition of 1N aqueous hydrochloric acid solution and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography to give the corresponding product 8 (23.4 mg, 53% yield).
1H NMR (400 MHz, CDCl3) δ 7.30–7.12 (m, 5H), 6.23 (s, 1H), 5.21 (s, 1H), 2.91 (qd, J = 15.9, 6.6 Hz, 2H), 2.22 (dq, J = 13.2, 6.9 Hz, 1H), 1.59 (s, 3H), 1.49 (s, 3H), 1.33 (s, 3H), 1.11 (s, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 211.8, 206.4, 197.5, 165.3, 162.8, 159.6, 154.4, 143.9, 128.5, 128.3, 126.9, 113.2, 108.1, 105.3, 95.0, 56.5, 53.2, 47.3, 33.4, 25.1, 24.9, 24.7, 24.6, 23.3, 22.9, 22.9; HR-ESI-MSm/z 463.2121 [M+H]+。
Example 9
Preparation of 6, 8-dihydroxy-7- (2-methylbutyryl) -9-isopropyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (10)
Figure DEST_PATH_IMAGE014
Titanium tetrachloride (0.4 mmol, 1.0M in CH) was added at room temperature2Cl2) And 2-methylbutyryl chloride (0.11 mmol) were added to a solution of compound 31 (0.1 mmol) in dichloromethane, respectively, and stirred at ordinary temperature. After 24 hours of reaction, the reaction was quenched by addition of 1N aqueous hydrochloric acid solution and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography to give the corresponding product 10 (23.4 mg, 45% yield).
1H NMR (500 MHz, CDCl3) δ 12.33 (s, 1H), 7.96 (s, 1H), 6.14 (s, 1H), 4.32 (d, J = 3.5 Hz, 1H), 3.76 (q, J = 6.7 Hz, 1H), 1.98 (td, J = 6.9, 3.5 Hz, 1H), 1.86 (ddd, J = 13.5, 7.4, 6.1 Hz, 1H), 1.58 (s, 3H), 1.45 (m, 1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.37 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H), 0.78 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 212.3, 211.1, 198.2, 168.3, 162.2, 158.9, 156.5, 112.0, 107.5, 104.9, 95.1, 56.3, 47.5, 46.6, 34.7, 32.0, 26.9, 25.3, 25.2, 24.7, 24.1, 19.4, 18.9, 16.7, 12.1; HR-ESI-MSm/z 429.2277 [M+H]+。
Example 10
Preparation of 6, 8-dihydroxy-7-acetyl-9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (11)
At room temperature, compound 26 (44.2 mg, 0.1 mmol) was dissolved in glacial acetic acid (4 mL) solution, acetic anhydride (20.6 μ L, 0.22 mmol) and boron trifluoride ethyl ether (13.6 μ L, 0.105 mmol) were added, respectively, and the temperature was raised to 100 ℃. After 3 hours of reaction, the reaction was quenched by addition of 1N aqueous sodium hydroxide (4 mL) and extracted 3 times with ethyl acetate (8 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was recrystallized from a mixture of dichloromethane and n-hexane to give Compound 11 (16.4 mg, yield 41%).
1H NMR (500 MHz, CDCl3) δ 13.12 (s, 1H), 7.73 (s, 1H), 6.17 (s, 1H), 4.30 (t, J = 5.5 Hz, 1H), 2.75 (s, 3H), 1.58 (s, 3H), 1.46 (m, 3H), 1.46 (s, 3H), 1.44 (s, 3H), 1.40 (s, 3H), 0.89 (d, J = 6.0 Hz, 3H), 0.86 (d, J = 5.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 212.2, 204.2, 198.1, 167.2, 162.7, 158.8, 156.0, 114.3, 107.6, 106.4, 94.7, 56.1, 47.2, 45.9, 33.2, 25.1, 24.8, 24.6, 24.2, 23.5, 23.2; HR-ESI-MSm/z 401.1957 [M+H]+。
Example 11
Preparation of 6, 8-dihydroxy-7-propionyl-9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (12)
Titanium tetrachloride (0.4 mmol, 1.0M in CH) was added at room temperature2Cl2) And propionyl chloride (0.11 mmol) were added to a solution of compound 26 (0.1 mmol) in dichloromethane, respectively, and stirred at ordinary temperature. After 24 hours of reaction, the reaction was quenched by addition of 1N aqueous hydrochloric acid solution and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by silica gel chromatography to give compound 12 (17.8 mg, yield 43%).
