CN111494381B - Application of alkenyl quinoline compound in preparation of antitumor drugs - Google Patents

Application of alkenyl quinoline compound in preparation of antitumor drugs Download PDF

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CN111494381B
CN111494381B CN202010367197.8A CN202010367197A CN111494381B CN 111494381 B CN111494381 B CN 111494381B CN 202010367197 A CN202010367197 A CN 202010367197A CN 111494381 B CN111494381 B CN 111494381B
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quinoline compound
alkenyl
alkyl
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substituted
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CN111494381A (en
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吴婷
唐晓冬
梁恩
石杰
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Southern Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses application of an alkenyl quinoline compound in preparation of antitumor drugs. The structure of the alkenyl quinoline compound is shown as a formula (I); wherein R is 1 Is hydrogen, C 1‑6 Alkyl, substituted C 1‑6 Alkyl, C 5‑6 Aryl, substituted C 5‑6 Aromatic groups or C 9‑10 A fused bicyclic aromatic group; r is R 2 Is C 1‑6 Alkyl, substituted C 1‑6 Alkyl, C 5‑6 Aryl, substituted C 5‑6 Aromatic groups or C 9‑10 Fused bicyclic aromatic groups. The alkenyl quinoline compound provided by the invention has a certain inhibition effect on breast cancer, colon cancer and liver cancer cells, wherein the inhibition effect on liver cancer cells is particularly obvious and even obviously superior to that of a positive control medicament, and can be prepared into an anti-tumor medicament for application; meanwhile, the preparation method of the alkenyl quinoline compound is simple and efficient, raw materials are easy to obtain, industrial production can be realized, and the alkenyl quinoline compound has great application value in resisting tumors.

