CN115650913B - Quinone quinoline compound and preparation method and application thereof - Google Patents

Quinone quinoline compound and preparation method and application thereof Download PDF

Info

Publication number
CN115650913B
CN115650913B CN202211248380.1A CN202211248380A CN115650913B CN 115650913 B CN115650913 B CN 115650913B CN 202211248380 A CN202211248380 A CN 202211248380A CN 115650913 B CN115650913 B CN 115650913B
Authority
CN
China
Prior art keywords
quinoid
cancer
fraction
alkyl
methanol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202211248380.1A
Other languages
Chinese (zh)
Other versions
CN115650913A (en
Inventor
柴兴云
焦顺刚
沙娜·吾肯
李俊俊
刘长鑫
高小力
屠鹏飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing University of Chinese Medicine
Original Assignee
Beijing University of Chinese Medicine
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing University of Chinese Medicine filed Critical Beijing University of Chinese Medicine
Priority to CN202211248380.1A priority Critical patent/CN115650913B/en
Publication of CN115650913A publication Critical patent/CN115650913A/en
Application granted granted Critical
Publication of CN115650913B publication Critical patent/CN115650913B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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 a quinoid quinoline compound, a preparation method and application thereof. The quinoid quinoline compound has excellent anti-tumor and antibacterial activities.