1H NMR (500 MHz, CD3OD) δ 6.16 (s, 1H), 4.21 (t, J = 5.2 Hz, 1H), 3.16 (q, J = 7.1 Hz, 2H), 1.55 (s, 3H), 1.46 (s, 3H), 1.38 (m, 3H), 1.37 (s, 3H), 1.35 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H), 0.86 (d, J = 5.8 Hz, 3H), 0.81 (d, J= 5.7 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 211.8, 207.6, 197.9, 167.3, 162.6, 160.2, 155.9, 113.9, 107.0, 104.8, 93.6, 55.7, 46.9, 45.2, 37.2, 25.0, 24.9, 24.0, 23.8, 23.5, 22.9, 22.7, 22.3, 7.5; HR-ESI-MSm/z 415.2112 [M+H]+。
Example 12
Preparation of 6, 8-dihydroxy-7- (2-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (13)
Titanium tetrachloride (0.4 mmol, 1.0M in CH) was added at room temperature2Cl2) And 2-methylbutyryl chloride (0.11 mmol) were added to a solution of compound 26 (0.1 mmol) in dichloromethane, respectively, and stirred at ordinary temperature. After 24 hours of reaction, the reaction was quenched by addition of 1N aqueous hydrochloric acid solution and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography to give the corresponding product 13 (23.4 mg, 53% yield).
1H NMR (400 MHz, CDCl3) δ 13.37 (s, 1H), 8.03 (s, 1H), 6.20 (s, 1H), 4.29 (d, J = 5.0 Hz, 1H), 3.80 (q, J = 6.6 Hz, 1H), 1.87 (dt, J = 13.5, 6.5 Hz, 1H), 1.56 (s, 3H), 1.44 (m, 7H), 1.42 (s, 3H), 1.39 (s, 3H), 1.17 (d, J = 6.7 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.86 (d, J = 5.6 Hz, 3H), 0.84 (d, J = 5.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 212.3, 211.4, 198.8, 167.8, 163.1, 158.6, 155.7, 114.4, 107.4, 106.6, 95.0, 56.2, 47.4, 46.5, 46.0, 26.9, 25.4, 25.3, 24.9, 24.8, 24.4, 23.7, 23.3, 16.7, 12.1; HR-ESI-MSm/z 443.2438 [M+H]+。
Example 13
Preparation of 6, 8-dihydroxy-7-decanoyl-9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (14)
Titanium tetrachloride (0.4 mmol, 1.0M in CH) was added at room temperature2Cl2) And decanoyl chloride (0.11 mmol) were added to a solution of compound 26 (0.1 mmol) in dichloromethane, respectively, and stirred at room temperature. After 24 hours of reaction, the reaction was quenched by addition of 1N aqueous hydrochloric acid solution and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by silica gel chromatography to give compound 14 (20.0 mg, 39% yield).
1H NMR (300 MHz, CDCl3) δ 13.56 (s, 1H), 8.33 (s, 1H), 6.26 (s, 1H), 4.33 (t, J = 5.1 Hz, 1H), 3.16 (t, J = 7.3 Hz, 2H), 1.73 (m, 2H), 1.59 (s, 3H), 1.47 (s, 3H), 1.45 (s, 3H), 1.42 (s, 3H), 1.40 (m, 15H), 0.88 (t, J = 4.9 Hz, 9H); 13C NMR (75 MHz, CDCl3) δ 212.1, 207.4, 198.9, 168.0, 162.9, 158.9, 155.7, 114.3, 107.5, 106.2, 94.74, 56.1, 47.3, 45.9, 44.6, 31.9, 29.6, 29.5, 29.5, 29.3, 25.1, 24.8, 24.7, 24.6, 24.3, 23.6, 23.2, 22.7, 14.1; HR-ESI-MSm/z 513.3210 [M+H]+。
Example 14
Preparation of 6, 8-dihydroxy-7- (3-methylbutyryl) -9-cyclobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (17)
Titanium tetrachloride (0.4 mmol, 1) was added at room temperature.0 M in CH2Cl2) And cyclobutylylchloride (0.11 mmol) were added to a solution of compound 29 (0.1 mmol) in dichloromethane, respectively. After the reaction was stirred for 24 hours, the reaction was quenched by adding 1N aqueous hydrochloric acid solution and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by silica gel chromatography to give compound 17 (18.0 mg, 41% yield).