Description

Application of alkenyl quinoline compound in preparation of antitumor drugs
Technical Field
The invention relates to the technical field of medicines, in particular to application of an alkenyl quinoline compound in preparation of an antitumor drug.
Background
Cancer has become a serious health hazard to humans and is currently the second leading killer to cardiovascular disease. At present, clinical antitumor drugs mainly comprise alkylating agents, antimetabolites, antitumor antibiotics, antitumor plant drugs, immunotherapeutic drugs and the like, but a plurality of antitumor drugs have obvious toxic and side effects on normal organisms, such as mutation, genetic toxicity and the like, so the research of the antitumor drugs has become a popular subject at present. The existing antitumor drugs have complex and various structures, and the compounds with different structures show excellent antitumor activity. Finding an effective antitumor drug with little toxic and side effects has become a hotspot in the current research and development of new antitumor drugs.
Alkenyl quinoline compounds have a wide range of biological activities and are important functional structures of many bioactive macromolecules and natural products. For example, the leukotriene receptor antagonist montelukast sodium, which is clinically used to treat asthma. The biological activities reported also mainly include anti-Alzheimer's disease, antifungal and antiparasitic (Bioorganic & Medicinal Chemistry Letters (2018) 1011-1019;European Journal of Medicinal Chemistry 89 (2015) 349-361;European Journal of Medicinal Chemistry 130 (2017) 139-153;Bioorganic&Medicinal Chemistry 20 (2012) 6960-6968), and no anti-tumor activity has been reported.
Disclosure of Invention
The invention aims to provide an application of an alkenyl quinoline compound in preparing an anti-tumor drug. The invention discloses application of the alkenyl quinoline in resisting tumors, and belongs to new application of alkenyl quinoline compounds.
The invention also aims to provide an application of the isomer or the pharmaceutically acceptable salt of the alkenyl quinoline compound in preparing antitumor drugs.
The above object of the present invention is achieved by the following means:
the application of the alkenyl quinoline compound in preparing the antitumor drugs is that the structure of the alkenyl quinoline compound is shown as a formula (I):
wherein R is 1 Is hydrogen, C 1-6 Alkyl, C 5-6 Aromatic groups or C 9-10 A fused bicyclic aromatic group;
R 2 is C 1-6 Alkyl, C 5-6 Aromatic groups or C 9-10 A fused bicyclic aromatic group;
the C is 1-6 Alkyl or C 5-6 One or more hydrogens in the aryl group may be independently substituted with substituents selected from the group consisting of: halogen, perhalogenated C 1-2 Alkyl, halogenated C 1-4 Alkyl, hydroxy, C 1-6 Straight-chain or branched alkoxy, C 1-6 Cycloalkoxy, nitro, cyano, amino, C 1-6 Monoalkylamino, C 1-6 Dialkylamino, C 5-8 Monocycloalkylamino, C 5-6 Mono-heterocyclylamino, C 5-6 Monoarylamino, C 1-6 Alkylamido, C 5-6 Aryl amido, aminocarbonyl, C 1-6 Monoalkylaminocarbonyl, C 1-6 Dialkyl aminocarbonyl, C 1-6 Alkyl acyl, C 5-8 Aryl acyl, amino sulfonyl, C 1-6 Mono-alkylamino sulfonyl, C 1-6 Dialkyl amino sulfonyl, C 5-8 Aryl amino sulfonyl, C 1-6 Alkylsulfonylamino, carboxyl, straight-chain or branched alkyl, C 5-8 Cycloalkyl, C 5-8 Substituted cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, aryl C 1-3 Alkyl, C 5-6 Aromatic radicals, C 5-6 Substituted aryl, C 5-6 Polysubstituted arylamino, C 5-6 Condensed bicyclic aryl, C 5-6 Heterocyclyl, C 5-6 Aromatic heterocyclic radical, C 9-10 Condensed bicyclic aromatic radicals or C 5-6 Fused bicyclic aromatic heterocyclic groups.
The inventor researches in 2019 disclose a simple and efficient synthesis method of the alkenyl quinoline compound, and the synthesis method has the advantages of easiness in reaction control, simple reaction conditions, low-cost and readily available raw materials, easiness in industrialization realization and the like, and greatly develops the application value of the alkenyl quinoline compound. Before that, the inventor has unexpectedly found that the alkenyl quinoline compound prepared by the method has good anti-tumor activity and shows a certain inhibition effect on breast cancer, colon cancer, liver cancer cells and the like, wherein the inhibition effect on liver cancer cells is particularly obvious and even obviously superior to that of positive control drugs, and the alkenyl quinoline compound can be prepared into anti-tumor drugs for application, and has great application prospect.
Preferably, the antitumor drug is an anti-breast cancer drug, an anti-colon cancer drug and/or an anti-liver cancer drug.