Description

Quinone quinoline compound and preparation method and application thereof
Technical Field
The invention relates to a quinoid quinoline compound, a preparation method and application thereof.
Background
The lignum Aquilariae Resinatum is peeled root, stem and coarse branch of Eugenia caryophyllata Syringa pinnatifolia Hemsl of Eugenia of Oleaceae, and is concentrated in Helan mountain region of inner Mongolia and Ningxia. The lignum Aquilariae Resinatum mainly contains lignan and sesquiterpene components, and is commonly used for treating heart and lung diseases such as myocardial ischemia, chest distress, short breath, etc.
CN104606176a discloses a monocyclic sesquiterpene compound extracted from aquilaria sinensis, which can be used for treating cancer. CN105982966a discloses an extract of aquilaria sinensis, which is obtained by extracting aquilaria sinensis with organic solvent by ultrasonic extraction, concentrating the extract, and separating with silica gel column. The obtained extract can be used for preparing antitumor drugs. CN109020986a discloses a quinoline quinone heterocycle derivative, which can be used for preparing an antitumor drug. CN109121411a discloses a pyrimidine-isoquinoline-quinone derivative, which is capable of treating bacterial diseases and resistant bacterial diseases.
Disclosure of Invention
An object of the present invention is to provide a quinoid quinoline compound having antitumor and antibacterial activities. It is another object of the present invention to provide a process for preparing the above compound. It is a further object of the present invention to provide the use of the above compounds.
In one aspect, the present invention provides a quinoid quinoline compound having a structure represented by formula (I):
wherein R is 1 And R is 4 Each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, or C1-C6 alkylthio;
R 2 selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylthio orWherein R is 6 Selected from C1-C6 alkylene, C2-C6 heteroalkylene, R 5 Selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 heteroalkyl;
R 3 selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylthio or C1-C6 ester.
The quinoid quinoline according to the present invention is preferably one or more selected from N, O, S as a hetero atom in a hetero alkyl group or a hetero alkylene group.
The quinoid quinoline compounds according to the invention, preferably R 1 Is C1-C6 alkoxy;
R 4 selected from hydrogen or C1-C6 alkyl; r is R 3 Is a C1-C6 ester group; r is R 2 Is thatWherein R is 6 Selected from C1-C6 alkylene, R 5 Selected from C1-C6 alkanesA base.
The quinoid quinoline compounds according to the invention, preferably R 1 Is C1-C3 alkoxy; r is R 4 Is hydrogen; r is R 3 Is a C1-C3 ester group; r is R 2 Is thatWherein R is 6 Selected from C1-C3 alkylene, R 5 Selected from C1-C3 alkyl.
The quinoid quinoline compound according to the present invention is preferably selected from the group consisting of compounds shown below or isomers thereof or pharmaceutically acceptable salts thereof:
the quinoid quinoline compound according to the present invention is preferably selected from the group consisting of compounds shown below or pharmaceutically acceptable salts thereof:
the quinoid quinoline according to the invention is preferably a pharmaceutically acceptable salt selected from one or more of hydrochloride, besylate, tosylate, mesylate, tartrate, malate, maleate, fumarate, hydrobromide, sulphate, ethanesulfonate.
In another aspect, the present invention provides a method for preparing the quinoid quinoline compound, comprising the steps of:
(1) Eluting the ethanol extract of the Chinese eaglewood with normal phase silica gel chromatographic column by using petroleum ether-ethyl acetate-methanol system, dichloromethane-ethyl acetate-methanol system and dichloromethane-methanol system as solvent to obtain a first fraction;
(2) Eluting the first fraction with a sephadex chromatographic column using a dichloromethane-methanol system as a solvent to obtain a second fraction;
(3) Eluting the second fraction with ODS chromatographic column using methanol-water system as solvent to obtain third fraction;
(4) Eluting the third fraction with a sephadex chromatographic column and methanol as a solvent to obtain a fourth fraction;
(5) And separating the fourth fraction by a semi-preparative liquid chromatograph by taking a methanol aqueous solution as a mobile phase to obtain the quinoid quinoline compound.
In still another aspect, the present invention provides the use of the above quinoid quinoline compound in the preparation of an antitumor and/or antibacterial agent.
Preferably, the tumor is selected from one or more of liver cancer, breast cancer, prostate cancer, skin cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, pancreatic cancer, colon cancer, kidney cancer, ureter cancer, bladder cancer; the bacteria are selected from one or more of bacillus subtilis, candida albicans, staphylococcus aureus, pseudomonas aeruginosa and salmonella.
The present invention has unexpectedly found that the quinoid quinoline compounds of the present invention have excellent antitumor and antibacterial activities.
Drawings
FIG. 1 is an ECD map.
FIG. 2 is a graph showing the relationship between the concentration of Compound C and the survival rate of HepG2 cells.
FIG. 3 is a graph of compound C concentration versus MCF-7 cell viability.
FIG. 4 is a graph showing the relationship between the concentration of Compound D and the survival rate of HepG2 cells.
FIG. 5 is a graph of compound D concentration versus MCF-7 cell viability.
FIG. 6 is a graph of compound D concentration versus PC-3M-IE8 cell viability.
