CN114213406B - Myricetin derivative of 1,3, 4-oxadiazole thioether sulfonate, preparation method and application - Google Patents
Myricetin derivative of 1,3, 4-oxadiazole thioether sulfonate, preparation method and application Download PDFInfo
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Abstract
The invention discloses myricetin derivatives of 1,3, 4-oxadiazole thioether sulfonic acid ester, a preparation method and application thereof, and application of the 1,3, 4-oxadiazole thioether sulfonic acid esterThe myricetin derivative has the following structural general formula,
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a myricetin derivative of 1,3, 4-oxadiazole thioether sulfonate, a preparation method and application thereof.
Background
Myricetin is a natural flavonoid compound widely existing in plants. Pharmacological studies have now shown that myricetin is a flavonoid with a wide range of biological activities, e.g., anti-tumor, anti-bacterial, anti-viral, hypoglycemic and other biological activities. The natural products have various chemical components and novel structures, and play an important role in the discovery of new drugs and lead compounds. The flavonoid myricetin has attracted extensive attention and research due to the advantages of wide plant sources, biological activity and the like.
In 2014, zhao et al (Zhaohu Ju. Myricetin derivative synthesis and bioactivity research [ D ]. Guizhou university, 2014) reported a series of derivatives containing heterocycloalkyl myricetin, and the in vitro proliferation inhibition activity of the synthesized compound on breast cancer cells MDA-MB-231 was tested by using an MTT method, wherein the inhibition activity of part of the compounds is higher than that of a control drug gefitinib (9.73 +/-8.04%) at a concentration of 1 mu mol/L.
In 2015, xue et al (Xue, W.; song, B.A.; et al, eur.J.Med.chem.,2015,97, 155-163.) reported a series of acylhydrazone-containing myricetin derivatives. The MTT method is utilized to carry out in-vitro proliferation inhibition activity test of human breast cancer cells MDA-MB-231 on the synthesized compound, and research results show that: the myricetin acylhydrazone derivatives have good inhibition rate on human breast cancer cells MDA-MB-231.
In 2020, tang et al (Tang, X.; zhang, C.; et. New J. Chem.2020,44, 2374-2379.) synthesized a series of myricetin ferulate derivatives and tested the antiviral activity (TMV) of the synthesized compounds using the semi-leaf cumic spot method, the results showed that: part of the compounds have protective activity EC on tobacco mosaic virus at the concentration of 500 mu g/mL 50 Values of 196.1, 425.3 and 386.7 μ g/mL were superior to the control drug ningnanmycin (447.9 μ g/mL).
The 1,3, 4-oxadiazole thioether is a five-membered nitrogen-containing heterocyclic ring and has wide application prospect. It has wide application in the fields of medicine and organic synthesis. 1,3, 4-oxadiazole thioether has been widely researched and developed because it exhibits various biological activities of anticancer, bacteriostatic, antiviral, antifungal, insecticidal, etc. Meanwhile, sulfonate or carboxylate derivatives have a broad spectrum of biological activity and are receiving increasing attention in the agricultural field. It has been shown to have biological activities such as anti-tumor, anti-viral, anti-bacterial, anti-fungal, etc.
A series of 2-substituted methylthio-5- (4-amino-2-methylpyrimidin-5-yl) -1,3, 4-oxadiazole sulfide derivatives were synthesized in 2015 by Wu et al (Wu, W.N.; chen, Q.; et al (Wu, W.N.; med. Chem. Lett.2015,25, 2243-2246.) by active group splicing. The synthesized compound is tested for anti-TMV activity, and the result shows that the compound has the advantages ofHas good antiviral activity, wherein the half-maximal effective concentration EC of the compound 50 246.48 mug/mL is better than 301.83 mug/mL of the contrast drug ningnanmycin.
