CN113045461B - Stilbene type compound and synthesis method and application thereof - Google Patents
Stilbene type compound and synthesis method and application thereof Download PDFInfo
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a stilbene compound, a synthesis method and application thereof, wherein the stilbene compound is obtained by using an intermediate 2 and an intermediate 4 as starting materials and refining the stilbene compound after a Wittig reaction, a reduction reaction, an amino protection reaction, a condensation reaction, a deprotection reaction and an amidation reaction in sequence. The synthesis process has strong controllability, the used reagent has low price, the method is simple and easy to industrialize. The stilbene compounds can be used as medicines for resisting tumor and virus, and treating fungal infection and cardiovascular and cerebrovascular diseases.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a novel stilbene type compound and a synthesis method and application thereof.
Background
Stilbene compounds are compounds with 1, 2-stilbene skeleton structure, widely exist in nature, and are mainly distributed in resveratrol, polygonum multiflorum, grapes, peanuts and other plants. Researches show that the compounds have wide biological activity and pharmacological effects, such as multiple effects of resisting bacteria, tumors, cancers, thrombus, senile dementia and the like, so that the compounds have wide attention in the medical field. Compared with the agricultural field, the application in the field of motion protection is less concerned. Meanwhile, due to the limited existence of species in nature, the extraction of the compounds from plants is very limited. Based on the above, the synthesis of a novel stilbene compound and its derivatives has become an urgent need in the human health and animal health industries.
Disclosure of Invention
Based on the above problems, the present invention aims to provide a novel stilbene type compound and its derivatives, and to provide a synthetic route for the compound, which has not been reported so far. And the stilbene type compound has good anti-tumor effect and simultaneously has obvious effects on resisting fungal infection and preventing and treating cardiovascular and cerebrovascular diseases. The stilbene type compound with the functions of preventing and treating cardiovascular and cerebrovascular diseases, resisting tumors and viruses is used in the fields of human beings and animal protection, and has milestone significance in the field of new drug research and development.
In one aspect of the present invention, a novel stilbene type compound is provided, which has a structure represented by formula (1):
formula (1)
Wherein R1, R2, R3, R4, R5 and R6 can be selected from hydrogen, hydroxyl, methoxy, sulfonyl, amido, aldehyde group, ester group, ketone group and derivatives thereof.
Preferably, the novel stilbene type compound provided by the invention is one or two of a compound A or a compound B, and the specific structural formula is as follows:
in another aspect of the present invention, a method for synthesizing the stilbene-type compound is also provided, wherein the synthetic route comprises the following steps:
the intermediate 6 (4, 4-diamino-stilbene-2, 2-disulfonic acid) is subjected to amino protection reaction (g), condensation reaction (h), deprotection reaction (i) and amidation reaction (j/k), and finally refined to obtain the stilbene compound, wherein the specific synthetic route is as follows:
wherein the intermediate 6 is 4, 4-diamino-stilbene-2, 2-disulfonic acid which is commercially available.
In the amidation reaction, the amidation reagent is p-methoxybenzoyl chloride to prepare a compound A; and when the amidation reagent is benzoyl chloride, preparing the compound B.
To better control the quality of the synthesized compound, the present invention may employ a method of self-synthesis of intermediate 6: the intermediate 2 and the intermediate 4 are used as initial reactants and are prepared by a wittig reaction e and a reduction reaction f in sequence; the intermediate 2 is obtained by sulfonation reaction and additive Teman-Koch reaction of a compound Q1 (nitrobenzene); the intermediate 4 is obtained by sulfonation reaction and bromination reaction of a compound Q2 (p-methyl nitrobenzene), and the specific scheme is as follows:
further, the synthesis steps are as follows:
step a: and (3) performing sulfonation reaction, dropwise adding a sulfonation reagent into the compound Q1, stirring, heating, cooling after complete reaction, adding a saturated sodium bicarbonate solution to stop the reaction, separating liquid, washing with water, and performing reduced pressure distillation to obtain an intermediate 1.
Step b: adding a Tetman-Koch reaction, dissolving the intermediate 1 in a solvent, adding a proper amount of Lewis acid, introducing carbon monoxide gas, stirring, heating, fully reacting, cooling, adding ice water to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 2.
Step c: and (3) performing sulfonation reaction, namely dropwise adding a sulfonation reagent into the compound Q2, stirring and heating, stirring and cooling after full reaction, adding a saturated sodium bicarbonate solution to stop the reaction, separating liquid, washing with water, and then performing reduced pressure distillation to obtain an intermediate 3.
Step d: and (2) carrying out bromination reaction, dissolving the intermediate 3 in a solvent, adding a proper amount of initiator, dropwise adding a quantitative bromization reagent after the addition is finished, heating while stirring, cooling while stirring after full reaction, adding a saturated sodium bicarbonate solution to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 4.
Step e: and (3) carrying out a Wittig reaction, dissolving the intermediate 2 in a solvent, adding a nucleophilic reagent, reacting with the intermediate 4 under an alkaline condition, adding ice water to stop the reaction, separating liquid, washing with water, concentrating and recrystallizing to obtain an intermediate 5.
Step f: and (3) carrying out reduction reaction, namely dissolving the intermediate 5 in a solvent, adding a proper amount of reducing agent, introducing hydrogen, reacting at room temperature, filtering, cooling, concentrating, recrystallizing and drying after full reaction to obtain an intermediate 6.
Step g: and (3) performing amino protection reaction, namely dissolving the intermediate 6 in an alkaline solvent, dropwise adding an amino protective agent, keeping the temperature at room temperature after dropwise adding, and filtering, cooling, concentrating and drying after full reaction to obtain an intermediate 7.
Step h: and (3) performing condensation reaction, namely dissolving the intermediate 7 in an organic solvent, adding a condensation reagent under an alkaline condition, cooling, adding the reaction reagent under stirring, after complete reaction at room temperature, diluting with ice water, and filtering to obtain an intermediate 8.
Step i: and (3) deprotection reaction, namely adding the intermediate 8 into a deprotection agent, controlling the reaction temperature, filtering and drying after the reaction is completed, dissolving by using an organic solvent, cooling, recrystallizing and drying to obtain the intermediate 9.