1H NMR (500 MHz, CDCl3) δ 11.74 (s, 1H), 9.40 (s, 1H), 6.23 (s, 1H), 4.43 (d, J = 5.5 Hz, 1H), 3.05 (m, 2H), 2.70 (m, 1H), 2.32 (m, 1H), 1.62 (m, 6H), 1.59 (s, 3H), 1.47 (s, 6H), 1.42 (s, 3H), 1.01 (d, J = 3.5 Hz, 3H), 1.00 (d, J = 3.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 212.0, 206.6, 198.6, 168.5, 161.2, 160.2, 156.0, 111.5, 108.0, 103.1, 95.5, 56.0, 53.4, 47.3, 41.3, 29.4, 25.4, 25.0, 24.6, 24.6, 24.4, 22.9, 22.8, 17.8; HR-ESI-MSm/z 441.2268 [M+H]+。
Example 15
Preparation of 6, 8-dihydroxy-7- (cyclobutylcarbonyl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (18)
Titanium tetrachloride (0.4 mmol, 1.0M in CH) was added at room temperature2Cl2) And cyclobutyl chloride (0.11 mmol) were added to a solution of compound 26 (0.1 mmol) in dichloromethane, respectively, and stirred at room temperature. After 24 hours of reaction, the reaction was quenched by addition of 1N aqueous hydrochloric acid solution and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by silica gel chromatography to give compound 18 (18.9 mg, 43% yield).
1H NMR (300 MHz, CDCl3) δ 13.50 (s, 1H), 8.26 (s, 1H), 6.20 (s, 1H), 4.27 (m, 2H), 2.34 (m, 4H), 1.96 (m, 2H), 1.58 (s, 3H), 1.48 (m, 3H), 1.46 (s, 3H), 1.44 (s, 3H), 1.41 (s, 3H), 0.88 (d, J = 4.5 Hz, 3H), 0.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 212.2, 207.2, 198.6, 167.7, 163.0, 158.8, 155.7, 114.3, 106.4, 106.1, 94.6, 77.5, 77.0, 76.6, 56.1, 47.3, 46.6, 45.9, 25.2, 25.1, 24.9, 24.8, 24.6, 24.2, 23.6, 23.2, 17.6; HR-ESI-MSm/z 441.2271 [M+H]+。
Example 16
Preparation of 6, 8-diacetoxy-7- (3-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (20)
Acetic anhydride (30.6 mg, 0.3 mmol) and triethylamine (40.4 mg, 0.4 mmol) were added to a solution of compound 6 (44.2 mg, 0.1 mmol) in dichloromethane (2 mL) at room temperature and heated to reflux. After overnight reaction was cooled to room temperature, the reaction was quenched by addition of 1N aqueous HCl (3 mL) and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give compound 20 (48.4 mg, 92% yield).
