CN108530427B - Quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, and preparation method and application thereof - Google Patents

Quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, and preparation method and application thereof Download PDF

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CN108530427B
CN108530427B CN201810317834.3A CN201810317834A CN108530427B CN 108530427 B CN108530427 B CN 108530427B CN 201810317834 A CN201810317834 A CN 201810317834A CN 108530427 B CN108530427 B CN 108530427B
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薛伟
李琴
付应霄
刘芳
怀自友
夏榕娇
郭涛
陈英
蒋仕春
汤旭
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Abstract

The invention discloses a quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, a preparation method and application thereof, wherein the general formula (I) is as follows:
Figure DEST_PATH_IMAGE001
wherein R is1、R2Is phenyl, substituted phenyl or substituted aromatic heterocyclic radical; r3Is more than one hydrogen atom, methoxy, nitro, methyl, trifluoromethyl or halogen atom contained in 5, 6, 7 or 8 position of quinazoline. The compound has excellent inhibitory activity on liver cancer SMMC-7721 cells, shows higher antitumor activity and can be used as a potential antitumor agent.

Description

Quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemical industry, in particular to a quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, a preparation method of the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, and application of the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative in preparation of anti-human liver cancer drugs.
Background
Curcumin, a polyphenol compound derived from turmeric, is widely used as a spice, a food preservative, monosodium glutamate and a dye. 1, 4-pentadiene-3-ketone compound is an important curcumin derivative, which has become an important medical lead and is attracted by people because of having broad-spectrum biological activities of killing insects, inhibiting bacteria, resisting plant viruses, resisting tumors, diminishing inflammation, resisting oxidation and the like. Researches in recent years show that the 1, 4-pentadiene-3-ketone compound has important functions in preventing and treating agricultural diseases and has important application value in the field of medicines.
Xuehei et al (Xuehei, Chenyu, Boehung, Gonghuayu, Liheng, Popule.) study on the synthesis and antitumor Activity of curcumin derivatives containing oxime esters [ J ] St.Mol.Sci, 2013,29(3),198-204.) synthesized a series of asymmetric 1, 5-diaryl-1, 4-pentadiene-3-ketoxime ester compounds, which were found to exhibit a certain inhibitory activity against PC3 cells of prostate cancer cells after 72 hours of treatment at a drug concentration of 10. mu.g/L. Luo et al (Luo, H.; Yang, S.; Cai, Y.; Peng, Z.; Liu, T.Synthesis and biological evaluation of novel 6-chloro-quinazoline derivatives as potential inhibitors [ J ]. European Journal of medicinal Chemistry,2014,84:746-752.) synthesized a series of quinazoline-containing 1, 4-pentadien-3-one compounds that were found to have certain inhibitory activity against human gastric cancer cells (MGC-803), human breast cancer cells (Bcap-37) and prostate cancer cells (PC3) after 72 hours of treatment at a drug concentration of 10 μ M.
A series of 2-imidazolyl-1, 4-pentadiene-3-ketone derivatives are synthesized by Liuchunli and the like (Liuchunli, Schuman, Liujinyan, Weibingo, Maofei, Yanjie, Li Jian. 2-imidazolyl-1, 4-pentadiene-3-ketone derivatives are synthesized and antibacterial activity research [ J ]. Chinese medicinal chemistry J, 2015,25:15-23.) shows that the compounds have a certain inhibiting effect on staphylococcus epidermidis and staphylococcus aureus. Baldwin et al (Baldwin, P.R.; Reeves, A.Z.; Powell, K.R.; Napier, R.J.; Swimm, A.I.; Sun, A.; Giesler, K.; Bommarius, B.; Shinnick, T.M.; Snyder, J.P.; Liotta, D.C.; Kalman, D.Monocarbyl analogs of current inhibition of reactive inhibition of curcumin, 2015,92: 693-.
Quinazolinone compounds, as an important heterocyclic compound, are hot spots in the field of medicament creation because of the structure in the variability and the broad-spectrum and high-efficiency biological activity. Recent studies have shown that: the compound has wider prospect in the aspect of resisting plant viruses.