Step j: and (3) performing amidation reaction, namely dissolving the intermediate 9 in an alkaline organic solvent, dropwise adding alkali while stirring, cooling, dropwise adding an amidation reagent, reacting at a certain temperature, stopping the reaction by using water or an alcohol-water solution, and performing aftertreatment to obtain a crude product of the compound A or the compound B.
Step k: and (3) refining, namely adding the crude product of the compound A or the compound B obtained in the step j into an alcohol solution, stirring, adding alkali to adjust the pH value to be fully dissolved, cooling, adjusting the pH value to be acidic, separating out a solid, and filtering to obtain the stilbene type compound.
Preferably, in the above synthesis step, the amino protecting agent in step g is Boc anhydride.
In the step h, the condensing agent is one or more of DCC, HOBT, HBTU, HATU and EDCI.
A more specific synthesis method comprises the following steps:
step a: performing sulfonation reaction, namely dripping a sulfonation reagent chlorosulfonic acid into the compound Q1 cooled to 0-10 ℃, stirring and heating to 80-150 ℃, and cooling to 0-10 ℃ after complete reaction; adding saturated sodium bicarbonate solution to stop reaction, separating liquid, washing with water, and distilling under reduced pressure to obtain an intermediate 1; the dropping amount of the chlorosulfonic acid is 1.2-2.0 times of the molar amount of the compound Q1; the volume amount of the saturated sodium bicarbonate solution is 1-10 times of the mass of the compound Q1.
Step b: adding a Tetman-Koch reaction, dissolving the intermediate 1 in a solvent carbon tetrachloride with the mass ratio of 5-10 times of that of the intermediate 1, adding a proper amount of Lewis acid, introducing carbon monoxide gas with the pressure of 0.4-0.5 Mpa, stirring and heating to the temperature of 30-50 ℃, cooling to the temperature of 0-10 ℃ after full reaction, adding ice water to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 2; the Lewis acid is one or more of aluminum trichloride and cuprous chloride; the adding amount of the aluminum trichloride is 2.0-3.0 times of the 1 molar amount of the intermediate, and the adding amount of the cuprous chloride is 0.2-0.5 times of the 1 molar amount of the intermediate.
Step c: and (2) performing sulfonation reaction, namely dripping sulfochlorination reagent chlorosulfonic acid which is 1.2-2.0 times of the molar weight of Q2 into the compound Q2 at 0-10 ℃, stirring and heating to 120-150 ℃, fully reacting, stirring and cooling to 0-10 ℃, adding saturated sodium bicarbonate solution to stop the reaction, separating, washing with water, and performing reduced pressure distillation to obtain an intermediate 3.
Step d: and (2) performing bromination reaction, dissolving the intermediate 3 in carbon tetrachloride which is a solvent and has a volume 3-10 times of the mass of the intermediate 3, adding dibenzoyl peroxide which is an initiator and has a molar weight 0.1-0.3 times of that of the intermediate 3, dropwise adding N-bromosuccinimide which is a bromination reagent and has a molar weight 3.0-5.0 times of that of the intermediate 3 after the dibenzoyl peroxide is added, stirring and heating to 60-80 ℃, stirring and cooling to 0-10 ℃ after full reaction, adding a saturated sodium bicarbonate solution to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 4.
Step e: performing a Wittig reaction, dissolving an intermediate 2 in a solvent N, N-dimethylformamide under the protection of nitrogen, adding a nucleophilic reagent, stirring and heating to 60-80 ℃, cooling to 0-10 ℃ after the reaction is completed, adding an alkaline reagent sodium methoxide and an intermediate 4, stirring and heating to 60-80 ℃, cooling to 0-10 ℃ after the reaction is completed, adding ice water to stop the reaction, separating, washing with water, concentrating, and recrystallizing to obtain an intermediate 5; the molar ratio of the intermediate 2 to the intermediate 4 is 1:1.5, and the addition volume of the solvent N, N-dimethylformamide is 1-10 times of the mass of the intermediate 2; the nucleophilic reagent is triphenylphosphine, and the addition amount of the nucleophilic reagent is 1.0-2.0 times of the molar amount of the intermediate 2; the addition amount of the sodium methoxide is 1.0-2.0 times of the molar amount of the intermediate 2.
Step f: and (3) carrying out reduction reaction, dissolving the intermediate 5 in methanol with the volume 1-10 times of the mass of the intermediate 5, adding reducing agent palladium/carbon with the molar weight 0.1-0.5 times of that of the intermediate 5, introducing hydrogen, reacting at room temperature, filtering, cooling, concentrating, recrystallizing and drying after full reaction to obtain an intermediate 6.
Step g: performing amino protection reaction, namely dissolving the intermediate 6 in an alkaline solvent, dropwise adding an amino protective agent with the molar weight 2-2.3 times that of the intermediate 6 at the temperature of 20-40 ℃, keeping the temperature at room temperature for reaction for 10-18 hours after dropwise adding, and after full reaction, filtering, cooling, concentrating and drying to obtain an intermediate 7; the alkaline solvent is one of potassium carbonate, sodium hydroxide and potassium hydroxide, and the solvent is one or more of ethanol, methanol, isopropanol, DMF, DMA, THF and acetone, or an aqueous solution of one or more selected solvents; the mass volume ratio of the intermediate 6 to the selected solvent is 1g: 8-12 ml; the molar ratio of the intermediate 6 to the base is 1: 2-2.5.
Step h: performing condensation reaction, namely dissolving the intermediate 7 in an organic solvent with the volume consumption of 1-10 times of the mass of the intermediate 7, adding a condensation agent with the molar quantity of 2-2.5 times of the intermediate 7 under an alkaline condition, adding a reaction reagent with the molar quantity of 2-5 times of the intermediate 7, completely reacting at room temperature, diluting with ice water, and filtering to obtain an intermediate 8; the organic solvent is one or more of DMF, acetone and DMSO, and the alkali is one of DMAP, triethylamine, potassium carbonate and sodium hydroxide.