1H NMR (300 MHz, CDCl3) δ 6.92 (s, 1H), 3.99 (t, J = 6.0 Hz, 1H), 2.60 (dd, J = 6.7, 4.6 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 2.19 (dd, J = 13.2, 6.5 Hz, 1H), 1.52 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.34 (m, 3H), 1.32 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H), 0.89 (d, J = 6.1 Hz, 3H), 0.79 (d, J = 6.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 211.6, 199.7, 197.2, 168.4, 168.1, 167.4, 152.0, 146.5, 145.4, 125.1, 118.7, 112.9, 109.0, 56.0, 52.6, 47.2, 47.1, 26.3, 24.8, 24.5, 24.4, 24.2, 24.1, 23.2, 22.8, 22.5, 22.5, 21.0, 20.7; HR-ESI-MSm/z 527.2637 [M+H]+。
Example 17
Preparation of 6-methanesulfonyloxy-8-hydroxy-7- (3-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (20)
Methanesulfonyl chloride (13.7 mg, 0.12 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) were added to a solution of compound 6 (44.2 mg, 0.1 mmol) in dichloromethane (2 mL) at room temperature. After 2 hours of reaction, the reaction was quenched by addition of 1N aqueous HCl (3 mL) and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by silica gel chromatography to give compound 20 (42.1 mg, yield 81%).
1H NMR (300 MHz, CDCl3) δ 13.27 (s, 1H), 6.75 (s, 1H), 4.35 (d, J = 5.2 Hz, 1H), 3.29 (s, 3H), 2.97 (m, 2H), 2.28 (m, 1H), 1.56 (s, 3H), 1.45 (s, 6H), 1.41 (m, 3H), 1.40 (s, 3H), 1.37 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 0.89 (d, J = 5.3 Hz, 3H), 0.84 (d, J = 5.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 211.7, 205.0, 197.4, 166.6, 162.5, 154.8, 147.8, 114.4, 113.9, 111.4, 101.6, 56.2, 52.7, 47.1, 46.1, 38.7, 25.4, 25.2, 25.0, 24.7, 24.6, 24.5, 24.0, 23.2, 23.1, 22.6, 22.6; HR-ESI-MSm/z 521.2204 [M+H]+。
Example 18
Preparation of 6- (2, 2-dimethylpropionyloxy) -8-hydroxy-7- (3-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (22)
tert-Butylacetyl chloride (16.1mg, 0.12 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) were added to a solution of compound 6 (44.2 mg, 0.1 mmol) in dichloromethane (2 mL) at room temperature. After 2 hours of reaction, the reaction was quenched by addition of 1N aqueous HCl (3 mL) and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by silica gel chromatography to give compound 22 (18.4 mg, 35% yield).
1H NMR (500 MHz, CDCl3) δ 13.56 (s, 1H), 6.22 (s, 1H), 4.36 (t, J = 4.9 Hz, 1H), 2.81 (d, J = 6.6 Hz, 2H), 2.35 (m, 1H), 1.56 (s, 3H), 1.46 (s, 3H), 1.44 (s, 9H), 1.44 (m, 3H), 1.42 (s, 3H), 1.38 (s, 3H), 0.99 (d, J = 3.5 Hz, 3H), 0.98 (d, J = 3.7 Hz, 3H), 0.90 (d, J = 4.9 Hz, 3H), 0.86 (d, J = 4.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 212.0, 204.5, 197.4, 176.9, 166.6, 162.5, 154.9, 151.5, 113.9, 112.8, 111.9, 102.2, 56.2, 52.3, 47.1, 45.9, 39.5, 27.2, 25.5, 25.2, 24.7, 24.7, 24.4, 24.2, 24.2, 23.3, 23.2, 22.7, 22.7; HR-ESI-MSm/ z 527.3001 [M+H]+。
Example 19
Preparation of 6-benzoyloxy-8-hydroxy-7- (3-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (23)
Benzoyl chloride (16.9 mg, 0.12 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) were added to a solution of compound 6 (44.2 mg, 0.1 mmol) in dichloromethane (2 mL) at room temperature. After 2 hours of reaction, the reaction was quenched by addition of 1N aqueous HCl (3 mL) and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by silica gel chromatography to give compound 23 (23.5 mg, yield 43%).