A series of 1-aryl-4-hydroxy-1H-pyrrole-2 (5H) -ketone derivatives containing 1,3, 4-oxadiazole thioether groups are synthesized by Wang et al (Wang, P.Y.; chen, L.; et al, saudi chem.Soc.2017,21, 315-323.) in 2017, and antibacterial activity determination is carried out on the synthesized compounds, and the results show that the compounds have good antibacterial activity, and partial compounds have EC (effective chemical formula) on rice bacterial blight 50 The values are respectively 8.6 mu g/mL and 7.3 mu g/mL, which are superior to the control drug bismerthiazol (92.6 mu g/mL).
In 2020 Guo et al (Guo, T.; xia, R.J.; et al. Phosphorus, sulfurr silicon relat. Elem.2020,195, 123-130.) synthesized a series of thiophene sulfonate containing 1, 4-pentadien-3-one derivatives, and the antibacterial activity of the synthesized compounds was determined, the results showed that the compounds had good antibacterial activity, and some of the compounds had EC against citrus canker pathogen 50 The values are 11.0 mug/mL respectively, which is better than the control drug bismerthiazol (51.6 mug/mL).
In summary, myricetin, 1,3, 4-oxadiazole thioether and sulfonate all have certain biological activity, but no report exists that the myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate is synthesized by introducing an active group containing 1,3, 4-oxadiazole thioether sulfonate into myricetin and medical activity test is carried out.
Disclosure of Invention
The invention provides a myricetin derivative of 1,3, 4-oxadiazole thioether sulfonate, a preparation method and application, aims to overcome the defects and provide a myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate and having better inhibitory activity on cancer cells.
In order to achieve the purpose, the invention provides the following technical scheme:
the first technical scheme is as follows: a myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate has the following structural general formula:
wherein R is substituted phenyl or aromatic heterocyclic radical; n is the number of carbons in the carbon chain and is any integer between 2 and 6.
Further, the substituted phenyl is an alkyl group containing C1-6, an alkoxy group containing C1-6, a nitro group, a halogen atom or a hydrogen atom at the ortho, meta or para positions of the benzene ring.
Furthermore, the substituted aromatic heterocyclic group is an alkyl group containing C1-6, an alkoxy group containing C1-6, a nitro group, halogen or hydrogen at the ortho, meta or para position on the substituted aromatic heterocyclic group.
Further, the aromatic heterocyclic group includes a thienyl group, a furyl group, a pyrrolyl group or a pyridyl group.
The second technical scheme is as follows: a preparation method of myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate comprises the following steps:
(1) Taking myricitrin and methyl iodide as raw materials, taking crystallized potassium carbonate as a catalyst, and preparing 3-hydroxy-3 ',4',5, 7-pentamethoxyl myricetin (an intermediate 1) by acid regulation:
(2) Taking the intermediate 1 and dibromoalkane with different chain lengths as raw materials, potassium carbonate as a catalyst, and N, N-Dimethylformamide (DMF) as a solvent to prepare 3-bromo-5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
(3) Preparing 2-hydroxyacetylhydrazine (intermediate 3) by using ethyl glycolate and 80% hydrazine hydrate by mass and ethanol as a solvent:
(4) Taking the intermediate 3, potassium hydroxide and carbon disulfide as raw materials, taking ethanol as a solvent, and adjusting the pH to 1-3 by using 5% by mass of dilute hydrochloric acid to prepare the (5-mercapto-1, 3, 4-oxadiazole-2-yl) methanol (intermediate 4):
(5) Taking the intermediate 2 and the intermediate 4 as raw materials, potassium carbonate as a catalyst, and N, N-dimethylformamide as a solvent to prepare the myricetin derivative (compound A) containing 1,3, 4-oxadiazole thioether:
(6) The myricetin derivative (target compound B) containing 1,3, 4-oxadiazole thioether sulfonate is prepared by taking a compound A and a substituted sulfonyl chloride compound as raw materials, sodium hydride as an acid-binding agent and dichloromethane as a solvent:
the technical scheme is as follows: an application of myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate in preparing medicine for inhibiting cancer cells is disclosed.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, 1,3, 4-oxadiazole thioether and sulfonic ester with activity are introduced into a myricetin structure to synthesize a series of myricetin derivatives containing 1,3, 4-oxadiazole thioether sulfonate, compared with a lead compound myricetin, the sulfonic ester group structure of the compound is opened, the compound can play an alkylation role with guanine in DNA of cells to destroy the structure and function of the DNA, and the inhibitory activity on cancer cells is tested by an MTT method, which shows that the myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate has better inhibitory activity on the cancer cells.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but rather as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
Example 1
A process for the preparation of methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) benzenesulfonate (target compound B1), comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate 1):
5.00g (10.77 mmol) of myricitrin and 19.34g (140 mmol) of crystal K are added into a 250mL round-bottom flask in sequence 2 CO 3 And 80mL of DMF, and after stirring at room temperature for 0.5 to 1h, 7.50mL (120 mmol) of methyl iodide was slowly added dropwise, stirring at room temperature for 48h, and the reaction was followed by tlc (methanol: ethyl acetate =1, 4, V/V. After the reaction is stopped, filtering and precipitating, washing filter residues by dichloromethane, combining the filter residues, diluting the filter residues by 100mL of water, extracting the filter residues for three times by dichloromethane, combining organic layers, decompressing and concentrating, then dissolving the concentrate in 100mL of absolute ethyl alcohol, heating to reflux, adding 10mL of concentrated hydrochloric acid (commercial concentrated hydrochloric acid with the concentration of 35-37%) under reflux after the solution is clarified, then separating out yellow solid, continuing to react for 2h, cooling to room temperature, and filtering to obtain a crude product of 3-hydroxy-3 ',4',5, 7-pentamethoxyl myricetin (intermediate 1) with the yield: 62 percent.
(2) Preparation of 3- (3-bromopropoxy) -5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
1.17g (3 mmol) of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate 1) and 1.66g K are sequentially added into a 100mL single-neck round-bottom flask 2 CO 3 (12 mmol) and 30mL DMF, stirring at room temperature for 0.5-1h, adding 2.42g 1, 3-dibromopropane (12 mmol), continuing the reaction at this temperature for 12h, and monitoring the reaction by TLC (ethyl acetate). After the reaction was stopped, the reaction mixture was dispersed in 50mL of water, extracted with ethyl acetate (3X 25 mL), and the resulting ethyl acetate layer was washed with 1mol/L HCl and saturated NaHCO in that order 3 After washing with a saturated aqueous NaCl solution 2 times, the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography purification under reduced pressure (petroleum ether: ethyl acetate =2:1,v/V) was performed to obtain a white solid (intermediate 2) in yield: 81.6 percent.
(3) Preparation of 2-hydroxyacetylhydrazide (intermediate 3):
in a 50mL three-necked flask, 1.04g (10 mmol) of ethyl glycolate and 20mL of ethanol were sequentially added and dissolved by stirring, and then 0.7mL (15 mmol) of 80% hydrazine hydrate was added dropwise to the system, and after completion of the dropwise addition, the mixture was stirred under reflux for about 24 hours. After the reaction is finished, most of the solvent is removed under reduced pressure, the mixture is placed into a refrigerator at 4 ℃ to precipitate white solid, and the yield is 89 percent after suction filtration.
(4) Preparation of (5-mercapto-1, 3, 4-oxadiazol-2-yl) methanol (intermediate 4):
in a 50mL three-necked flask, 0.18g (2 mmol) of 2-hydroxyacetylhydrazide (intermediate 3), 0.17g (3 mmol) of potassium hydroxide and 18mL of ethanol were sequentially added, and after stirring uniformly, 0.18mL (3 mmol) of carbon disulfide was slowly added dropwise, and then the mixture was refluxed at 80 ℃ for 5h and followed by tlc (petroleum ether: ethyl acetate = 1. After the reaction was stopped, the solvent was removed under reduced pressure, the residue was poured into 50mL of distilled water, followed by suction filtration, the pH of the filtrate was adjusted to 1-3, extraction was performed with ethyl acetate (3X 25 mL), the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to give a yellow oil, which was cooled and left to stand to form a yellow solid with a yield of 85%.