Step i: carrying out deprotection reaction, wherein a deprotection agent is 6mol/L hydrochloric acid solution, adding the intermediate 8 into the 6mol/L hydrochloric acid solution, controlling the temperature to be 30-80 ℃, filtering, drying after the reaction is completed, dissolving and recrystallizing by one or more of organic solvents of acetone, methanol or methanol-dichloromethane, and drying to obtain an intermediate 9; the mass volume ratio of the intermediate 8 to the organic solvent is 1g: 1-3 ml, and the mass volume ratio of the intermediate 8 to the deprotection agent is 1g:10 ml.
Step j: performing amidation reaction, namely dissolving the intermediate 9 in an organic solvent, dropwise adding alkali while stirring, cooling to 0-5 ℃, dropwise adding an amidation reagent with the molar weight 2-2.3 times that of the intermediate 9, controlling the reaction temperature to be 20-80 ℃, reacting for 3-8 hours, stopping the reaction with water or an alcohol-water solution, and separating to obtain a crude product of the compound A or the compound B; the organic solvent is selected from one or more of dimethyl sulfoxide, DMF, chlorobenzene, toluene, benzene, dichloromethane, tetrahydrofuran and acetone, and the mass volume ratio of the intermediate 9 to the organic solvent is 1g: 5-10 ml; the alkali in the alkaline organic solvent is one or more of potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine, N-diisopropylethylamine and triethylamine; the dropwise adding amount of the alkali is 3-4 times of the molar amount of the intermediate 9.
Step k: refining, namely adding the crude product of the compound A or B obtained in the step j into an alcohol solution, stirring, dropwise adding NaOH to adjust the pH value to 9-11, fully dissolving the crude product of the compound, cooling to 0-10 ℃, adjusting the pH value to 2-3 by using 6M hydrochloric acid solution, separating out a solid, and filtering to obtain a stilbene type compound; the alcohol solution is a solution with the volume ratio of methanol to water being 1: 1; the mass volume ratio of the crude compound to the alcohol solution is 1g:5 ml.
The stilbene type compound can be used for preparing medicaments for resisting tumors, viruses and fungal infection and preventing and treating cardiovascular and cerebrovascular diseases.
Has the advantages that:
1. the intermediate 2 and the intermediate 4 are used as starting materials and are refined after undergoing a Wittig reaction, a reduction reaction, an amino protection reaction, a condensation reaction, a deprotection reaction and an amidation reaction in sequence, the synthesis process has strong controllability, the used reagents are low in price, the method is simple and easy, industrialization is easy to realize, the yield is high, and the total yield is more than 300%;
2. the stilbene type compound prepared by the synthesis method provided by the invention has high purity, has no drug resistance as a novel compound, has good anti-tumor and anti-virus effects, and has obvious effect on treating fungal infection and cardiovascular and cerebrovascular diseases.
Detailed Description
The invention will now be further described by way of specific examples, which are not intended to limit the scope of the invention. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.
In the following examples, Q1 is nitrobenzene, Q2 is p-methylnitrobenzene, and intermediate 6 is 4, 4-diamino-stilbene-2, 2-disulfonic acid, all commercially available; the instruments, reagents, materials and the like used in the present examples are conventional instruments, reagents, materials and the like in the prior art and are commercially available in the normal market unless otherwise specified, and the experimental methods, detection methods and the like used in the following examples are conventional experimental methods, detection methods and the like in the prior art unless otherwise specified.
Example 1
A method for synthesizing a stilbene type compound having the structure of the compound formula (1), comprising the steps of:
example 1-a: sulfonation reaction
Cooling Q1 to 0-10 ℃ under stirring, then dropwise adding chlorosulfonic acid (1.2 eq, eq in the following examples are expressed as molar ratio) which is 1.2 times of the molar amount of Q1, stirring and heating to 130 ℃ after dropwise adding, monitoring a TLC plate layer, stirring and cooling to 0-10 ℃ after reaction is completed, then adding saturated sodium bicarbonate solution (1 g in mass-to-volume ratio: 10ml in the following examples is expressed as mass-to-volume ratio) relative to Q110V to stop reaction, washing with liquid separation water, and then distilling under reduced pressure to obtain an intermediate 1 with mass yield: 142 percent.
Example 1-b: gatemman-koch reaction
Taking the intermediate 1 and carbon tetrachloride 5V (the mass volume ratio is 1g:5 ml), adding aluminum trichloride of which the molar weight is 2.0 times (2.0 eq) and cuprous chloride of which the molar weight is 0.3 times (0.3 eq) relative to the intermediate 1, introducing carbon monoxide gas (the pressure is 0.4-0.5 Mpa), stirring and heating to 30-50 ℃, stirring and cooling to 0-10 ℃ after full reaction, adding ice water to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 2, wherein the mass yield is: 106 percent.
Example 1-c: sulfonation reaction
Dropwise adding chlorosulfonic acid with the molar weight 1.2 times (1.2 eq) into Q2 at 0-10 ℃, stirring and heating to 120 ℃ after dropwise adding, monitoring a TLC (thin layer chromatography) plate layer, stirring and cooling to 0-10 ℃ after reaction, adding saturated sodium bicarbonate solution 8V (the mass-volume ratio is 1g:8 ml) to stop the reaction, washing with liquid separation water, and distilling under reduced pressure to obtain an intermediate 3 with the mass yield: 131 percent.
Examples 1-d: bromination reaction
Dissolving the intermediate 3 in 3V (mass volume ratio is 1g:3 ml) of carbon tetrachloride, adding dibenzoyl peroxide with the molar weight of 0.2 times (0.2 eq) of that of the intermediate 3, after the addition is finished, dropwise adding N-bromosuccinimide with the molar weight of 4.0 times (4.0 eq) of that of the intermediate 3, stirring and heating to 70 ℃, stirring and cooling to 0-10 ℃ after full reaction, adding a saturated sodium bicarbonate solution to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 4, wherein the mass yield is as follows: 121 percent.