In fig. 2 to 6, P <0.01 and P <0.001.
Detailed Description
The present invention will be further described with reference to specific examples, but the scope of the present invention is not limited thereto.
< explanation of terms >
In the present invention, cm-Cn represents a compound having m to n carbon atoms; for example, C1-C10 alkyl represents an alkyl group having 1 to 10 carbon atoms.
In the present invention, "alkyl" means a group derived from a straight-chain or branched aliphatic hydrocarbon having one point of attachment. "heteroalkyl" means an alkyl group having at least one heteroatom with one point of attachment. "cycloalkyl" means a group derived from an aliphatic cyclic hydrocarbon having one point of attachment. The prefix "hetero" indicates that one or more carbon atoms have been replaced by a different atom.
Unless specifically stated, all groups may be substituted or unsubstituted. According to some embodiments of the invention, the substituents are selected from halogen, alkyl, alkoxy, aryl.
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 methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, preparations and examples are illustrative only and are not intended to be limiting.
< quinone quinoline Compound >
The quinoid quinoline compound has a structure shown in a formula (I) or an isomer or pharmaceutically acceptable salt thereof:
in the present invention, R 1 And R is 4 Each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, or C1-C6 alkylthio. Preferably, R 1 Selected from C1-C6 alkoxy or C1-C6 alkylthio. More preferably, R 1 Is C1-C6 alkoxy. According to one embodiment of the inventionEmbodiments, R 1 Is C1-C3 alkoxy. Preferably, R 4 Selected from hydrogen, halogen or C1-C6 alkyl. More preferably, R 4 Selected from hydrogen or C1-C6 alkyl. According to one embodiment of the invention, R 4 Is hydrogen.
In the present invention, R 2 Selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylthio orWherein R is 6 Selected from C1-C6 alkylene, C2-C6 heteroalkylene, R 5 Selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 heteroalkyl. Preferably, R 2 Is->More preferably, R 2 Is->Wherein R is 6 Is C1-C6 alkylene, R 5 Is hydrogen or C1-C6 alkyl. According to one embodiment of the invention, R 6 Is C1-C3 alkylene, R 5 Is a C1-C3 alkyl group.
In the present invention, R 3 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylthio or C1-C6 ester. Preferably, R 3 Is a C1-C6 ester group. More preferably, R 3 Is thatR 7 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl. According to one embodiment of the invention, R 3 Is->R 7 Is a C1-C6 alkyl group.
In the present invention, examples of halogen include, but are not limited to, fluorine, chlorine, bromine, iodine.
In the present invention, C1-C6 alkyl groups may include, but are not limited to, straight chain alkyl groups or branched alkyl groups; preferably C1-C3 alkyl, more preferably C1-C3 straight chain alkyl. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, hexyl and the like. Furthermore, the C1-C6 alkyl groups of the present invention may include substituted alkyl groups or unsubstituted alkyl groups. The substituents in the substituted alkyl groups may contain heteroatoms, such as O, S, N or halogen atoms. Halogen atoms of the present invention include, but are not limited to, fluorine, chlorine, bromine, iodine.
In the present invention, C2-C6 heteroalkyl may include, but is not limited to, straight chain heteroalkyl or branched heteroalkyl; preferably C2-C5 heteroalkyl, more preferably C2-C3 heteroalkyl. The heteroalkyl group of the present invention means a group in which a carbon atom on the alkyl chain is substituted with another heteroatom. The above hetero atom includes O, S or N, preferably O or S. Specific examples of C2-C6 heteroalkyl groups of the invention include, but are not limited to, -CH 2 -O-CH 3 、-CH 2 -O-CH 2 CH 3 、-CH 2 -O-CH(CH 3 )CH 3 、-CH 2 -S-CH 3 、-CH 2 -S-CH 2 CH 3 、-CH 2 -S-CH(CH 3 )CH 3 。
In the present invention, the C2-C6 heteroalkylene may include, but is not limited to, a linear heteroalkylene or a branched heteroalkylene; preferably C2-C5 heteroalkylene, more preferably C2-C3 heteroalkylene. The heteroalkylene group of the present invention means a group in which a carbon atom on the alkylene chain is substituted with another heteroatom. The above hetero atom includes O, S or N, preferably O or S. Specific examples of C2-C6 heteroalkylene groups of the invention include, but are not limited to, -CH 2 -O-CH 2 -、-CH 2 -O-CH 2 CH 2 -、-CH 2 -O-CH(CH 3 )CH 2 -、-CH 2 -S-CH 2 -、-CH 2 -S-CH 2 -CH 2 -、-CH 2 -S-CH(CH 3 )CH 2 -。
In the present invention, the C3-C6 cycloalkyl group may include a substituted cycloalkyl group and an unsubstituted cycloalkyl group; preferably C5-C6 cycloalkyl, more preferably C5 cycloalkyl. Specific examples of C3-C6 cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-methylcyclopentyl, 3-methylcyclohexyl, 3-ethylcyclohexyl, preferably cyclopentyl, cyclohexyl.
In the present invention, C1-C6 alkoxy groups may include, but are not limited to, straight chain alkoxy groups or branched alkoxy groups; preferably C1-C3 alkoxy, more preferably C1-C3 straight-chain alkoxy. Examples of C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexoxy, and the like.
In the present invention, C1-C6 alkylthio may include, but is not limited to, straight-chain alkylthio or branched-chain alkylthio; preferably C1-C3 alkylthio, more preferably C1-C3 straight-chain alkylthio. Examples of C1-C6 alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio, n-pentylthio, isopentylthio, neopentylthio, hexylthio, and the like.