1H NMR(500 MHz, CDCl3) δ 13.54 (s, 1H), 8.14 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 7.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 6.42 (s, 1H), 4.31 (d, J = 5.4 Hz, 1H), 2.70 (d, J = 6.8 Hz, 2H), 2.13 (m, 1H), 1.47 (s, 3H), 1.41 (m, 3H), 1.37 (s, 3H), 1.34 (s, 3H), 1.31 (s, 3H), 0.84 (d, J = 5.2 Hz, 3H), 0.80 (d, J = 5.0 Hz, 3H), 0.71 (t, J = 5.8 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 212.0, 204.7, 197.5, 166.7, 164.7, 162.8, 155.0, 150.6, 134.5, 130.3, 129.0, 128.6, 114.0, 113.2, 111.5, 103.0, 56.2, 52.7, 47.2, 46.1, 25.5, 25.2, 24.7, 24.6, 24.42, 24.3, 23.3, 23.2, 22.5, 22.4; HR-ESI-MSm/z 549.2687 [M+H]+。
Example 20
Preparation of 6-trifluoromethanesulfonyloxy-8-hydroxy-7- (3-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (24)
Trifluoromethanesulfonyl chloride (20.2 mg, 0.12 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) were added to a solution of compound 6 (44.2 mg, 0.1 mmol) in dichloromethane (2 mL) at room temperature. After 2 hours of reaction, the reaction was quenched by addition of 1N aqueous HCl (3 mL) and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by silica gel chromatography to give compound 24 (27.0 mg, 47% yield).
1H NMR (500 MHz, CDCl3) δ 13.19 (d, J = 15.9 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 4.38 (m, 1H), 2.93 (m, 2H), 2.29 (m, 1H), 1.59 (s, 3H), 1.47 (s, 3H), 1.45 (m, 3H), 1.43 (s, 3H), 1.39 (d, J = 2.5 Hz, 3H), 0.99 (d, J = 2.5 Hz, 3H), 0.97 (s, 3H), 0.92 (d, J = 5.0 Hz, 3H), 0.85 (d, J = 5.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 211.5, 204.4, 197.3, 166.5, 162.5, 154.7, 147.2, 115.8, 113.9, 110.9, 101.5, 56.2, 52.6, 47.1, 46.0, 25.5, 25.2, 25.1, 24.7, 24.6, 24.5, 23.9, 23.2, 23.1, 22.5, 22.4; HR-ESI-MSm/z 575.1918 [M+H]+。
Example 21
Preparation of 6-phenylacetyloxy-8-hydroxy-7- (3-methylbutyryl) -9-isobutyl-2, 2,4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione (25)
Phenylacetyl chloride (18.6 mg, 0.12 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) were added to a solution of compound 6 (44.2 mg, 0.1 mmol) in dichloromethane (2 mL) at room temperature. After 2 hours of reaction, the reaction was quenched by addition of 1N aqueous HCl (3 mL) and extracted 3 times with dichloromethane (3 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by silica gel chromatography to give compound 25 (21.8 mg, yield 39%).
1H NMR (500 MHz, CDCl3) δ 13.49 (s, 1H), 7.40 (m, 5H), 6.36 (s, 1H), 4.35 (t, J = 5.1 Hz, 1H), 3.95 (s, 2H), 2.71 (d, J = 6.6 Hz, 2H), 2.27 (m, 1H), 1.56 (s, 3H), 1.45 (m, 3H), 1.44 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.90 (d, J = 5.1 Hz, 3H), 0.85 (d, J = 5.0 Hz, 3H);HR-ESI-MSm/z 587.2843 [M+H]+。
Example 22
Evaluation of Activity of polyketides against SARS-CoV-2 in vitro
Materials: the SARS-CoV-2 virus strain is isolated by Guangdong provincial disease prevention control center (CDC) (whole genome sequence data is shown in GISAID database, the serial number is EPI _ ISL _403934, the strain number is BetacoV/Guangdong/20SF 014/2020); the cell culture medium is a MEM medium containing 10% Fetal Bovine Serum (FBS) and 1% penicillin-streptomycin (PS), and the cell culture medium is a MEM medium containing 2% FBS and 1% PS. The cells were cultured at 37 ℃ and 5% CO2In an incubator, passage is carried out for 1 time for 2-3 days; SARS-CoV-2 was cultured in Vero-E6 cells and stored in a freezer at-80 ℃ for use. FBS, MEM and PS were purchased from Life Technologies, Chloroquin (Chloroquin diphosphonate), Sigma-Aldrich, Inc., CCK-8 kit, Shanghai Bin Yuntan Biotechnology, Inc., and Virus fluorescent quantitative RT-PCR kit, Daan Gene technology, Inc., Guangzhou.