(5) Preparation of 3- (3- ((5- (hydroxymethyl) -1,3, 4-oxadiazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one (Compound A1):
in a 250mL three-necked flask were charged 1.59g (12 mmol) of (5-mercapto-1, 3, 4-oxadiazol-2-yl) methanol (intermediate 4) and K 2 CO 3 2.49g (18 mmol) and 100mL DMF, stirring for 5min, then adding 5.09g (10 mmol) of 3- (3-bromopropoxy) -5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2), then reacting the mixture at 80-90 ℃ for 5H, TLC tracing reaction (petroleum ether: ethyl acetate = 1. After the reaction is stopped, pouring the reaction solution into 90mL of distilled water, precipitating a large amount of white solid, then performing suction filtration and drying to obtain a crude product, and purifying by column chromatography (petroleum ether: ethyl acetate =1, 2, V/V) to obtain a compound A1, wherein the yield is as follows: 91 percent.
(6) Preparation of methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) benzenesulfonate (target compound B1):
in a 50mL three-necked flask, 0.89g (1.6 mmol) of 3- (3- ((5- (hydroxymethyl) -1,3, 4-oxadiazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one (compound A1) and 20mL of dichloromethane were charged, and after dissolving with stirring at ordinary temperature, 0.08g (2.0 mmol) of NaH was charged, and after stirring for 3 to 5 minutes, 0.34g (1.9 mmol) of benzenesulfonyl chloride was added, followed by reaction at room temperature for 3 to 5 hours. The reaction was followed by TLC (petroleum ether: ethyl acetate = 1. When the reaction was completed, the reaction was stopped, the reaction solution was dispersed with 50mL of water, extracted with dichloromethane (3 × 25 mL), and the organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate =1, 2, V/V) to obtain the objective compound B1, yield: 40 percent.
Example 2
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 4-bromobenzenesulfonyl chloride. Methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-bromobenzenesulfonate (target compound B2) was produced in 52% yield.
Example 3
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 4-nitrobenzenesulfonyl chloride. Methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-nitrobenzenesulfonate (target compound B3) was produced in a yield of 31%.
Example 4
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 2-thiophenesulfonyl chloride. (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) methylthiophene-2-sulfonate (target compound B4) was produced in a yield of 36%.
Example 5
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 2-bromobenzenesulfonyl chloride. Methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 2-bromobenzenesulfonate (target compound B5) was produced in 52% yield.
Example 6
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 4-methoxybenzenesulfonyl chloride. Methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-methoxybenzenesulfonate (target compound B6) was produced in 45% yield.
Example 7
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 4-methylbenzenesulfonyl chloride. Methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-methylbenzenesulfonate (target compound B7) was produced in 61% yield.
Example 8
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 3-fluorobenzenesulfonyl chloride. Methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 3-fluorobenzenesulfonate (target compound B8) was produced in 56% yield.
Example 9
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 4-chlorobenzenesulfonyl chloride. Methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-chlorobenzenesulfonate (target compound B9) was produced in 44% yield.
Example 10
The same as example 1 except that in step (6), benzenesulfonyl chloride was replaced with 4-cyanobenzenesulfonyl chloride. Methyl (5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-cyanobenzenesulfonate (target compound B10) was produced in 41% yield.
Example 11
The difference from example 1 is that in step (2), 1, 3-dibromopropane is replaced by 1, 4-dibromobutane. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) benzenesulfonate (target compound B11) was produced in a yield of 47%.
Example 12
The same as example 2 except that in step (2), 1, 3-dibromopropane was replaced with 1, 4-dibromobutane, and in step (6), benzenesulfonyl chloride was replaced with 4-bromobenzenesulfonyl chloride. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-bromobenzenesulfonate (target compound B12) was produced in 54% yield.
Example 13
The difference from example 3 is that in step (2), 1, 3-dibromopropane is replaced by 1, 4-dibromobutane. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-nitrobenzenesulfonate (target compound B13) was produced in 37% yield.
Example 14
The procedure is as in example 4, except that in step (2), 1, 3-dibromopropane is replaced by 1, 4-dibromobutane. (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) methylthiophene-2-sulfonate (target compound B14) was produced in 38% yield.