Examples 1-e: wittig reaction
Under the protection of nitrogen, dissolving the intermediate 2 in N, N-dimethylformamide 3V (the mass volume ratio is 1g:3 ml), adding triphenylphosphine with the molar quantity being 1.2 times (1.2 eq), stirring and heating to 60 ℃; after full reaction, stirring and cooling to 0-10 ℃, adding sodium methoxide (1.5 eq) with the molar weight of 1.5 times and intermediate 4 with the molar weight of 1.5eq (1.5 eq), continuing stirring and heating to 70 ℃, stirring and cooling to 0-10 ℃ after full reaction, adding ice water to stop reaction, separating liquid, washing with water, concentrating and recrystallizing to obtain intermediate 5 with the mass yield of 182%.
Example 1-f: reduction reaction
Dissolving the intermediate 5 in methanol (5V), adding palladium/carbon (0.3 eq) with the molar weight of 0.3 time, introducing hydrogen, preserving the temperature at room temperature under normal pressure, fully reacting, filtering, cooling, concentrating, recrystallizing and drying to obtain an intermediate 6 with the mass yield of 92%.
Example 1-g
Taking intermediate 6, dissolving it in solvent DMF/H2And in O (volume ratio is 5: 1), namely, the volume ratio of DMF to water in the solvent is 5:1, the mass volume ratio of the intermediate 6 to the solvent is 1g:10ml (10V), potassium carbonate (2.5 eq) with the molar weight 2.5 times that of the intermediate is added, Boc anhydride (2.2 eq) with the molar weight 2.2 times that of the intermediate is added dropwise at 20-30 ℃, the mixture is subjected to heat preservation reaction at room temperature for 12-14 h after the dropwise addition is finished, the TLC monitoring of a plate layer is carried out, after the reaction is finished, the mixture is filtered, the filtrate is condensed to separate out a large amount of solid, the temperature is reduced to 0-5 ℃, the solid is concentrated and dried to obtain an intermediate 7, the mass yield is 137.6%, and the intermediate is directly used for the next reaction without further purification.
Examples 1-h
Dissolving the intermediate 7 in DMF (1V), fully dissolving the intermediate with stirring, adding a condensing agent DCC (3.0 eq) with 3 times of molar weight of the intermediate 7 and an alkali DMAP (1.2 eq), cooling to 5-10 ℃, stirring, adding a reaction reagent p-aminobenzoic acid (2.0 eq) with 2 times of molar weight of the intermediate 7, heating to room temperature for reaction for 6 hours after the dropwise addition is finished, displaying that the raw materials are completely reacted by a TLC plate layer, adding a 2M (mol/L) HCl solution to adjust to be neutral, diluting the mixture into 50V ice water with stirring, filtering to obtain an intermediate 8, and directly using the intermediate 8 in the next step without drying.
Example 1-i
Adding the intermediate 8 into a 6M hydrochloric acid aqueous solution, heating to 50-60 ℃, reacting for 3 hours, discharging a large amount of bubbles, completely reacting the raw materials on a plate layer, filtering, drying to obtain an intermediate 9 crude product, dissolving the intermediate 9 crude product into a methanol/dichloromethane (volume ratio of 1: 1) solution, stirring at room temperature for 2 hours, cooling to 0-5 ℃, filtering, and drying to obtain an intermediate 9 fine product, wherein the mass volume ratio of the intermediate 8 to the hydrochloric acid aqueous solution is 1g:10ml (10V), and the mass volume ratio of the intermediate 9 crude product to the methanol/dichloromethane organic solvent is 1g:2ml (2V).
Example 1-j
Dissolving the intermediate 9 in DMF (5V) with the mass-volume ratio of 1g to 5ml, stirring at room temperature to completely dissolve the intermediate, adding triethylamine (4.0 eq) with the amount of 4 times of the molar amount of the intermediate 9, cooling to 0-5 ℃, dropwise adding a solution of p-methoxybenzoyl chloride (benzoyl chloride) (2.1 eq) with the amount of 2.1 times of the molar amount of the intermediate 9, heating to 30 ℃ after dropwise adding, reacting for 4-6 h, diluting the mixture into 50V (V is the mass-volume ratio) water after the reaction is finished, and filtering to obtain a crude product of the compound A (compound B).
Example 1-k
Adding the crude compound A (compound B) into a methanol/water (1: 1) 5V (V is a mass-volume ratio) solution, stirring for insolubilization, adding NaOH to adjust the pH to be about =10 for complete dissolution, cooling to 0-10 ℃, adopting 6M hydrochloric acid to adjust the pH to be about = 2-3, precipitating a large amount of solid, and filtering to obtain a refined compound A (compound B) with the mass yield of 108.2% (104.7%).
Example 2
Example 2-a: sulfonation reaction
Cooling Q1 to 0-10 ℃ under stirring, then dropwise adding chlorosulfonic acid (1.5 eq, eq in the following examples are expressed as molar ratio) with the molar weight being 1.5 times that of Q1, stirring and heating to 120 ℃ after dropwise adding, monitoring a TLC plate layer, stirring and cooling to 0-10 ℃ after reaction is completed, then adding saturated sodium bicarbonate solution with the molar weight being 1g to 8ml relative to Q18V (mass to volume ratio, V in the following examples is expressed as mass to volume ratio), stopping reaction, washing with liquid separation water, and then distilling under reduced pressure to obtain an intermediate 1 with mass yield: 138% of the total weight.
Example 2-b: gatemman-koch reaction
Dissolving the intermediate 1 in 7V (mass volume ratio is 1g:7 ml) of carbon tetrachloride, adding 1.8 times (1.8 eq) of aluminum trichloride and 0.2 times (0.2 eq) of cuprous chloride relative to the molar amount of the intermediate 1, introducing carbon monoxide gas (pressure is 0.4-0.5 Mpa), stirring and heating to 40 ℃, stirring and cooling to 0-10 ℃ after full reaction, adding ice water to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 2, wherein the mass yield is: 112 percent.
Example 2-c: sulfonation reaction
Dropwise adding chlorosulfonic acid with the molar weight 1.7 times (1.7 eq) into Q2 at 0-10 ℃, stirring and heating to 120 ℃ after dropwise adding, monitoring a TLC (thin layer chromatography) plate layer, stirring and cooling to 0-10 ℃ after reaction, adding 10V (mass-volume ratio of 1g to 10 ml) of saturated sodium bicarbonate solution to stop reaction, separating liquid, washing with water, and then distilling under reduced pressure to obtain an intermediate 3 with the mass yield: 138% of the total weight.