Preferably, the antitumor drug is an anti-liver cancer drug.
Preferably, said R 1 H, C of a shape of H, C 1～4 Alkyl or phenyl; one or more hydrogens in the phenyl group may be independently substituted with substituents selected from the group consisting of: halogen, hydroxy, cyano, halo C 1～4 Alkyl, C 1～4 Alkoxy, C 1～4 Haloalkoxy or C 1-6 An amide group.
More preferably, the R 1 Is H, methyl, ethyl or phenyl.
Preferably, said R 2 Is C 1～4 Alkyl, phenyl or a four-or five-membered ring containing heteroatoms;
wherein C is 1～4 One or more hydrogens in the alkyl or phenyl groups may be independently substituted with substituents selected from the group consisting of: halogen, hydroxy, cyano, halo C 1～4 Alkyl, C 1～4 Alkoxy, C 1～4 Haloalkoxy or C 1-6 An amide group.
More preferably, the R 2 2-thiophene, 4-pyridine or phenyl; one or more hydrogens in the phenyl group may be independently substituted with substituents selected from the group consisting of: halogen, hydroxy, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, carboxamido or acetamido.
Preferably, the alkenyl quinoline compound has a structure as shown in one of the following structures:
the invention also protects the application of the isomer or pharmaceutically acceptable salt of the alkenyl quinoline compound in preparing antitumor drugs.
Preferably, the dosage form of the antitumor drug is a capsule, a tablet, a pill, a granule, an injection or a spray.
The preparation method of the alkenyl quinoline compound is simple, and the preparation process is as follows:
s1, accurately weighing substituted or unsubstituted 2-methylquinoline (5 mmol), aldehyde (5 mmol), acetic acid (1 mmol) and 1, 3-dimethylbarbituric acid (1 mmol) and adding the mixture into a clean round-bottomed flask; 20ml of water and a stirrer are added into a conical flask, and reflux reaction is carried out for 24 hours at 100 ℃;
s2, after the reaction is finished (TLC detection reaction is used), adding a proper amount of dichloromethane to extract a reaction liquid after cooling, taking a dichloromethane layer, and repeatedly extracting for three times; then adding proper amount of Na into the obtained dichloromethane layer 2 SO 4 Drying, and then concentrating by reduced pressure distillation;
s3, sequentially mixing the petroleum ether with the mobile phase according to different proportions: and (2) performing column chromatography by using the mixed solvent of ethyl acetate (2-30) and 1 as an eluent to obtain a synthesized target product.
Compared with the prior art, the invention has the following beneficial effects:
the alkenyl quinoline compound provided by the invention has a certain inhibition effect on breast cancer, colon cancer and liver cancer cells, wherein the inhibition effect on liver cancer cells is particularly obvious and even obviously superior to that of a positive control medicament, and can be prepared into an anti-tumor medicament for application;
meanwhile, the preparation method of the alkenyl quinoline compound is simple and efficient, raw materials are easy to obtain, industrial production can be realized, and the alkenyl quinoline compound has great application value in resisting tumors.
Detailed Description
The invention is further illustrated in detail below in connection with specific examples which are provided solely for the purpose of illustration and are not intended to limit the scope of the invention. The test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
The preparation route of the alkenylquinoline compounds described in the examples below is shown below:
the specific steps are as follows:
s1, accurately weighing R 1 Substituted 2-methylquinoline (5 mmol), aldehyde (5 mmol), acetic acid (1 mmol), 1, 3-dimethylbarbituric acid (1 mmol) were added to a clean round bottom flask; 20ml of water and a stirrer are added into a conical flask, and reflux reaction is carried out for 24 hours at 100 ℃;
s2, after the reaction is finished (TLC detection reaction is used), adding a proper amount of dichloromethane to extract a reaction liquid after cooling, taking a dichloromethane layer, and repeatedly extracting for three times; then adding proper amount of Na into the obtained dichloromethane layer 2 SO 4 Drying, and then concentrating by reduced pressure distillation;
s3, sequentially mixing the petroleum ether with the mobile phase according to different proportions: and (2) performing column chromatography by using the mixed solvent of ethyl acetate (2-30) and 1 as an eluent to obtain a synthesized target product.
Example 1