1. Inhibition of virus-induced cytopathic effect (CPE) by polyketides
The experimental method comprises the following steps: the inhibition of SARS-CoV-2-induced cytopathic effect of the test compound was determined by CPE assay. Inoculating Vero-E6 cells into a 96-hole cell culture plate, and placing at 37 ℃ and 5% CO2The culture was carried out in an incubator for 24 hours. Subsequently, the cell supernatant was aspirated off, and the compound diluted with the cell maintenance medium was added. The virus solution diluted with the maintenance solution was added at the same time, and the multiplicity of virus infection MOI = 0.1, 5 duplicate wells were set for each concentration, and a cell control group (no virus and compound added), a compound control group (no virus added), and a virus control group (no compound added) were set. Subsequently, the cells were placed at 37 ℃ and 5% CO2In the incubator, after the virus was adsorbed for 1 hour, the virus solution was discarded, and 0.1 mL of the cell maintenance solution containing the compound was added to each well. Place the cells at 37 ℃ and 5% CO2The cultures were incubated in an incubator and observed for cytopathic effect (CPE) at the P3 laboratory every 24 hours. CPE results were recorded in each well 48 hours after virus infection.
The experimental results are as follows: as shown in Table 1, compounds 1 to 25 can inhibit SARS-CoV-2-induced cytopathic effect to various degrees, whichThe activity of compound 13 is the most remarkable, and the half inhibitory concentration IC thereof50The value is 0.70 +/-0.03 mu M, and the activity of the compound is stronger than that of chloroquine phosphate (1.50 +/-0.15 mu M). Compound 13 selection index SI value (CC)50/IC50) Is 48.69, and is close to the SI value of 66.67 of chloroquine phosphate.
2. Toxicity test of polyketides on Vero-E6 cells
The experimental method comprises the following steps: the cytotoxicity of the test compounds was determined using the CCK-8 kit. Inoculating Vero-E6 cells into a 96-hole cell culture plate, and placing the culture plate at 37 ℃ and 5% CO2Culturing in an incubator. After 24 hours, the cell supernatant was aspirated off, and the compounds diluted with medium were added, 6 duplicate wells for each concentration, while a cell control group (no compound added) was set. After an additional 48 hours of incubation, the cell viability was determined using the CCK-8 kit and the cytotoxicity of the compounds was calculated.
The experimental results are as follows: as shown in Table 1, compounds 1 to 25 showed a certain cytotoxicity to Vero-E6, and the concentration of the cytotoxicity was CC at half50The value is between 18.00 and 84.00 mu M.
Figure DEST_PATH_IMAGE015
3. Inhibitory Effect of Compound 13 on viral nucleic acids
The experimental method comprises the following steps: the inhibition of the tested compound 13 on SARS-CoV-2 is detected by a fluorescent quantitative RT-PCR method. Vero-E6 cells were inoculated in 6-well cell culture plates at 37 ℃ with 5% CO2After 24 hours of culture in the incubator, the cell supernatant was discarded, and the cell maintenance solution containing compound 13 was added, and the virus solution (MOI = 0.1) diluted with the maintenance solution was added, and 3 replicate wells were provided for each group, and a cell control group (no virus and compound 13 added), a compound 13 control group (no virus added), and a virus control group (no compound 13 added) were provided. At 37 ℃ and 5% CO2Culturing in an incubator for 48 hours, extracting virus RNA, and detecting the content of virus nucleic acid by fluorescent quantitative RT-PCR.
The experimental results are as follows: as shown in FIG. 1, Compound 13 significantly reduced the nucleic acid level of SARS-CoV-2 in the cell and was concentration dependent. When the concentration of compound 13 was 2. mu.M, the inhibitory effect on SARS-CoV-2 nucleic acid was 97.5%.