A series of Schiff base compounds containing a 4(3H) -quinazolinone structure were designed and synthesized in 2007 Gao et al (Gao, X.; Cai, X.; Yan, K.; Song, B.; Gao, L.; Chen, Z. Synthesis and biological activities of 2-phenyl-3- (substitated-benzamine) -4(3H) -quinazolinone derivatives [ J ]. Molecules,2007,12:2621 and 2642.), and activity test of anti-TMV was performed on the compounds. The test result shows that: at a drug concentration of 500. mu.g/mL, most of the synthesized compounds had some in vivo inhibitory effect on TMV.
In 2014 Ma et al (Ma, J.; Li, P.; Li, X.; Shi, Q.; Wan, Z.; Hu, D.; Jin, L.; Song, B.Synthesis and antibiotic Bioactivity of Novel 3- ((2- ((1E,4E) -3-oxo-5-arylpenta-1,4-dien-1-yl) phenoxy) methyl) -4(3H) -quinazolinone Derivatives [ J ]. J.Agric.Food chem.,2014,62, 8928-pentadien 8934.) A series of quinazolinone-containing pentadienone compounds were synthesized and tested for their activity against TMV. The test result shows that: at a medicament concentration of 500 mug/mL, most of the synthesized compounds have certain in-vivo inhibition and cure effects on TMV. Wherein the partial compound has excellent effect on in-vivo treatment, and the inhibition rate of the partial compound is better than that of a control medicament, namely ningnanmycin.
Disclosure of Invention
The invention aims to overcome the defects and provide the 1, 4-pentadiene-3-ketoxime ether derivative which has good inhibition effect on human liver cancer cells, shows higher antitumor activity and can be used for preparing an antitumor agent.
The invention also aims to provide a preparation method of the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative.
The invention also aims to provide application of the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative in preparation of anti-human liver cancer drugs.
The invention relates to a quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, which has the following general formula:
Figure BDA0001624378420000021
wherein R is1、R2Is phenyl, substituted phenyl or substituted aromatic heterocyclic radical; r3Is more than one hydrogen atom, methoxy, nitro, methyl, trifluoromethyl or halogen atom contained in 5, 6, 7 or 8 position of quinazoline.
The invention relates to a preparation method of quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives, which comprises the following steps: (1) preparing 2- (hydroxyphenyl) -3-butene-2-one or 4- (hydroxyphenyl) -3-butene-2-one from acetone, salicylaldehyde or 4-hydroxybenzaldehyde under alkaline conditions:
Figure BDA0001624378420000031
(2) preparing 1-substituted aryl-5- (4-hydroxyphenyl) -1, 4-pentadiene-3-ketone or 1-substituted aryl-5- (2-hydroxyphenyl) -1, 4-pentadiene-3-ketone under alkaline conditions by using substituted aromatic aldehyde, 2- (hydroxyphenyl) -3-buten-2-ketone or 4- (hydroxyphenyl) -3-buten-2-ketone as raw materials:
Figure BDA0001624378420000032
(3) preparing 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadien-3-one or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadien-3-one by using substituted benzyl chloride, 1-substituted aryl-5- (4-hydroxyphenyl) -1, 4-pentadien-3-one as raw materials:
Figure BDA0001624378420000033
(4) preparing 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime by taking hydroxylamine hydrochloride and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketone or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials:
Figure BDA0001624378420000034
(5) preparing 4-chloroquinazoline containing substituent groups by using quinazolinone containing substituent groups and thionyl chloride as raw materials:
Figure BDA0001624378420000035
(6) preparing the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives by using 4-chloroquinazoline containing substituent groups and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1-2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials:
Figure BDA0001624378420000041
the invention relates to application of quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives in preparation of anti-human liver cancer drugs.
Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can show that: the invention relates to a method for preparing quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives by using substituent-containing 4-chloroquinazoline and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials. The invention uses salicylaldehyde and p-hydroxybenzaldehyde to react with acetone for aldol condensation reaction to generate 4- (2-hydroxyphenyl) -3-butylene-2-ketone and 4- (4-hydroxyphenyl) -3-butylene-2-ketone, 4- (2-hydroxyphenyl) -3-butylene-2-ketone and 4- (4-hydroxyphenyl) -3-butylene-2-ketone are subjected to aldol condensation reaction with substituted aromatic formaldehyde to generate 1- (2-hydroxyphenyl) -5- (substituted aryl) -1, 4-pentadiene-3-ketone and 1- (4-hydroxyphenyl) -5- (substituted aryl) -1, 4-pentadiene-3-ketone, 1- (2-hydroxyphenyl) -5- (substituted aryl) -1, 4-pentadiene-3-ketone and 4-chloroquinazoline containing substituent are subjected to etherification reaction to generate 1, 4-pentadiene-3-ketoxime ether derivatives containing quinazoline. The quinazoline structure with excellent activity is introduced into the structure of the pentadiene ketoxime ether to synthesize a series of pentadiene ketoxime ether compounds containing quinazoline in the structure, and the synthesized 1, 4-pentadiene-3-ketoxime ether compounds containing quinazoline are applied to the aspect of anticancer activity, experiments show that the compounds have more outstanding activity compared with the current commercial medicaments in the aspect of anticancer activity, wherein most compounds show obvious inhibition effect on human liver cancer SMMC-7721 cells for 72 hours in the aspect of anticancer activity, show higher antitumor activity and can be used as antitumor agents.
Detailed Description
Example 1
Synthesis of (4-chloroquinazolinyl) -1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridinyl) -1, 4-pentadien-3-one oxime ether (compound No. M1), comprising the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
adding 4-hydroxybenzaldehyde (50mmol) into 60mL of acetone, stirring for about 15min, carrying out ice-bath on the reaction system for about 30min, adding about 100mL of 5% NaOH solution into the system, removing the ice-bath chamber after the dropwise addition is finished, and stirring at normal temperature for about 24 h. And after the reaction is finished, transferring the system into a 500mL beaker, adding a proper amount of ice water, adjusting the pH of the system to be about 5-6 by using a 5% dilute hydrochloric acid solution, separating out a large amount of yellow solid, pumping out the solid, and finally recrystallizing by using an ethanol/water system to obtain the yellow solid with the yield of 68%.
(2) Synthesis of 1- (2-pyridyl) -5- (4-hydroxyphenyl) -1, 4-pentadien-3-one:
adding 4- (hydroxyphenyl) -3-buten-2-one (24.7mmol), pyridine-2-formaldehyde (29.6mmol) and 50mL of ethanol into a 250mL three-neck flask, stirring for about 30min, adding 60mL of 5% NaOH solution into the system, removing the ice bath chamber after dropwise addition, and stirring at normal temperature for about 24 h. After the reaction is finished, transferring the system to a 500mL beaker, adding a proper amount of ice water, adjusting the pH of the system to be about 5-6 by using a 5% dilute hydrochloric acid solution, separating out a large amount of yellow solid, and extracting the solid to obtain the yellow solid with the yield of 82%.
(3) Synthesis of 1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
1- (2-pyridyl) -5- (4-hydroxyphenyl) -1, 4-pentadiene-3-one (9.95mmol), m-methylbenzyl chloride (11.94mmol), potassium carbonate (14.92mmol), potassium iodide (4.97mmol) and acetone (60mL) are sequentially added into a 100mL three-neck flask, after uniform stirring, heating and refluxing are carried out, after about 3-4 h, the reaction is finished, desolventization and column chromatography are carried out, so that a yellow solid is obtained, and the yield is 39%.
(4) Synthesis of 1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime:
1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one (8.44mmol), hydroxylamine hydrochloride (25.32mmol), pyridine (25mL) and ethanol (50mL) are sequentially added into a 100mL three-necked bottle, and after stirring at normal temperature for about 24 hours, a white solid is separated out in the system, and the solid is extracted and rinsed with ethanol to obtain the white solid with the yield of 60%.
(5) Synthesis of 4-chloroquinazoline:
and (3) sequentially adding quinazolinone (20.53mmol), 5 drops of DMF (dimethyl formamide), 1, 2-dichloroethane (15mL) and thionyl chloride (30mL) into a 100mL three-necked bottle, and after uniformly stirring, heating and refluxing for 1-2 h to finish the reaction. Recovering solvent, and vacuum distilling to obtain yellow solid. After dissolution with dichloromethane, the pH was adjusted to basic with saturated sodium carbonate solution. Separating liquid, washing with water for three times, collecting organic phase, drying, concentrating to obtain light yellow solid, and recrystallizing with petroleum ether. White crystals are obtained. The yield was 81%.