(E) -2- (3-hydroxy-4-methoxystyryl) -quinoline: 87% of the total amount of the ethylene, 1 H NMR(400MHz,CDCl 3 )δ8.11(d,J＝8.5Hz,2H),7.78(d,J＝8.0Hz,1H),7.71(t,J＝7.2Hz,1H),7.62(dd,J＝19.3,12.4Hz,2H),7.50(t,J＝7.4Hz,1H),7.30(d,J＝9.5Hz,2H),7.14(dd,J＝8.3,1.7Hz,1H),6.87(d,J＝8.3Hz,1H),3.91(s,3H). 13 C NMR(100MHz,CDCl 3 )δ156.2,148.0,147.4,145.9,136.4,134.4,130.1,129.7,128.8,127.4,127.2,127.0,126.0,120.3,119.1,112.8,110.7,55.9。
example 2
(E) -2- (4-cyanostyryl) -quinoline: 76% of the total of all the two, 1 H NMR(400MHz,CDCl 3 )δ8.19(d,J＝8.5Hz,1H),8.12(d,J＝8.5Hz,1H),7.83(d,J＝8.1Hz,1H),7.79–7.65(m,7H),7.58–7.46(m,2H). 13 C NMR(101MHz,CDCl 3 )δ154.7,148.1,140.9,136.7,132.5,132.2,132.2,130.0,129.3,127.6,127.5,126.7,119.6,118.8,111.6。
example 3
(E) -2- (3-methyl-4-fluoro-styryl) -quinoline: 75% of the total of all the two, 1 H NMR(400MHz,CDCl 3 )δ8.11–8.08(m,2H),7.76(d,J＝8.1Hz,1H),7.75–7.67(m,1H),7.65–7.59(m,2H),7.53–7.39(m,3H),7.30(d,J＝16.3Hz,1H),7.02(t,J＝8.9Hz,1H).2.31(s,3H). 13 C NMR(100MHz,CDCl 3 )δ161.6(d,J＝246Hz),155.8,148.1,136.4,133.5,132.3(d,J＝3.7Hz),130.3(d,J＝5.4Hz),129.8,129.0,128.3,127.5,127.3,126.3(d,J＝8.1Hz),126.1,125.2(d,J＝17.7Hz),119.1,115.4(d,J＝22.7Hz),14.6(d,J＝3.4Hz)。
example 4
(E) -2- (3, 4, 5-trimethoxystyryl) -quinoline: 70% of the total of all the components in the mixture, 1 H NMR(400MHz,CDCl 3 )δ8.09(dd,J＝18.7,8.5Hz,2H),7.77(d,J＝8.0Hz,1H),7.73–7.65(m,2H),7.58(d,J＝16.3Hz,1H),7.48(t,J＝7.5Hz,1H),7.33(d,J＝16.3Hz,1H),6.87(s,2H),3.91(s,6H),3.89(s,3H). 13 C NMR(100MHz,CDCl 3 )δ155.8,153.4,148.1,138.7,136.4,134.4,132.1,129.8,129.0,128.4,127.5,127.3,126.2,118.8,104.3,60.9,56.1。
example 5
(E) -2- (pyridylvinyl) -quinoline: 49% of the total of all the components in the sample, 1 H NMR(400MHz,CDCl 3 )δ8.60(dd,J＝4.0,2.2Hz,2H),8.16–8.06(m,2H),7.80–7.68(m,2H),7.63–7.49(m,4H),7.43(d,J＝6.0Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ154.6,150.2,148.1,143.7,136.6,133.2,131.4,129.9,129.3,127.6,127.5,126.7,121.3,119.5。
example 6
(E) -2- (4-carboxamidylstyryl) -quinoline, 83% yield, 1 H NMR(400MHz,CDCl 3 )δ8.08(dd,J＝14.0,8.6Hz,2H),7.77(d,J＝8.1Hz,1H),7.72–7.67(m,1H),7.66–7.54(m,6H),7.52–7.45(m,1H),7.32(d,J＝16.3Hz,1H),2.18(s,3H). 13 C NMR(100MHz,CDCl 3 )δ168.4,156.0,148.2,138.3,136.4,133.8,132.5,129.8,129.0,128.0,127.5,127.3,126.1,119.9,119.2,24.6。
example 7
(E) -2- (4-trifluoromethylstyryl) -quinoline: 94% of the total of all the two, 1 H NMR(400MHz,CDCl 3 )δ8.10(d,J＝8.5Hz,2H),7.77–7.66(m,5H),7.63–7.60(m,3H),7.54–7.42(m,2H). 13 C NMR(101MHz,CDCl 3 )δ155.1,148.1,139.9,136.5,132.6,131.2,130.2,129.9,129.2,127.5,127.5,127.2,126.5,125.7(q,J＝3.8Hz),122.8,119.4。
example 8
(E) -2- (thiophenyl-vinyl) -quinoline: 82% of the total of all the two, 1 H NMR(400MHz,CDCl 3 )δ8.08(dd,J＝14.9,8.6Hz,2H),7.88–7.83(m,1H),7.77–7.68(m,2H),7.54(d,J＝8.6Hz,1H),7.51–7.46(m,1H),7.30(d,J＝5.7Hz,1H),7.26–7.19(m,2H),7.06(dd,J＝5.0,3.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ155.4,148.1,142.0,136.2,129.6,129.0,128.1,128.0,127.7,127.4,127.2,127.1,126.0,125.9,119.2。
result detection
The invention uses MTT experiment to prove the effect of compound on the proliferation activity of tumor cells.
Experimental results show that the compound has obvious inhibition effect on tumor cells, and can be used for treating cancers. The specific test method is as follows:
1. purpose and principle of experiment
The purpose of the experiment is as follows: the MTT method is adopted to measure the inhibition effect of the series compounds in the patent on the proliferation activity of different types of tumor cells.
Experimental principle: MTT is known as 3- (4, 5) -dimethylthiahiazo (-z-y 1) -3, 5-di-phenyltetrazolium romide, chinese chemical name 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyltetrazolium bromide, trade name: thiazole blue, a yellow colored dye. The MTT colorimetric method used in this patent is a method for detecting cell survival and growth, and its principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT into water-insoluble blue-violet crystalline formazan and deposit it in cells, while dead cells lack this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in living cells, an enzyme-linked immunosorbent assay (ELISA) is used for detecting an absorbance value (OD value) at 570nm, the number of living cells can be reacted according to the absorbance value, and the smaller the OD value is in a certain range, the weaker the cell activity is, and the better the proliferation inhibition effect of the drug is.
2. Basic information of reagents
3. Reagent preparation
DMEM complete medium
Preparing a complete culture medium containing 10% of fetal bovine serum for later use.
MTT solution configuration
Dissolving 250mg MTT powder in 50mL centrifuge tube, adding 50mL PBS solution, wrapping with tinfoil paper, avoiding light, sufficiently shaking to dissolve completely, filtering with microporous membrane with 0.22 μm pore diameter for sterilization, packaging, and preserving at-20deg.C in avoiding light.