Preferably, the quinoid quinoline compound of the present invention has a chiral structure. The carbon at the 4-position is in the S configuration.
In the present invention, the pharmaceutically acceptable salt is selected from one or more of hydrochloride, benzenesulfonate, toluenesulfonate, methanesulfonate, tartrate, malate, maleate, fumarate, hydrobromide, sulfate, and ethanesulfonate.
The quinoid quinoline compounds of the present invention may be selected from one of the following compounds:
preferably, the quinoid quinoline compounds of the present invention are selected from one of the following compounds:
< preparation method >
The preparation method of the quinoid quinoline compound comprises the following steps: (1) separating the ethanol extract of the wild linaloe; (2) a first partial separation step; (3) a second fraction separation step; (4) a third fraction separation step; (5) a fourth partial separation step; and optionally, (6) a step of chemical modification. In some embodiments, the method may further comprise a step of preparing an aquilaria sinensis ethanol extract.
The step of preparing the ethanol extract of the shan-tendril
Extracting lignum Aquilariae Resinatum with ethanol water solution, and concentrating the extractive solution to obtain lignum Aquilariae Resinatum ethanol extract. Specifically, the aquilaria sinensis is extracted by adopting a first ethanol aqueous solution and a second ethanol aqueous solution in sequence to obtain a first extracting solution and a second extracting solution respectively. And combining the first extract and the second extract, and concentrating to obtain the agalloch eaglewood ethanol extract. The lignum Aquilariae Resinatum may be pulverized lignum Aquilariae Resinatum.
The concentration of the first ethanol water solution is 90-97 vol%; preferably 95vol%. Taking 35.0kg of agilawood as a reference, and the dosage of the first ethanol aqueous solution is 10-40L; preferably 20 to 30L.
The concentration of the second ethanol water solution is 75-85 vol%; preferably 80vol%. Taking 35.0kg of agilawood as a reference, and the dosage of the second ethanol aqueous solution is 10-40L; preferably 20 to 30L.
The extraction time is 0.5-3 h each time; preferably 1 to 2 hours; more preferably 1.5h.
The extraction mode can be reflux extraction. The concentration may be performed under reduced pressure.
Separating the ethanol extract of the Chinese eaglewood
Eluting the ethanol extract of the wild linalool by adopting a normal phase silica gel chromatographic column, and combining normal phase thin layer chromatography detection to obtain the components A-Z. Fractions J or K are the first fractions.
The eluting solvent adopts petroleum ether-ethyl acetate-methanol system, methylene dichloride-ethyl acetate-methanol system and methylene dichloride-methanol system in sequence. The elution mode is gradient elution.
The elution conditions of the petroleum ether-ethyl acetate-methanol system are as follows: the volume ratio is (8-12) 1:0, (3-7) 1:0, (0.8-1.5) 1: (0.1-0.3), and (0.8-1.5), wherein (0.8-1.5) and a mixture of petroleum ether, ethyl acetate and methanol in a ratio of 0:0:1 are eluted. Preferably, elution is performed sequentially with a mixture of petroleum ether, ethyl acetate and methanol in a volume ratio of 10:1:0, 5:1:0, 1:1:0.2, 1:1:1 and 0:0:1.
The elution conditions of the methylene chloride-ethyl acetate-methanol system are as follows: the eluting is carried out by adopting the mixture of dichloromethane, ethyl acetate and methanol with the volume ratio of (18-22) 1:0 (8-12) 1:0 (0.8-1.5) 1 (0.1-0.3) and (0.8-1.5) 1 (0.8-1.5) and 0:0:1 in sequence. Preferably, elution is performed sequentially with a mixture of dichloromethane, ethyl acetate and methanol in a volume ratio of 20:1:0, 10:1:0, 1:1:0.2, 1:1:1 and 0:0:1.
The elution conditions of the methylene chloride-methanol system are as follows: the elution is carried out by adopting a mixture of dichloromethane and methanol with the volume ratio of (18-22) to (8-12) to (1) to (3-7) to (1) and (0.8-1.5) to (1) and 0:1 in sequence. Preferably, elution is performed sequentially with a mixture of dichloromethane and methanol in a volume ratio of 20:1, 10:1, 5:1, 1:1 and 0:1.
Step of first fraction separation
Eluting the first fraction with a sephadex column to obtain a second fraction. The chromatographic column according to one embodiment of the invention is a sephadex LH-20 column.
The eluting solvent is dichloromethane and methanol. The elution mode is isocratic elution. The volume ratio of the methylene dichloride to the methanol is 1 (2-6); preferably 1:4.
When the first stream is fraction J, fraction Ja-Jd is obtained. Jc is used as the second fraction.
When the first stream is fraction K, fraction Ka-Kc is obtained. Kc is used as the second fraction.
Step of separating the second fraction
Eluting the second fraction with ODS chromatographic column to obtain third fraction.
The eluting solvent is methanol and water. The elution mode is gradient elution.
The elution conditions were: the volume ratio is (55-70): (30-45), and 100:0. In certain embodiments, elution is performed sequentially with a mixture of methanol and water in a volume ratio of 65:35, 100:0. In other embodiments, elution is performed sequentially with a 60:40, 100:0 volume ratio of methanol to water mixture.
When the second stream is split into fractions Jc, jc1-Jc5 are obtained. Jc4 was used as the third fraction.
When the second stream is split into fractions Kc, kc1-Kc6 are obtained. Kc4 was used as the third fraction.
A third separation step
Eluting the third fraction with a sephadex column to obtain a fourth fraction. The chromatographic column according to one embodiment of the invention is a sephadex LH-20 column.