Example 2-d: bromination reaction
Dissolving the intermediate 3 in 5V (mass-volume ratio is 1g:5 ml) of carbon tetrachloride, adding 0.3 time (0.3 eq) of dibenzoyl peroxide, after the addition is finished, dropwise adding 3.2 times (3.2 eq) of N-bromosuccinimide of the intermediate 3, stirring and heating to 70 ℃, after full reaction, stirring and cooling to 0-10 ℃, adding 8V (mass-volume ratio is 1g:8 ml) of saturated sodium bicarbonate solution to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 4, wherein the mass yield is: 128 percent.
Example 2-e: wittig reaction
Under the protection of nitrogen, dissolving the intermediate 2 in N, N-dimethylformamide 10V (the mass volume ratio is 1g:10 ml), adding triphenylphosphine with the molar weight being 1.5 times (1.5 eq), stirring and heating to 60 ℃; and after full reaction, stirring and cooling to 0-10 ℃, adding sodium methoxide (1.8 eq) with the molar weight of 1.8 times and intermediate 4 with the molar weight of 2.0 times (2.0 eq), continuing stirring and heating to 60 ℃, after full reaction, stirring and cooling to 0-10 ℃, adding ice water to stop reaction, separating, washing with water, concentrating, and recrystallizing to obtain intermediate 5 with the mass yield of 190%.
Example 2-f: reduction reaction
Dissolving the intermediate 5 in methanol (8V), adding 0.2 times of palladium/carbon (0.2 eq) in molar weight, introducing hydrogen, keeping the temperature at room temperature under normal pressure, fully reacting, filtering, cooling, concentrating, recrystallizing and drying to obtain an intermediate 6 with the mass yield of 93%.
Example 2-g
Dissolving the intermediate 6 in ethanol/water (volume ratio of 10: 1) (8V), adding sodium hydroxide (2.0 eq), dropwise adding Boc anhydride (2.2 eq) at 20-30 ℃, keeping the temperature at room temperature for reaction for 10-12 h after dropwise adding, monitoring a TLC plate layer, filtering after the reaction is finished, condensing the filtrate to separate out a large amount of solid, cooling to 0-5 ℃, concentrating and drying to obtain an intermediate 7, wherein the mass yield is 139.7%, and the intermediate is directly used for the next reaction without further purification.
Example 2-h
Dissolving the intermediate 7 in acetone (10V), fully dissolving the intermediate under stirring, adding a condensing agent DCC (2.2 eq), cooling alkali DMAP (1.0 eq) to 5-10 ℃, adding a reaction reagent p-aminobenzoic acid (2.0 eq) in batches under stirring, heating to room temperature to react for 4 hours after the addition is finished, displaying that the raw materials are completely reacted by a TLC plate layer, filtering, cooling the filtrate to 0-5 ℃, standing overnight, filtering, concentrating the filtrate to 2V, slowly diluting the filtrate into 50V ice water, and filtering to obtain an intermediate 8 which is not dried and directly used for the next reaction.
Example 2-i
Adding the intermediate 8 into 6M hydrochloric acid aqueous solution (10V), heating to 50-60 ℃, reacting for 4h, discharging a large amount of bubbles, completely reacting the raw materials on a plate layer, filtering and drying to obtain an intermediate 9 crude product, dissolving the intermediate 9 crude product into methanol 1V solution, stirring for 2h at room temperature, cooling to 0-5 ℃, filtering, and drying to obtain an intermediate 9 fine product, wherein the two-step quality yield is 102.3%.
Example 2-j
Dissolving the intermediate 9 in dichloromethane (10V), stirring at room temperature until the intermediate is not completely dissolved, adding triethylamine (3.0 eq), cooling to 0-5 ℃, dropwise adding a benzoyl chloride (2.2 eq) solution, heating to 40 ℃ after the dropwise adding is finished, reacting for 4 hours, adding 20V of water after the reaction is finished, stopping the reaction, adding 10V of methanol, stirring to completely dissolve the intermediate, separating liquid, and concentrating an organic phase to obtain a crude compound B.
Example 2-k
And adding methanol/water (1: 1) into the crude compound B, pulping at 5V room temperature, stirring, dropwise adding NaOH to adjust the pH to 9-11, fully dissolving the crude compound, cooling to 0-10 ℃, adjusting the pH to 2-3 by using 6M hydrochloric acid solution, and filtering to obtain a refined compound B with the mass yield of 105.7%.
Example 3
Example 3-a: sulfonation reaction
Cooling Q1 to 0-10 ℃ under stirring, then dropwise adding chlorosulfonic acid (1.7 eq, eq in the following examples are expressed as molar ratio) with the molar weight being 1.7 times that of Q1, stirring and heating to 150 ℃ after dropwise adding, monitoring a TLC plate layer, stirring and cooling to 0-10 ℃ after reaction is completed, then adding saturated sodium bicarbonate solution with the molar weight being 1g to 5ml relative to Q15V (mass to volume ratio, V in the following examples is expressed as mass to volume ratio), quenching reaction, washing with liquid separation water, and then distilling under reduced pressure to obtain an intermediate 1 with mass yield: 145 percent.
Example 3-b: gatemman-koch reaction
Dissolving the intermediate 1 in 10V (mass volume ratio is 1g:10 ml) of carbon tetrachloride, adding 2.2 times (2.2 eq) of aluminum trichloride and 0.5 times (0.5 eq) of cuprous chloride relative to the molar quantity of the intermediate 1, introducing carbon monoxide gas (pressure is 0.4-0.5 Mpa), stirring and heating to 50 ℃, stirring and cooling to 0-10 ℃ after full reaction, adding ice water to stop the reaction, separating liquid, washing with water, concentrating and drying to obtain an intermediate 2, wherein the mass yield is: 112 percent.
Example 3-c: sulfonation reaction
Dropwise adding chlorosulfonic acid with the molar weight 2.0 times (2.0 eq) into Q2 at 0-10 ℃, stirring and heating to 150 ℃ after dropwise adding, monitoring a TLC (thin layer chromatography) plate layer, stirring and cooling to 0-10 ℃ after reaction, adding saturated sodium bicarbonate solution 8V (the mass-volume ratio is 1g:8 ml) to stop the reaction, separating liquid, washing with water, and then distilling under reduced pressure to obtain an intermediate 3 with the mass yield: 135 percent.