Example 15
The same as in example 5 except that in the step (2), 1, 3-dibromopropane was replaced with 1, 4-dibromobutane. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 2-bromobenzenesulfonate (target compound B15) was produced in 53% yield.
Example 16
The same as in example 6 except that in the step (2), 1, 3-dibromopropane was replaced with 1, 4-dibromobutane. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-methoxybenzenesulfonate (target compound B16) was produced in 54% yield.
Example 17
The same as in example 7 except that in the step (2), 1, 3-dibromopropane was replaced with 1, 4-dibromobutane. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-methylbenzenesulfonate (target compound B17) was produced in 56% yield.
Example 18
The same as in example 8 except that in the step (2), 1, 3-dibromopropane was replaced with 1, 4-dibromobutane. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 3-fluorobenzenesulfonate (target compound B18) was produced in 64% yield.
Example 19
The same as in example 9 except that in the step (2), 1, 3-dibromopropane was replaced with 1, 4-dibromobutane. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-chlorobenzenesulfonate (target compound B19) was produced in 47% yield.
Example 20
The same as in example 10 except that in the step (2), 1, 3-dibromopropane was replaced with 1, 4-dibromobutane. Methyl (5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-cyanobenzenesulfonate (target compound B20) was produced in 34% yield.
The physicochemical properties of myricetin derivatives containing 1,3, 4-oxadiazole thioether sulfonic acid esters synthesized in examples 1 to 20 are shown in Table 1, hydrogen nuclear magnetic resonance spectrum: ( 1 HNMR), carbon spectrum (C) 13 CNMR) and fluorine spectrum ( 19 FNMR) data are shown in table 2.
TABLE 1 physicochemical Properties of the target Compounds obtained in examples 1 to 20
TABLE 2 NMR spectra data of the target compounds
Test example 1
1 test method
1) Cell culture and drug action
Using 1640 medium containing 10% fetal bovine serum at 37 ℃ and 5% CO 2 Culturing A2780 cells in a saturated humidity incubator, changing culture solution every two days, and carrying out subculture once every 3-4 days. The drug is prepared into 1mM and 10mM stock solutions by taking DMSO as a solvent, and is diluted into action concentrations of 1 mu M and 10 mu M by using a culture medium when in use, and acts on A2780 cells in a logarithmic growth phase by taking DMSO as a negative control group and cisplatin as a positive control group.
2) MTT colorimetric method
Cells in the logarithmic growth phase were taken, digested with 0.25% trypsin, then the digestion was stopped with 1640 medium containing 10% fetal bovine serum, and after centrifugation, resuspended in 1640 medium containing 10% fetal bovine serum. A96-well plate is taken, and 200 mu L of PBS is added to each well on the periphery of the plate for sealing, so that the saturation humidity in the experiment is ensured. In the middle six rows, each with 100. Mu.LCell suspension with cell density of 2 x 10 3 About one/hole. The last row was a blank control group to which the same volume of complete medium was added. At 37 ℃ C, 5% CO 2 Culturing for 24h in a saturated humidity incubator, completely attaching cells to the wall, removing the culture medium, adding complete culture media containing different drugs, taking 100 mu L of the complete culture media in each hole, respectively taking DMSO and cisplatin as a negative control and a positive control to carry out the same treatment, and adding 100 mu L of the complete culture media in a blank control group. And (5) continuing culturing. After 24h, the effect of the drug is observed under an inverted microscope and photographed, after 48h, the effect of the drug is also observed under the inverted microscope and photographed, then 100 mu L of 0.5mg/mL MTT solution is added into each hole, and the MTT solution is shaken up and down and left and right to enable the MTT to be fully mixed. After further incubation at 37 ℃ for 4h, 100. Mu.L DMSO was added to each well, incubated overnight at 37 ℃ and the absorbance at 490nm was measured using a microplate reader. The inhibition rate per well was calculated by repeating 3 wells per sample concentration.