The solvent is methanol. The elution mode is isocratic elution.
When the third stream is fraction Jc4, jc4a-Jc4c are obtained. Jc4b was used as the fourth fraction.
When the third stream is fraction Kc4, kc4a-Kc4d are obtained. Kc4c was used as the fourth fraction.
Fourth step of partial separation
Separating the fourth fraction by semi-preparative liquid chromatograph to obtain quinoid quinoline compound.
The mobile phase is aqueous methanol. The concentration of the methanol aqueous solution is 50-70 vol%; preferably 55 to 65vol%. The flow rate is 1-8 mL/min. In certain embodiments, the flow rate is 2 to 4mL/min. In other embodiments, the flow rate is 5 to 7mL/min.
In some embodiments, fraction Jc4b is separated using a semi-preparative liquid chromatograph using 60-70 vol% aqueous methanol as the mobile phase at a flow rate of 5.0-7.0 mL/min to yield Jc4b1-Jc4b6. Separating the fraction Jc4b3 by a semi-preparative liquid chromatograph with 50-58 vol% methanol water solution as a mobile phase, wherein the flow rate is 2.0-4.0 mL/min, and obtaining the compound D. Preferably, fraction Jc4b is separated by semi-preparative liquid chromatograph using 65vol% aqueous methanol as mobile phase at a flow rate of 6.0mL/min to yield Jc4b1-Jc4b6. The fraction Jc4b3 was separated by semi-preparative liquid chromatography using 55vol% aqueous methanol as mobile phase at a flow rate of 3.0mL/min to give compound D.
In other embodiments, the fraction Kc4C is separated using a semi-preparative liquid chromatograph with 55-60 vol% methanol in water as the mobile phase at a flow rate of 2.0-4.0 mL/min to provide compound C. Preferably, fraction Kc4C is separated using a semi-preparative liquid chromatograph using 58vol% aqueous methanol as the mobile phase at a flow rate of 3.0mL/min to give compound C.
Step of chemical modification
And chemically modifying the substituent by adopting a method conventional in the art to obtain the quinoid quinoline compound.
< use >
The quinoid quinoline compound has anti-tumor and antibacterial activities, so the invention provides the application of the quinoid quinoline compound in preparing anti-tumor and/or antibacterial drugs. In certain embodiments, the invention provides the use of the quinoid quinoline compound in preparing an anti-tumor medicament. In other embodiments, the present invention provides the use of the quinoid quinoline compound described above for the preparation of an antibacterial agent.
In the present invention, examples of tumors include, but are not limited to, liver cancer, breast cancer, prostate cancer, skin cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, pancreatic cancer, colon cancer, kidney cancer, ureter cancer, bladder cancer. Preferably, the tumor is one or more of breast cancer, liver cancer and prostate cancer. More preferably, the tumor is one or more of breast cancer and liver cancer.
In the invention, the bacteria are selected from one or more of bacillus subtilis, candida albicans, staphylococcus aureus, pseudomonas aeruginosa and salmonella. Preferably, the bacterium is bacillus subtilis.
Example 1
35.0kg of eaglewood is crushed, and then 25L of 95vol% ethanol aqueous solution and 25L of 80vol% ethanol aqueous solution are sequentially adopted for reflux extraction, wherein each extraction time is 1.5 hours, and a first extract and a second extract are respectively obtained. And combining the first extract and the second extract, and concentrating under reduced pressure to obtain the agalloch eaglewood ethanol extract.
The method comprises the steps of (1) adopting a normal phase silica gel chromatographic column to extract the shan-zhu ethanol extract, sequentially using a petroleum ether-ethyl acetate-methanol system (10:1:0-5:1:0-1:1:0-1:1.2-1:1-0:1) and a methylene dichloride-ethyl acetate-methanol system (20:1:0-10:1:0-1:1-1:0.2-1:1-0:1) as a solvent gradient for elution, and combining normal phase thin-layer chromatography detection to obtain a fraction A-Z.
Example 2
The fraction J obtained in example 1 was eluted with a Sephadex LH-20 column using methylene chloride and methanol in a volume ratio of 1:4 as solvents to give 4 fractions Ja-Jd.
The Jc fractions were eluted with an ODS column using a methanol-water system (65:35→100:0) as a solvent gradient to obtain 5 fractions Jc1-Jc5.
Eluting the Jc4 fraction with Sephadex LH-20 column and methanol as solvent to obtain 3 fractions Jc4a-Jc4c.
The Jc4b fractions were separated by semi-preparative liquid chromatography using 65vol% aqueous methanol as the mobile phase at a flow rate of 6.0mL/min to give 6 fractions Jc4b1-Jc4b6.
Separating the Jc4b3 fraction with a semi-preparative liquid chromatograph using 55vol% methanol aqueous solution as mobile phase at a flow rate of 3.0mL/min to give compound D (10.0 mg, t) R ＝28.2min)。
Example 3
The fraction K obtained in example 1 was eluted with a Sephadex LH-20 column in a volume ratio of 1:4 of dichloromethane and methanol as solvents to give 3 fractions Ka-Kc.
The fraction Kc was eluted with a gradient of an ODS column using a methanol-water system (60:40. Fwdarw.100:0) as a solvent to obtain 6 fractions Kc1 to Kc6.
Eluting the fraction Kc4 with Sephadex LH-20 column and methanol as solvent to obtain 4 fractions Kc4a-Kc4d.
Separating fraction Kc4C with semi-preparative liquid chromatograph using 58vol% methanol aqueous solution as mobile phase at flow rate of 3.0mL/min to obtain compound C (1.5 mg, t) R ＝31.5min)。
Compound C and compound D 1 H-NMR(500MHz，CDCl 3 ) And 13 C-NMR(125MHz，CDCl 3 ) The data are shown in table 1 below: TABLE 1