(6) Synthesis of (4-quinazolinyl) -1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
1- (4- (3-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime (1.28mmol), 4-chloroquinazoline (1.54mmol), potassium carbonate (2.56mmol) and acetonitrile (35mL) are sequentially added into a 50mL three-necked bottle, and after the mixture is uniformly stirred, the mixture is heated and refluxed for 3-4 h, and then the reaction is finished. The system was filtered while hot, the filtrate was desolventized, and then recrystallized with acetonitrile (35mL × 3) to obtain white needle crystals with a yield of 86%.
Example 2
Synthesis of (8-methyl-4-chloroquinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether (compound No. M2), comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and 2, 4-dichlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesis of 8-methyl-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 8-methyl-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (8-methyl-4-chloroquinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime and 8-methyl-4-chloroquinazoline are used as starting materials.
Example 3
Synthesis of (4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether (compound No. M3), comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and o-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesis of 4-chloroquinazoline:
as in step (5) of example 1.
(6) Synthesis of (4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime is used as the starting material.
Example 4
Synthesis of (4-chloroquinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether (compound No. M4), comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and 2, 4-dichlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesis of 4-chloroquinazoline:
as in step (5) of example 1.
(6) Synthesis of (4-chloroquinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime is used as the starting material.
Example 5
Synthesis of (8-methyl-4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether (compound No. M5), comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and o-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesis of 8-methyl-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 8-methyl-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (8-methyl-4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime and 8-methyl-4-chloroquinazoline are used as starting materials.
Example 6
Synthesis of (8-methyl-4-chloroquinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether (compound No. M6), comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and p-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesis of 8-methyl-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 8-methyl-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (8-methyl-4-chloroquinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime and 8-methyl-4-chloroquinazoline are used as starting materials.
Example 7
Synthesis of (6-chloro-4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether (compound No. M7), comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and o-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloro-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
Example 8
Synthesis of (6-chloro-4-chloroquinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridinyl) -1, 4-pentadien-3-one oxime ether (compound No. M8), comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and 2, 4-dichlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloro-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-chloroquinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
Example 9
Synthesis of (6-chloro-4-chloroquinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether (compound No. M9), comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and p-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloro-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-chloroquinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
Example 10
Synthesis of (6-chloro-4-chloroquinazolinyl) -1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether (compound No. M10) comprising the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1 except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one and o-fluorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloro-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-chloroquinazolinyl) -1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
The physicochemical properties of the synthetic quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives are shown in Table 1, and the nuclear magnetic resonance hydrogen spectrum (C: (R))1H NMR) and carbon Spectroscopy (13C NMR) data are shown in table 2.
TABLE 1 physicochemical Properties of the target Compounds
Figure BDA0001624378420000111
TABLE 2 NMR and C spectra data for target compounds
Figure BDA0001624378420000121
Antitumor Activity of the above target Compound
Test method
A. Culturing cell strain and treating medicament: human liver cancer SMMC-7721 cells are cultured in RPMI1640 medium containing 10% FBS at 37 deg.C and 5% CO2The saturated humidity incubator is changed every other dayLiquid, passage for 1-2 days. Compounds were dissolved in DMSO as stock solutions. Before use, it is diluted to the desired concentration directly with the culture medium. The blank control group is added with DMSO with the same volume as the drug, and the positive control group is added with gemcitabine with the same concentration as the tested drug. The final concentration of DMSO in the treatment formulation did not exceed 0.1% (V/V).
The principle of the screening experiment of the in vitro anti-tumor drug by the MTT colorimetric method: MTT is a dye that accepts hydrogen ions, and acts on the respiratory chain in mitochondria of living cells, and the tetrazole ring is cleaved by succinate dehydrogenase and cytochrome c to produce blue-purple formazan crystals. Formazan crystals are produced in an amount proportional to the number of living cells, while dead cells do not have this function. The crystal can be dissolved by dimethyl sulfoxide and SDS, and the absorbance at 595nm can be measured by an enzyme-linked immunosorbent assay, so that the number of living cells can be indirectly reflected. Within a certain cell range, the amount of MTT-forming crystals is proportional to the number of cells. The method can be used for large-scale screening of anti-tumor drugs, cytotoxicity experiments, tumor radiosensitivity determination and the like.