Example 3-d: bromination reaction
Dissolving the intermediate 3 in 6V (mass-volume ratio is 1g:6 ml) of carbon tetrachloride, adding 0.1 time (0.1 eq) of dibenzoyl peroxide by molar weight, dropwise adding 2.5 times (2.5 eq) of N-bromosuccinimide by molar weight relative to the intermediate 3 after the dibenzoyl peroxide is added, stirring and heating to 70 ℃, stirring and cooling to 0-10 ℃ after full reaction, adding a saturated sodium bicarbonate solution to stop the reaction, separating, washing with water, concentrating and drying to obtain an intermediate 4 with mass yield: 116 percent.
Example 3-e: wittig reaction
Under the protection of nitrogen, dissolving the intermediate 2 in 8V N, N-dimethylformamide (the mass volume ratio is 1g:8 ml), adding triphenylphosphine with the molar weight being 2.0 times (2.0 eq), and stirring and heating to 80 ℃; and after full reaction, stirring and cooling to 0-10 ℃, adding 2.0 times of molar weight of sodium methoxide (2.0 eq) and 2.5 times of molar weight of intermediate 4 (2.5 eq), continuing stirring and heating to 80 ℃, after full reaction, stirring and cooling to 0-10 ℃, adding ice water to stop reaction, separating, washing, concentrating and recrystallizing to obtain intermediate 5.
Example 3-f: reduction reaction
Dissolving the intermediate 5 in methanol (10V), adding palladium/carbon (0.1 eq) with the molar weight of 0.1 time, introducing hydrogen, keeping the temperature at room temperature under normal pressure, fully reacting, filtering, cooling, concentrating, recrystallizing and drying to obtain an intermediate 6.
Example 3-g
Taking intermediate 6 and dissolving the intermediate in THF/H2Adding potassium hydroxide (2.0 eq) into O (12V) with the volume ratio of 5:1, dropwise adding Boc anhydride (2.1 eq) at 20-30 ℃, and after dropwise adding, carrying out heat preservation reaction at room temperature for 12-13 h, wherein TLAnd (3) monitoring the C plate layer, filtering after the reaction is finished, condensing the filtrate to separate out a large amount of solid, cooling to 0-5 ℃, concentrating and drying to obtain an intermediate 7, wherein the mass yield is 138.5%, and the intermediate is directly used for the next reaction without further purification.
Example 3-h
Dissolving the intermediate 7 in DMSO (10V), fully dissolving the intermediate under stirring, adding a condensing agent EDCI (1.5 eq), HOBT (1.0 eq) and an alkali triethylamine (2.0 eq) into the DMSO, cooling to 5-10 ℃, adding a reaction reagent aminobenzoic acid (2.5 eq) in batches under stirring, heating to room temperature after the addition is finished, reacting for 8 hours, displaying that the raw materials are completely reacted by a TLC plate layer, diluting the raw materials into 50V ice water under stirring, filtering to obtain an intermediate 8, and directly using the intermediate 8 for the next reaction without drying.
Example 3-i
Adding the intermediate 8 into 6M hydrochloric acid aqueous solution (10V), heating to 50-60 ℃, reacting for 3h, discharging a large amount of bubbles, completely reacting the raw materials on a plate layer, filtering and drying to obtain an intermediate 9 crude product, dissolving the intermediate 9 crude product into acetone (2V) solution, stirring for 2h at room temperature, cooling to 0-5 ℃, filtering, and drying to obtain an intermediate 9 fine product, wherein the two-step quality yield is 97.4%.
Example 3-j
Dissolving the intermediate 9 in DMA (5V), stirring at room temperature to fully dissolve the intermediate, adding triethylamine (3.5 eq), cooling to 0-5 ℃, dropwise adding a p-methoxybenzoyl chloride solution (2.2 eq) or a benzoyl chloride solution (2.2 eq), heating to 60 ℃ after dropwise adding is finished, reacting for 4 hours, diluting the mixture into 50V water after the reaction is finished, and filtering to obtain a crude compound A or B.
Example 3-k
Adding the crude product of the compound A or B into a methanol/water solution (1: 1) at 5V, stirring for insolubilization, dropwise adding NaOH to adjust the pH to 9-11, fully dissolving the crude product of the compound, cooling to 0-10 ℃, adjusting the pH to 2-3 by using a 6M hydrochloric acid solution, and filtering to obtain a refined product of the compound A or B, wherein the mass yield of the compound A is 106.4% or the mass yield of the compound B is 102.6%.
Example 4
Bacteriostatic test of stilbene type compound
4.1 Experimental principle
Broth dilution 96-well plate method.
4.2 Experimental procedures
(1) Bacterial Activity assay
Preparing a bacterial culture medium, dipping standard strains and clinical strains of staphylococcus aureus liquid, escherichia coli liquid, pleuropneumonia liquid and streptococcus pneumoniae by using an inoculating ring, coating the standard strains and the clinical strains on the culture medium, placing the culture medium in a constant-temperature incubator at 37 ℃, and culturing for 16-24 hours.
(2) Preparation of bacterial liquid
Preparing nutrient broth culture medium, picking single bacterial colony from the bacterial culture medium, adding the single bacterial colony into 1ml of nutrient broth, and recovering the bacteria by shaking.
(3) Preparation of medicinal liquid
The stilbene type compound A, B synthesized in example 1 of the present invention was dissolved in 50ml of sterilized water, and prepared into 512 μ g/ml of a drug, which was filtered through a sterile filter head for use. If insoluble drugs are encountered, 1-2 ml of organic solvent is used for completely dissolving the drugs, and then the drugs are diluted to the required concentration by sterile water.
(4) 96 well plate addition
a) Each well of the 96-well plate was added to 100 μ L of broth (except for negative control wells).
b) And adding 100 mu L of the filtered medicine into the first holes of the ABCDEF rows of the 96-hole plate (uniformly beating and mixing for 5-10 times), and sucking 100 mu L of the filtered medicine from the first holes to the second holes in sequence by taking the rows as the direction, and so on to prepare the liquid medicines with different concentration gradients.
c) The diluted bacterial solution was added to each well in an amount of 100. mu.L (except for positive control).