Compound C: the detection by HR-ESI-MS shows the excimer ion peak [ M-H ]]372.1063 (calculated 372.1078), combined with 13 C-NMR data confirm that its molecular formula is C 19 H 17 NO 7 The unsaturation was 12. 1 The H-NMR data showed four olefinic hydrogens, one methine, one methylene, three methoxy groups, one primary amine hydrogen in the molecule. 13 C-NMR data showed that the molecule contained 19 carbon atoms including 4 carbonyl carbons, 10 unsaturated carbons, a methine group, a methylene group, and three methoxy groups. Combining HSQC and HMBC patterns 1 H and 13 the C NMR data were assigned as shown in Table 1. The above information speculates that compound C is a alkaloid and contains a quinoid fragment in its structure. The absolute configuration was determined to be 4S by the method of calculating ECD. The structure of compound C is shown below:
compound D: the detection by HR-ESI-MS shows the excimer ion peak [ M-H ]]386.1222 (calculated 386.1234), combined with 13 C-NMR data confirm that its molecular formula is C 20 H 19 NO 7 The unsaturation was 12. 1 H-NMR 13 Comparison of the C-NMR data with the data for Compound C revealed that the C-13 position in Compound D was substituted with ethoxy, thereby determining the planar structure of Compound D, combining the HSQC and HMBC pattern pairsWhich is a kind of 1 H and 13 the C NMR data were assigned as shown in Table 1. The absolute configuration of compound C was determined to be 4S by comparison with the ECD profile of this compound. The structure of compound D is shown below:
experimental example 1-MTT method test of Compounds for Effect on proliferation of cancer cells
Taking 3 cancer cells MCF-7, hepG2 and PC-3M-IE8 cultured in logarithmic growth phase, culturing with fresh 1640 medium containing 10% foetal calf serum, respectively, and adjusting cell density to 5×10 4 Each of the cells was inoculated into a 96-well plate. The well plate was placed in a solution containing 5% CO 2 Incubation was carried out at 37℃for 24h, and then 0. Mu.M, 1. Mu.M, 5. Mu.M, 10. Mu.M, 15. Mu.M, 20. Mu.M and 30. Mu.M of Compound C or Compound D, respectively, were added. After 48 hours of pretreatment, the medium was aspirated, and 100. Mu.L of 500. Mu.g/mL MTT solution was added to the medium and the culture was continued for 4 hours. MTT was carefully pipetted off, 150. Mu.L of DMSO was added to each well, and the well plate was then shaken on a plate shaker for 10 minutes. The 96-well plate was placed in an enzyme-labeled instrument and the OD at 570nm was measured. Performing data processing by using an enzyme-labeled instrument and corresponding software, and calculating the cell survival rate and the inhibition rate according to the following formula: cell viability% = sample OD mean/placebo OD mean x 100%. Inhibition% = 100% -cell viability%. The results obtained are shown in FIGS. 2 to 6.
Compound C has obvious inhibitory activity on HepG2 and MCF-7 cells. At a concentration of 30. Mu.M, the inhibition rate of MCF-7 cells was 94% and HepG2 cells was 93%. IC of Compound C on MCF-7 cells 50 IC for HepG2 cells at 5.0. Mu. Mol/L 50 9.1. Mu. Mol/L.
Compound D has obvious inhibitory activity on MCF-7, hepG2 and PC-3M-IE8 cells. When the concentration of Compound D was 30. Mu.M, the inhibition rate for MCF-7 cells was 93%, the inhibition rate for HepG2 cells was 91%, and the inhibition rate for PC-3M-IE8 cells was 71%. IC of Compound D on MCF-7 cells 50 10.3. Mu. MolL, IC for HepG2 cells 50 IC for PC-3M-IE8 cells at 12.1. Mu. Mol/L 50 18.1. Mu. Mol/L.
Experimental example 2-Effect of test Compounds on Bacillus subtilis and Candida albicans
Bacillus subtilis ATCC6633 (purchased from China general microbiological culture collection center) and Candida albicans ATCC10231 (purchased from China general microbiological culture collection center) were grown in yeast extract-peptone-glucose medium (YPD) to mid-log phase, respectively, and then diluted to 5X 10 with the same medium 5 The density of CFU/mL is used for obtaining bacillus subtilis bacterial liquid and candida albicans bacterial liquid. The bacillus subtilis liquid and the candida albicans liquid are respectively formed into a series of bacillus subtilis liquid and candida albicans liquid containing the compound C with gradient concentration (the content of the compound C is 1-87 mu g/mL) and a series of bacillus subtilis liquid and candida albicans liquid containing the compound D with gradient concentration (the content of the compound D is 1-87 mu g/mL). The bacillus subtilis liquid containing the compound C, the candida albicans liquid containing the compound C, the bacillus subtilis liquid containing the compound D and the candida albicans liquid containing the compound D are respectively distributed into sterile 96-well plates at a ratio of 0.2 ml/well. After incubation at 37 ℃ for 17 hours, the Minimum Inhibitory Concentration (MIC) was determined by measuring and comparing the optical diversity of the blank and test wells and recorded. The antibacterial positive control was rifampicin. All experiments were performed in triplicate.
The results show that compound C and compound D have an effect on bacillus subtilis and a insignificant effect on candida albicans. Compound C and compound D have significant antibacterial activity against Bacillus subtilis, and Minimum Inhibitory Concentrations (MIC) are 10.88 μg/mL and 5.31 μg/mL, respectively. The minimum inhibitory concentration of the positive control agent rifampicin is 0.04 mug/mL.
The present invention is not limited to the above-described embodiments, and any modifications, improvements, substitutions, and the like, which may occur to those skilled in the art, fall within the scope of the present invention without departing from the spirit of the invention.