3. Compound arrangement
A certain mass of compound is precisely weighed and dissolved in DMSO solution to prepare 100mM mother liquor, and the mother liquor is diluted to 0.05 mu M,0.5 mu M,5 mu M,10 mu M,30 mu M and 50 mu M working solution by using complete culture medium before use.
4. Experimental procedure
(1) Taking cells in logarithmic growth phase, digesting with pancreatin, and adjusting cell number concentration to 5.0X10 4 Per mL, 100 μl/well was seeded into 96-well plates. At 37 ℃,5% CO 2 The cells were cultured overnight in a cell incubator.
(2) After the cells are attached, the original culture medium is discarded, and a compound to be detected and a positive control drug 5-fluorouracil (5-Fu) are added at different concentrations, wherein the concentrations of the compound are respectively 0.05 mu M,0.5 mu M,5 mu M,10 mu M,30 mu M and 50 mu M, and 3 parallel holes are arranged at each concentration. After dosing the plates were placed at 37℃with 5% CO 2 The cell culture was continued for 48 hours in the incubator.
(3) The old solution in the wells was discarded, 100. Mu. LMTT working solution (5 mg/mL) was added to each well, and incubated in an incubator for 4 hours.
(4) The medium was discarded, 100 μL of MSO was added to each well and the formazan crystals were fully dissolved by shaking for 15 min.
(5) Absorbance at 570nm was measured with an enzyme-linked immunosorbent assay.
(6) The cell growth inhibition was calculated according to the following formula:
inhibition ratio = [ (As-Ab)/(Ac-Ab) ] ×100%
As: absorbance (containing cells, MTT, compounds) of experimental wells
Ac: absorbance (cell-containing, MTT, no compound) of control wells
Ab: absorbance of blank wells (without cell and compound, MTT-containing)
Based on the inhibition of cell proliferation by the drug at different doses, half Inhibition Concentration (IC) of the compound was calculated by GraphPad Prism 8 software 50 )。Experiments were repeated 3 times in total and the results were averaged ± standard deviation. The activity results of the compounds are shown in table 1.
Tumor inhibitory Effect of the Compounds of Table 1
According to the in vitro experimental results, the inhibition effect of the compounds 1, 2, 3,4 and 5 on the proliferation activity of liver cancer cells is stronger than that of 5-Fu, and particularly, the compound 2 has a remarkable inhibition effect on the proliferation of liver cancer cells, and the inhibition activity of the compound is about 22 times of that of 5-Fu; compound 4 has a greater inhibitory capacity for colon cancer cell proliferation than 5-Fu.
From the results, the compound protected by the invention has good anti-tumor effect, and the compound can be synthesized by the synthesis method of the invention with high efficiency, simplicity, atom economy and capability of realizing structural diversity and complexity of products, is easy to realize industrialization and has wide application value.
It should be noted that the above embodiments are merely for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and that other various changes and modifications can be made by one skilled in the art based on the above description and the idea, and it is not necessary or exhaustive to all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.

Claims (2)

1. The application of the alkenyl quinoline compound in preparing the antitumor drugs is characterized in that the alkenyl quinoline compound has the following structure:
；
the antitumor drug is an anti-liver cancer drug.
2. The use according to claim 1, wherein the anti-tumor medicament is in the form of a capsule, tablet, pill, granule, injection or spray.
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Citations (2)

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US20130035348A1 (en) * 2010-04-06 2013-02-07 Brigham Young University Antimetastatic compounds
WO2014012889A1 (en) * 2012-07-18 2014-01-23 University College Dublin - National University Of Ireland, Dublin Anti-angiogenic compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130035348A1 (en) * 2010-04-06 2013-02-07 Brigham Young University Antimetastatic compounds
WO2014012889A1 (en) * 2012-07-18 2014-01-23 University College Dublin - National University Of Ireland, Dublin Anti-angiogenic compounds

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Title
A new family of quinoline and quinoxaline analogues of combretastatins;Concepcion Perez-Melero等;《Bioorganic & Medicinal Chemistry Letters》;20040525;第14卷;第3771-3774页 *

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