(5) Culturing
And (3) putting the added 96-well plate into a constant-temperature incubator at 37 ℃, culturing for 16-24 hours, and taking out for observation.
4.3, result judgment
And (3) judging rules:
under the light lined with a black bottom plate, a negative control hole and a positive control hole are observed by naked eyes, wherein the negative control hole is in a turbid state under normal conditions, and the positive control hole is in a clear state.
Two positive control wells dosed, if the medium did not react with the drug, the wells were clear, otherwise, the wells were turbid or a precipitate was formed. If the control is normal, then the rest experimental holes are observed, the turbidity indicates that the medicine has no inhibition effect on the bacteria, and the clarification indicates that the medicine has the inhibition effect on the bacteria. The drug concentration corresponding to the last clear well is the minimum inhibitory concentration. The results of the experiments are tabulated below:
TABLE 1 test of bacteriostatic effect
In conclusion, the stilbene compound A, B synthesized by the invention has better inhibition effect on aspergillus, candida albicans, epidermophyton, histoplasma bacteria, cryptococcus neoformans and microsporum.
Example 5
In vitro antitumor cell test of stilbene type compound
In the experiment, human cervical cancer cell Hela, mouse liver cancer cell HEPA1-6 and pig kidney cell PM-15 are used as test cell strains, and the MTT method is used for respectively testing the antitumor activities of the stilbene compounds A and B. Adding 0.25% trypsin digestion solution, digesting to make adherent cells shed, making into cell suspension, counting 2 QUOTE
104～4 QUOTE 
104Inoculating 200 μ L/mL cell suspension onto 96-well plate, culturing in constant temperature carbon dioxide incubator for 24 hr, changing culture medium, and adding receptorAdding 10% serum culture solution into each hole with the amount of the test drug being 20 μ L/hole, and culturing for 48 hours with 3 times of each hole; adding MTT into a 96-well plate, reacting for 4 hours in an incubator at 20 mu L/well, absorbing supernatant, adding DMSO at 150 mu L/well, shaking for 5min on a shaking table, measuring the absorbance of each well at the position of 570 nm by using a multifunctional microplate reader, taking a test group which is not added with a test drug and is only added with a corresponding solvent as a negative control, and taking Vinorelbine (VBI) as a positive control to calculate the cell inhibition rate, wherein the calculation formula is as follows:
the experimental results are shown in the following table, the stilbene compound A, B in example 1 of the present invention has different degrees of inhibition on the proliferation of cells 1,2 and 3, and the inhibition rate on 3 cells is above 50% at a final concentration of 100 μ g/mL, which indicates that the stilbene compound in the present invention shows a certain antitumor activity at a certain concentration.
TABLE 2 Effect of stilbene-type compounds of the invention on tumor cell proliferation (n = 3)
Example 6
Studies on cardiovascular and cerebrovascular diseases with stilbene compounds of the present invention
1. Effect of stilbene-type Compound of the present invention on thrombosis in rabbits
The test animals were: 30 rabbits with half male and female, weight of 2.5-3.0kg
And (3) testing the sample: the invention relates to a stilbene type compound A and a stilbene type compound B
The test method comprises the following steps: 30 rabbits (2.5-3.0 kg) are selected, and the male and female rabbits are divided into 3 groups at random, and each group comprises 10 rabbits. Feeding water normally in a blank control group, not feeding the drug, feeding clopidogrel in a positive drug control group, feeding a stilbene type compound A in the invention example 1 in a test drug group A in a gavage manner, feeding a stilbene type compound B in the invention example 1 in a test drug group B in a gavage manner, continuously feeding the stilbene type compound B in the invention example 10 in a gavage manner for 10 days, feeding the stilbene type compound A in a gavage manner for 2 hours in the 10 th day, anesthetizing the rabbit with 3.5% sodium pentobarbital, fixing the rabbit in a supine manner, stripping off about 4cm of bilateral common carotid arteries, clamping two ends of the arteries with an artery clamp to block blood flow, penetrating a 12 # fine sewing needle into the carotid arteries from the proximal end, pushing the carotid arteries into 3cm along the blood vessels, penetrating the carotid arteries from the distal end, and introducing knotted cotton threads into the blood vessels. The cotton thread is cut off and allowed to float freely in the blood vessel. The arterial clamp is opened to allow blood flow therethrough. The carotid artery of the rabbit was excised 2h after opening the artery clamp. And taking out the cotton threads, quickly taking out the intravascular silk threads, weighing the wet weight, drying and then weighing the dry weight.
Test results and conclusions: the experimental results are shown in table 3, and the results show that the stilbene compound A, B has equivalent effects with a control drug clopidogrel, and can obviously reduce the wet weight and the dry weight of thrombus.
TABLE 3 Effect of stilbene-type compounds of the invention on arterial thrombosis in rabbits (n = 10)
Note: p <0.05 compared to the placebo control group.
2. Test of influence of stilbene compound on rat hyperlipidemia
The test animals were: 40 rats, male, weight 220-
And (3) testing the sample: lovastatin, Diphenyl Ether type Compound A of inventive example 1, Diphenyl Ether type Compound B of inventive example 1
Administration dose: lovastatin 8mg/kg
The test method comprises the following steps: after receiving the rats, adapting for 3-5 days, collecting blood, measuring the contents of cholesterol and triglyceride in the blood of the rats, establishing a hyperlipemia model, and feeding high-fat feed and a high-fat feed formula to other groups except a blank control group for feeding common rats with maintenance feed: the ordinary feed 87%, cholesterol 3%, lard 10% and the like are continuously fed until the experiment is finished, and the contents of cholesterol and triglyceride in the blood of the rat are measured on the 10 th day to determine that the rat high-fat model is successfully constructed. After the high fat model was successfully constructed, rats of the test drug group a and the test drug group B were administered the stilbene type compound a of example 1 of the present invention and the stilbene type compound B of example 1 of the present invention, respectively, rats of the control drug group were administered lovastatin 8mg/kg, rats of the blank control group and the high fat model group were administered physiological saline for 20 days, and blood was collected to determine the contents of cholesterol and triglyceride in the blood of the rats.