4. Inhibitory Effect of Compound 13 on the expression level of viral Nucleoprotein (nucleotein)
The experimental method comprises the following steps: the inhibition of the expression level of SARS-CoV-2 nuclear protein in the cell by the test compound 13 is detected by immunofluorescence labeling. Vero-E6 cells were seeded in 96-well plates and after the cells grew to a monolayer, the cell supernatant was discarded and a dilution of virus (MOI = 0.05) was added, along with different concentrations of compound 13. After 1 hour of infection at 37 ℃, virus and compound mixed liquor is discarded, and maintenance solutions containing different compound concentrations are added. After the virus is infected for 24 hours, 4% paraformaldehyde solution is added for fixation, PBS is used for washing, a virus nucleoprotein primary antibody and an Alexa488 nm fluorescent secondary antibody are sequentially added, DAPI is added for marking cell nucleus, the fluorescence intensity is measured by using Celigo scanning plate, and the inhibition rate of the compound on the virus infection is calculated.
The experimental results are as follows: as shown in FIG. 2, compound 13 significantly reduced the expression level of the nuclear protein of SARS-CoV-2 (green fluorescence in FIG. 2). After SARS-CoV-2 infects Vero-E6 cell, the expression level of virus nucleoprotein in cell can be detected to be higher, and after compound 13 is added, the expression level of nucleoprotein is obviously reduced. The inhibition rate of the compound concentration of 2 mu M on the expression level of SARS-CoV-2 nucleoprotein is higher than 95%.
It should be noted that the above detailed description is only for exemplary purposes, and the present invention is not limited to the above described embodiments. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.

Claims (8)

1. The application of polyketide with a structure shown in formula I or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof in preparing novel coronavirus resistant medicines:
Figure 508267DEST_PATH_IMAGE001
in the formula:
R1is selected from C1~C6Alkyl radical, C3~C6Cycloalkyl or aryl;
R2and R3Independently selected from a hydrogen atom or-C (O) R6；
R4And R5Independently selected from hydrogen atom, C1~C6Alkyl, -C (O) R6or-S (O)mR6；
R6Selected from hydrogen atoms, substituted or unsubstituted C1~C12Alkyl, substituted or unsubstituted C3~C6Cycloalkyl or substituted or unsubstituted aryl;
m is 1 or 2;
wherein each substitution independently refers to substitution by a substituent selected from the group consisting of: halogen, hydroxy, amino, C1~C3Alkyl radical, C1~C3Alkoxy, -NH (C)1~C3Alkyl), -N (C)1~C3Alkyl) (C1~C3Alkyl), -C (= O) (C)1~C3Alkyl groups).
2. Use according to claim 1, wherein R is3The polyketide is a hydrogen atom, and has a structural formula shown in a general formula II or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof:
Figure 831932DEST_PATH_IMAGE002
wherein: r1、R2、R4And R5As defined in claim 1.
3. Use according to claim 2, wherein said polyketides are selected from:
Figure 283773DEST_PATH_IMAGE003
。
4. use according to claim 1, wherein R is2The polyketide is a hydrogen atom, and has a structural formula shown in a general formula III or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof:
Figure 210140DEST_PATH_IMAGE004
wherein: r1、R3、R4And R5As defined in claim 1.
5. Use according to claim 4, said polyketides being selected from:
Figure 929573DEST_PATH_IMAGE005
。
6. the polyketide compounds represented by the general formulae I, II and III according to any one of claims 1 to 5, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrug molecules thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
7. Use of the polyketides represented by the general formulae I, II and III according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or the pharmaceutical composition according to claim 6, in the preparation of a medicament for resisting novel coronavirus SARS-CoV-2.
8. Use of the polyketides represented by the general formulae I, II and III according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or the pharmaceutical composition according to claim 6, in the preparation of a medicament for treating or preventing diseases such as pneumonia caused by the novel coronavirus SARS-CoV-2.
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