Claims (10)

1. A quinoid quinoline compound which has a structure represented by the formula (I):
wherein R is 1 And R is 4 Each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, or C1-C6 alkylthio;
R 2 selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylthio orWherein R is 6 Selected from C1-C6 alkylene, C2-C6 heteroalkylene, R 5 Selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 heteroalkyl;
R 3 selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylthio or C1-C6 ester.
2. The quinoid quinoline according to claim 1, wherein the heteroatom in the heteroalkyl or heteroalkylene is selected from one or more of N, O, S.
3. The quinoid quinoline compound according to claim 1, wherein R 1 Is C1-C6 alkoxy; r is R 4 Selected from hydrogen or C1-C6 alkyl; r is R 3 Is a C1-C6 ester group; r is R 2 Is thatWherein R is 6 Selected from C1-C6 alkylene, R 5 Selected from C1-C6 alkyl.
4. The quinoid quinoline compound according to claim 1, wherein R 1 Is C1-C3 alkoxy; r is R 4 Is hydrogen; r is R 3 Is a C1-C3 ester group; r is R 2 Is thatWherein R is 6 Selected from C1-C3 alkylene, R 5 Selected from C1-C3 alkyl.
5. The quinoid quinoline compound according to claim 1, wherein the quinoid quinoline compound is selected from the group consisting of the compounds shown below or isomers thereof or pharmaceutically acceptable salts thereof:
6. the quinoid quinoline compound according to claim 1, wherein the quinoid quinoline compound is selected from the group consisting of the compounds shown below or pharmaceutically acceptable salts thereof:
7. the quinoid quinoline according to claim 1, wherein the pharmaceutically-acceptable salt is selected from one or more of the group consisting of hydrochloride, besylate, tosylate, mesylate, tartrate, malate, maleate, fumarate, hydrobromide, sulfate and ethanesulfonate.
8. The method for producing a quinoid quinoline according to any one of claims 1 to 7, comprising the steps of:
(1) Eluting the ethanol extract of the Chinese eaglewood with normal phase silica gel chromatographic column by using petroleum ether-ethyl acetate-methanol system, dichloromethane-ethyl acetate-methanol system and dichloromethane-methanol system as solvent to obtain a first fraction;
(2) Eluting the first fraction with a sephadex chromatographic column using a dichloromethane-methanol system as a solvent to obtain a second fraction;
(3) Eluting the second fraction with ODS chromatographic column using methanol-water system as solvent to obtain third fraction;
(4) Eluting the third fraction with a sephadex chromatographic column and methanol as a solvent to obtain a fourth fraction;
(5) And separating the fourth fraction by a semi-preparative liquid chromatograph by taking a methanol aqueous solution as a mobile phase to obtain the quinoid quinoline compound.
9. Use of a quinoid quinoline compound according to any one of claims 1 to 7 for the preparation of an antitumor and/or antibacterial drug.
10. The use according to claim 9, wherein the tumour is selected from one or more of liver cancer, breast cancer, prostate cancer, skin cancer, head and neck cancer, lung cancer, oesophageal cancer, cervical cancer, pancreatic cancer, colon cancer, kidney cancer, ureter cancer, bladder cancer; the bacteria are selected from one or more of bacillus subtilis, candida albicans, staphylococcus aureus, pseudomonas aeruginosa and salmonella.
CN202211248380.1A 2022-10-12 2022-10-12 Quinone quinoline compound and preparation method and application thereof Active CN115650913B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211248380.1A CN115650913B (en) 2022-10-12 2022-10-12 Quinone quinoline compound and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211248380.1A CN115650913B (en) 2022-10-12 2022-10-12 Quinone quinoline compound and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN115650913A CN115650913A (en) 2023-01-31
CN115650913B true CN115650913B (en) 2024-03-01