Test results and conclusions: the experimental results are shown in tables 4 and 5, and the results show that the stilbene compound has equivalent effects with lipid-lowering positive drugs, and can obviously lower serum cholesterol and triglyceride of hyperlipidemic rats.
Table 4 effect of stilbene-type compounds of the invention on serum cholesterol in hyperlipidemic rats (n = 10)
Note: p <0.05 compared to the placebo control group and p <0.05 compared to the model group after dosing.
TABLE 5 Effect of stilbene-type compounds of the invention on serum triglycerides in hyperlipidemic rats
Note: p <0.05 compared to the placebo control group and p <0.05 compared to the model group after dosing.
Example 7
Antiviral test of stilbene-type Compound of the present invention
1. Toxicity test of stilbene-type Compound to chick embryo
The stilbene type compounds A and B in example 1 of the invention are respectively prepared into solutions with the concentrations of 20 mug/mL, 10 mug/mL, 5 mug/mL and 2.5 mug/mL by using physiological saline, the physiological saline and the solutions with the concentrations are respectively inoculated into allantoic cavities of 4 10-day-old chick embryos, each of which is 0.2mL, and the chick embryos are incubated in a 37 ℃ constant temperature incubator for 72 hours, the survival condition is observed every day, and the highest concentration of all the chick embryos which survive is the initial concentration of the antiviral proliferation inhibition test.
The physiological saline and the solution of the stilbene type compound A, B with different concentrations have no obvious lethal effect on the chick embryos. The survival is shown in Table 6. Therefore, the highest concentration of 20. mu.g/mL was used as the initial concentration for the antiviral proliferation inhibition assay.
TABLE 6 toxicity test results of inventive stilbene-type compounds on chick embryos
2.
3. The stilbene type compound of the invention is used for testing the inhibition effect of the compound on avian influenza virus
The results of the above chick embryo toxicity test for each of the stilbene type compounds A and B of example 1 of the present invention were 20. mu.g/mL as the drug inoculum size. Compounds A and B were tested separately and 100 embryos were randomly assigned to 5 groups of 20 embryos each. The specific grouping is as follows:
TABLE 7 inhibition test of avian influenza Virus by stilbene-type compound A, B of the present invention
After the inoculation of each group of chick embryos, the chick embryos are continuously incubated in a constant-temperature incubator at 37 ℃, and the survival condition of the chick embryos is observed after 1 time of illumination every 8-12 hours.
The test results are shown in the following table 8, the number of dead embryos in 24 hours in the treatment group and the prevention group is obviously less than that in the infection control group and the normal saline control group, and the number of live embryos in 72 hours is obviously higher than that in other groups without administration, which indicates that the stilbene compounds A and B have obvious inhibition effect on avian influenza virus.
TABLE 8 determination of inhibitory Effect of stilbene-type Compounds of the present invention on influenza Virus
Claims (1)
1. The application of a stilbene compound in preparing medicaments for resisting aspergillus, candida albicans, epidermophyton, histoplasma bacteria, cryptococcus neoformans and microsporum fungal infection, wherein the stilbene compound has a structural formula as follows:
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101367749A (en) * | 2008-09-28 | 2009-02-18 | 中国医学科学院医药生物技术研究所 | A set of mesidino mesitoyl derivant, preparation and application thereof |
| CN103547152A (en) * | 2011-02-23 | 2014-01-29 | 西奈山伊坎医学院 | Inhibitors of bromodomains as modulators of gene expression |
| WO2016094897A1 (en) * | 2014-12-12 | 2016-06-16 | The Jackson Laboratory | Compositions and methods relating to the treatment of cancer, autoimmune disease, and neurodegenerative disease |
| CN110496117A (en) * | 2019-09-30 | 2019-11-26 | 中国科学院微生物研究所 | A kind of new opplication of small molecule compound in the infection of anti-African swine fever virus |
| CN110903224A (en) * | 2018-09-18 | 2020-03-24 | 复旦大学 | Aryl sulfonamide compound, preparation method thereof, pharmaceutical composition and application |
-
2021
- 2021-05-31 CN CN202110596542.XA patent/CN113045461B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101367749A (en) * | 2008-09-28 | 2009-02-18 | 中国医学科学院医药生物技术研究所 | A set of mesidino mesitoyl derivant, preparation and application thereof |
| CN103547152A (en) * | 2011-02-23 | 2014-01-29 | 西奈山伊坎医学院 | Inhibitors of bromodomains as modulators of gene expression |
| WO2016094897A1 (en) * | 2014-12-12 | 2016-06-16 | The Jackson Laboratory | Compositions and methods relating to the treatment of cancer, autoimmune disease, and neurodegenerative disease |
| CN110903224A (en) * | 2018-09-18 | 2020-03-24 | 复旦大学 | Aryl sulfonamide compound, preparation method thereof, pharmaceutical composition and application |
| CN110496117A (en) * | 2019-09-30 | 2019-11-26 | 中国科学院微生物研究所 | A kind of new opplication of small molecule compound in the infection of anti-African swine fever virus |
Non-Patent Citations (5)
| Title |
|---|
| 3 种二苯乙烯类构物的生物活性与临床应用;刘芝兰 等;《广东医学》;20130228;第34卷(第4期);第633页1.6 * |
| Design, synthesis and biological evaluation of suramin-derived dual antagonists of the proinflammatory G protein-coupled receptors P2Y2 and GPR17;Thanigaimalai Pillaiyar 等;《European Journal of Medicinal Chemistry》;20191231;7-8页 * |
| Design, synthesis and structure–activity relationships of some novel，highly potent anti-invasive (E)- and (Z)-stilbenes;Bart I. Roman 等;《Bioorganic & Medicinal Chemistry》;20130627;第21卷;Scheme2，第5055页2.1 * |
| DSD酸的清洁生产工艺;吴仁涛 等;《青岛科技大学学报》;20030831;第24卷(第4期);第359-360页 * |
| Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors;Tuhin Bhowmick 等;《NATURE COMMUNICATIONS》;20140611;全文 * |
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