Screening experiment steps of the in vitro anti-tumor drug by MTT colorimetric method: the upper and lower rows of the 96-well plate were sealed with sterilized secondary water at 200. mu.L per well. Cells in logarithmic growth phase were taken, digested routinely, resuspended in RPMI1640 medium containing 10% FBS at 4X 104The final concentration of each/mL was inoculated in a 96-well plate at 100. mu.L per well, and the rightmost column was a blank control, to which cell-free serum RPMI1640 medium was added. Placing at 37 ℃ and 5% CO2The cells are cultured in an incubator with saturated humidity for 24 hours to adhere to the wall. The medium was aspirated off, and serum containing medium at different drug concentrations was added at 200. mu.L per well, taking care that the final DMSO concentration in the medium did not exceed 0.1%, and 200. mu.L of complete medium was added per well in the blank control. The required time for the experiment was treated separately, the supernatant removed and 100. mu.l/well of MTT at 0.5mg/mL was added. After 4h incubation, 100. mu.l/well of 10% SDS was added. Dissolving the crystal at 37 deg.C for 10 hr, taking out, slightly shaking for 5min, standing at room temperature for 30min, measuring OD value at A595 wavelength, and calculating cell activity, inhibition rate and P value.
The curve is plotted with the drug concentration or treatment time on the horizontal axis and the OD value or inhibition ratio on the vertical axis. Six wells were repeated for each sample concentration, three times for each experiment, and the average was taken as the final result.
The experimental result is analyzed by variance with SPSS software, and the difference is significant when p is less than 0.05 and is extremely significant when p is less than 0.01. The inhibition rate of cell proliferation is calculated as follows:
Figure BDA0001624378420000131
TABLE 3 in vitro inhibition rate of target compounds on liver cancer SMMC-7721 cells for 72 hours
Figure BDA0001624378420000141
The inhibitory activity of the target compound on the SMMC-7721 cells of the liver cancer was tested by the MTT method with the commercial drug gemcitabine as a positive control at test concentrations of 1. mu.M and 10. mu.M (see Table 3). The test results show that: most target compounds have good inhibitory activity on liver cancer SMMC-7721 cells. When the concentration is 10 mu M, the activity inhibition range of the series of compounds on liver cancer SMMC-7721 cells is 69.09% -95.72%, which is far better than that of a control medicament gemcitabine (42.52%); at the concentration of 1 mu M, the series of compounds (except the compound M4) have good inhibitory activity on liver cancer SMMC-7721 cells, and the inhibitory rate is higher than that of a control medicament gemcitabine (20.16%). Especially, the compounds M1, M5, M6, M7, M9 and M10 have excellent inhibitory activity on liver cancer SMMC-7721 cells, and the inhibitory activity is more than 90.00 percent and far better than gemcitabine (20.16 percent).
In order to further understand the anticancer activity of the compounds, the morphology of the liver cancer SMMC-7721 cells under an electron microscope is researched, and the morphology of the liver cancer SMMC-7721 cells after 24, 48 and 72 hours of medicament treatment is recorded by an inverted microscope, wherein the data show that: the compounds have obvious inhibition effect on the activity of liver cancer SMMC-7721 cells. The inhibitory activity of some compounds was higher than that of the positive drug gemcitabine at the same dose and duration of action (see table 3). It is worth mentioning that commercial drugs, i.e. positive drugs, have significantly higher toxicity to tumor cells (such that the cells are completely crushed and lysed), while the compound synthesized by the invention has an inhibitory effect on tumor cells at low concentration, but basically has little damage to target cells, and the inhibitory activity is mainly reflected in inhibiting cell proliferation (the number of cells is significantly reduced compared with that of a control) or inducing cell differentiation (from morphological observation, we can easily find that the cells are deformed while the number of the cells is reduced, but the damage is not significant), but the inhibitory activity is significantly enhanced as the concentration of the compound is increased overall. Wherein the partial compound has excellent inhibitory activity on liver cancer SMMC-7721 cells, and can be used as potential antitumor agent.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are within the scope of the present invention without departing from the technical spirit of the present invention.

Claims (1)

1. An application of quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives in preparation of anti-human liver cancer drugs is characterized in that: the concentrations of the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives are 1 mu M and 10 mu M, and the human liver cancer cells are liver cancer SMMC-7721 cells;
the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative is specifically one of the following compounds:
(4-chloroquinazolinyl) -1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether,
(4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether,
(8-methyl-4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether,
(8-methyl-4-chloroquinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether,
(6-chloro-4-chloroquinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether,
(6-chloro-4-chloroquinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether,
(6-chloro-4-chloroquinazolinyl) -1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one oxime ether.
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