CN109160902B - Asymmetric bisquinazoline Schiff base derivative for treating tumors and preparation and medical application thereof - Google Patents
Asymmetric bisquinazoline Schiff base derivative for treating tumors and preparation and medical application thereof Download PDFInfo
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- CN109160902B CN109160902B CN201811193229.6A CN201811193229A CN109160902B CN 109160902 B CN109160902 B CN 109160902B CN 201811193229 A CN201811193229 A CN 201811193229A CN 109160902 B CN109160902 B CN 109160902B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
The invention discloses an asymmetric bisquinazoline Schiff base derivative for treating tumors and preparation and medical application thereof. The asymmetric bisquinazoline Schiff base compound is formed by connecting two quinazolines with different structures, namely 4-aminoquinazoline and 2-aminoquinazoline, through a Schiff base structure; the research on the antitumor activity shows that the asymmetric bisquinazoline Schiff base compound has a certain antitumor effect, particularly has good activity on breast cancer, and can be used for preparing antitumor drugs.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an asymmetric bisquinazoline Schiff base compound, and preparation and medical application thereof.
Background
Quinazoline compounds are nitrogen-containing heterocyclic compounds with good biological activity, show excellent activity in the aspects of antibiosis, anti-inflammation, hypertension resistance, cancer resistance and the like, and a plurality of small-molecule drugs with quinazoline structures are on the market at present, such as EGFR inhibitors gefitinib, erlotinib, lapatinib and the like. There have also been many studies based on such quinazoline structures, such as CN201510875007, CN2017108670950, cn201210469118.x, etc. Schiff base and its derivatives have antibacterial and anticancer activities, and become important structures in drug development due to convenient synthesis and high activity, and are valuable pharmacophores.
In the former group, a Schiff base structure is used for connecting two identical quinazoline structure units to form a bisquinazoline Schiff base compound with a symmetrical structure, wherein 4-aminoquinazoline is used, but 2-aminoquinazoline in quinazoline derivatives also belongs to a very important raw material/intermediate, so that an attempt is made to design and synthesize the unsymmetrical bisquinazoline Schiff base compound, and the bisquinazoline Schiff base compound has potential application prospects in the field of biomedicine, particularly in the field of anticancer.
Disclosure of Invention
The invention aims to provide an asymmetric bisquinazoline Schiff base compound and preparation and application thereof.
The invention provides an asymmetric bisquinazoline Schiff base compound which is a compound shown in a formula 1 or a formula 2:
the invention also provides a preparation method of the asymmetric bis-quinazoline Schiff base compound, which comprises the steps of adding m-phthalaldehyde/2, 6-pyridinedicarboxaldehyde, an organic solvent and a catalyst into a dry reactor, uniformly stirring, slowly dripping 4-aminoquinazoline into the organic solution of the m-phthalaldehyde/2, 6-pyridinedicarboxaldehyde, continuously stirring for reflux reaction after dripping is finished, cooling to room temperature, adding 2-aminoquinazoline, continuously stirring for reflux reaction, cooling to room temperature, distilling under reduced pressure to remove the solvent, and performing silica gel column chromatography on the obtained residue to obtain a compound 1 or 2;
the synthetic route of the asymmetric bisquinazoline Schiff base compound is as follows:
wherein the organic solvent can be selected from methanol, ethanol, dichloromethane, ethyl acetate, toluene, DMSO, DMF, etc., and the organic solvent is preferably ethanol;
the molar ratio of the 4-aminoquinazoline to the m-phthalaldehyde/2, 6-pyridinedicarboxaldehyde is preferably 0.9-1:1,
the mol ratio of the 2-aminoquinazoline to the m-phthalaldehyde/2, 6-pyridinedicarboxaldehyde is preferably 1: 1;
the catalyst is p-toluenesulfonic acid (TsOH), and the addition amount of the catalyst is a catalytic amount.
The invention also provides the application of the asymmetric bisquinazoline Schiff base compound in the preparation of anti-cancer drugs; the cancer is selected from lung cancer, ovarian cancer, breast cancer or leukemia; wherein the cancer is preferably breast cancer.
The asymmetric bisquinazoline Schiff base compound provided by the invention is formed by connecting two quinazolines with different structures, namely 4-aminoquinazoline and 2-aminoquinazoline, through a Schiff base structure; the research on the antitumor activity shows that the asymmetric bisquinazoline Schiff base compound has a certain antitumor effect, particularly has good activity on breast cancer, and can be used for preparing antitumor drugs.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1: preparation of Compound 1
Adding m-phthalaldehyde (2.68g, 20mmol), 50mL ethanol and a catalyst TsOH (0.15g) into a dry reactor, stirring uniformly, slowly dropping 4-aminoquinazoline (2.83g,19.5mmol) into the ethanol solution of the m-phthalaldehyde, stirring continuously and refluxing for 3 hours after dropping is finished, cooling to room temperature, adding 2-aminoquinazoline (2.90g,20mmol), stirring continuously and refluxing for 3 hours, cooling to room temperature, distilling under reduced pressure to remove the solvent, separating and purifying the obtained residue by silica gel column chromatography (ethanol/ethyl acetate (V/V) ═ 1:3) to obtain 5.58g of compound 1, wherein the yield is 71.9%.
Mass Spectrometry (CI, m/z): 389[ M +1 ]] + .