3) Statistical method
The experimental results are analyzed by using SPSS statics and using One-Way ANOVA method, and P <0.05 shows that the data have significant difference.
2. Results of the test for inhibiting the activity of ovarian cancer A2780 cells are shown in Table 3.
TABLE 3 inhibition of ovarian cancer A2780 cells by 48h for samples prepared in examples 1-20
Note: the inhibition rate of different agents on A2780 cells at a set concentration is less than 0.05.
Through preliminary screening, some compounds have obvious potential of antitumor activity no matter at the concentration of 1 mu mol/L or 10 mu mol/L, even the potential is obviously higher than that of a positive control drug cisplatin, and the drugs belong to concentration dependence: at 1 mu mol/L, the compound shows that the compound can inhibit the proliferation of ovarian cancer A2780 cells; at 10. Mu. Mol/L, significant inhibitory activity was shown, such as B3, B6, B7, B16, B17; the inhibiting activity is obviously higher than that of a positive control drug cisplatin.
As shown by the experimental activity data, the myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate has a certain inhibitory effect on ovarian cancer A2780 cells, wherein part of target compounds have excellent inhibitory activity on ovarian cancer A2780 cells, can be used as a potential ovarian cancer A2780 cell inhibiting medicine, and has a good application prospect.
All experimental samples were compared to the negative control (dmso) in the experiment, and if the value is negative, the significant difference indicates that the compound has not only no inhibitory activity but also a proliferation promoting effect; if negative, there is no significant difference, indicating that the drug is inactive.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.
Claims (3)
1. A myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonic acid ester is characterized by comprising the following components in percentage by weight:
(methyl 5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) benzenesulfonate,
(methyl 5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-bromobenzenesulfonate,
(methyl 5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-nitrobenzenesulfonate,
(5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) methylthio-phene-2-sulfonate,
(methyl 5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 2-bromobenzenesulfonate,
(methyl 5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-methoxybenzenesulfonate,
(methyl 5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-methylbenzenesulfonate,
(methyl 5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 3-fluorobenzenesulfonate,
(methyl 5- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -1,3, 4-oxadiazol-2-yl) 4-cyanobenzenesulfonate,
(methyl 5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) benzenesulfonate,
(methyl 5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-methoxybenzenesulfonate,
(methyl 5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-methylbenzenesulfonate,
(5- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -1,3, 4-oxadiazol-2-yl) 4-cyanobenzenesulfonic acid methyl ester.
2. A method for preparing myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate according to claim 1, comprising the steps of:
(1) Taking myricitrin and methyl iodide as raw materials, taking crystallized potassium carbonate as a catalyst, and carrying out acid regulation to prepare 3-hydroxy-3 ',4',5, 7-pentamethoxyl myricetin, namely an intermediate 1;
(2) Preparing 3-bromo-5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one by using the intermediate 1 and dibromoalkane as raw materials, potassium carbonate as a catalyst and N, N-dimethylformamide as a solvent, wherein the intermediate 2 is obtained;
(3) Preparing 2-hydroxyacetylhydrazine, namely an intermediate 3, from ethyl glycolate and 80% hydrazine hydrate by using ethanol as a solvent;
(4) Taking the intermediate 3, potassium hydroxide and carbon disulfide as raw materials, taking ethanol as a solvent, and adjusting the pH to 1-3 by using 5% dilute hydrochloric acid to prepare (5-mercapto-1, 3, 4-oxadiazole-2-yl) methanol, namely the intermediate 4;
(5) Taking the intermediate 2 and the intermediate 4 as raw materials, potassium carbonate as a catalyst, and N, N-dimethylformamide as a solvent to prepare the myricetin derivative containing 1,3, 4-oxadiazole thioether, namely a compound A;
(6) The myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate is prepared by taking a compound A and a substituted sulfonyl chloride compound as raw materials, sodium hydride as an acid-binding agent and dichloromethane as a solvent, and the myricetin derivative is a target compound B.
3. Use of the myricetin derivative containing 1,3, 4-oxadiazole thioether sulfonate according to claim 1 in the preparation of a medical cancer cell inhibiting medicament.
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