1 HNMR(CDCl 3 ,300MHz):9.41(s,1H),9.35(s,1H),8.42(s,1H)，8.26(s,2H)， 8.15(d,2H)，7.95(d，2H)，7.65-7.74(m，6H)7.45(t，1H).
Example 2: preparation of Compound 2
Adding 2, 6-pyridinedicarboxaldehyde (2.70g, 20mmol), 45mL ethanol and catalyst TsOH (0.15g) into a dry reactor, stirring uniformly, slowly dropping 4-aminoquinazoline (2.80g,19.3mmol) into the ethanol solution of 2, 6-pyridinedicarboxaldehyde, continuing to stir and reflux for reaction for 3h after dropping is completed, cooling to room temperature, adding 2-aminoquinazoline (2.90g,20mmol), continuing to stir and reflux for reaction for 3h, cooling to room temperature, removing the solvent by reduced pressure distillation, separating and purifying the obtained residue by silica gel column chromatography (ethanol/ethyl acetate (V/V) ═ 1:3) to obtain 5.32g of compound 2 with a yield of 68.4%.
Mass Spectrometry (CI, m/z): 390[ M +1 ]] + .
1 HNMR(CDCl 3 ,300MHz):9.41(s,1H),9.35(s,1H),8.33(d，2H)，8.26 (t，1H)，8.15(d,2H)，7.65-7.74(m，6H),7.45(s，2H).
Example 3: determination of anticancer Activity
Cell lines: human non-small cell lung cancer cell (A-549), human ovarian cancer cell (SKOV-3), human breast cancer cell (MCF-7), and human leukemia cell (HL-60).
Cell culture: inoculating the cells in DMEM or DMEM/F12 complete culture solution containing 10% calf serum, 100IU/ml penicillin G sodium salt and 100ug/ml streptomycin sulfate, standing at 37 deg.C and 100% relative humidity, and containing 5% C0 2 The culture box of (5), passage 3 times for standby.
And (3) MTT colorimetric detection: taking cells in logarithmic growth phase, passing through 0.25% pancreasAfter protease digestion (suspension cells were not digested), the suspension was suspended in a culture medium containing 10% calf serum, and the suspension was gently blown with a glass dropper to form a single cell suspension, and viable cells were counted under a microscope using a blood cell counting plate. The 96-well culture plate is inoculated with 90. mu.l of cell suspension (cell concentration is 3-6X 10) 4 one/mL) in an incubator for 24 hours, and then 10. mu.l of the liquid medicine is added to each well. In addition, each concentration was set with a negative control (equal concentration of DMSO) and a blank background (no cells added), and each group was set with 6 replicate wells. The culture was continued for another 48 hours, then 10. mu.l of 5mg/mL MTT solution was added to each well, and after further culture for 4 hours, the supernatant was aspirated. Add 100 μ l DMSO into each well, shake for 5min in micro oscillator to dissolve the crystal completely, compare color at 530nm single wavelength with enzyme labeling instrument, determine OD value, the test result is shown in Table 1.
The inhibition ratio (%) was [1- (experimental OD mean-blank OD mean)/(control OD mean-blank OD mean) ] × 100%.
Calculation of test Compound IC by Bliss method 50 The value is obtained.
The control group positive drug is gefitinib.
Table 1: results of the measurement of tumor cell inhibitory activity:
the results show that the compound 1-2 has certain inhibitory activity on human non-small cell lung cancer cells (A-549), and the compound 2 also has certain inhibitory activity on human leukemia cells (HL-60), but the activities are not very high; however, the compound 1-2 has better activity on human breast cancer cells (MCF-7), and even the activity of the compound 1 is obviously better than that of a positive drug. Therefore, the compound 1-2 shows good specificity to human breast cancer cells (MCF-7) and can be used as a potential anti-breast cancer drug.
The above description is only a preferred embodiment of the present invention, and should not be taken as limiting the invention in any way, and any person skilled in the art can make any simple modification, equivalent replacement, and improvement on the above embodiment without departing from the technical spirit of the present invention, and still fall within the protection scope of the technical solution of the present invention.
Claims (2)
1. The application of a compound shown in a formula 1, wherein the compound shown in the formula 1 is used for preparing an anti-cancer medicament, the cancer is breast cancer,
2. the application of a compound shown in a formula 2, wherein the compound shown in the formula 2 is used for preparing an anti-cancer medicament, the cancer is breast cancer,
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Non-Patent Citations (5)
| Title |
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| A CHEF-based biocompatible turn ON ratiometric sensor for sensitive and selective probing of Cu2+;Chirantan Kar，等;《Sensors and Actuators B》;20130815;第188卷;1132-1140 * |
| 丁燕玲，等.双-（2,4-二氨基喹唑啉-6-取代氨基）烷烃或芳烷烃衍生物对大鼠肝脏二氢叶酸还原酶的抑制作用.《医药工业》.1984,6-10. * |
| 具有抗肿瘤作用的2,4-二氨基-6-取代氨基喹唑啉类化合物;张秀平，等;《医药工业》;19871231;第18卷(第4期);186-187 * |
| 双-（2,4-二氨基喹唑啉-6-取代氨基）烷烃或芳烷烃衍生物对大鼠肝脏二氢叶酸还原酶的抑制作用;丁燕玲，等;《医药工业》;19841231;6-10 * |
| 疟疾防治药物的研究 XV. 双-（2,4-二氨基喹唑啉-6-取代氨甲基）芳香类化合物的合成及其抗疟作用;周伟澄，;《药学学报》;19851231;第20卷(第7期);536-541 * |
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