Family

ID=84986702

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211248380.1A Active CN115650913B (en) 2022-10-12 2022-10-12 Quinone quinoline compound and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN115650913B (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB508708A (en) * 1938-01-14 1939-07-05 George William Johnson Improvements in the manufacture and production of anthraquinone derivatives
JPS61115081A (en) * 1984-11-09 1986-06-02 Ss Pharmaceut Co Ltd Novel antibiotic ss21020d and production thereof
EP0274545A1 (en) * 1986-07-21 1988-07-20 Kyowa Hakko Kogyo Co., Ltd. Novel substances dc-92b and dc-92d, and process for their preparation
EP0326173A2 (en) * 1988-01-28 1989-08-02 Meiji Seika Kaisha Ltd. Novel antitumor antibiotic substance and a method for production thereof
US5071848A (en) * 1989-10-23 1991-12-10 Abbott Laboratories Tricyclic quinoline antineoplastic agents
WO2013156563A1 (en) * 2012-04-20 2013-10-24 Rhodia Operations Quinone acceptors for photovoltaic use
CN107011143A (en) * 2017-05-05 2017-08-04 云南民族大学 The preparation method and application of two kinds of anthraquinone analog compounds

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB508708A (en) * 1938-01-14 1939-07-05 George William Johnson Improvements in the manufacture and production of anthraquinone derivatives
JPS61115081A (en) * 1984-11-09 1986-06-02 Ss Pharmaceut Co Ltd Novel antibiotic ss21020d and production thereof
EP0274545A1 (en) * 1986-07-21 1988-07-20 Kyowa Hakko Kogyo Co., Ltd. Novel substances dc-92b and dc-92d, and process for their preparation
EP0326173A2 (en) * 1988-01-28 1989-08-02 Meiji Seika Kaisha Ltd. Novel antitumor antibiotic substance and a method for production thereof
US5071848A (en) * 1989-10-23 1991-12-10 Abbott Laboratories Tricyclic quinoline antineoplastic agents
WO2013156563A1 (en) * 2012-04-20 2013-10-24 Rhodia Operations Quinone acceptors for photovoltaic use
CN107011143A (en) * 2017-05-05 2017-08-04 云南民族大学 The preparation method and application of two kinds of anthraquinone analog compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"喹啉氧基并四苯二醌的合成和光致变色性质";连慧琴等;《应用化学》;第22卷(第3期);第308-311页 *

Also Published As

Publication number Publication date
CN115650913A (en) 2023-01-31

Similar Documents

Publication Publication Date Title
KR101568724B1 (en) Novel compound, a preparing method thereof, and a use thereof as inhibitors of histone demethylase
US20190322638A1 (en) Dipyridyl alkaloid, preparation method therefor and use thereof
EP1976533A2 (en) Triterpenequinone and triterpenephenol derivatives and their application for the treatment of tumors and parasitic diseases
CN113698401B (en) Beta-elemene macrocyclic derivatives, preparation method and application thereof
CA2612482C (en) Biologically active compounds obtainable from sorangium cellulosum
CN115650913B (en) Quinone quinoline compound and preparation method and application thereof
US6403636B1 (en) Xanthone compounds, their preparation and use as medicament
WO2017151947A1 (en) 4-azapodophylotoxins compounds
JP2009519301A (en) Antitumor compounds
US8168648B2 (en) Camptothecin derivatives and uses thereof
JP4467985B2 (en) Novel opioid derivatives
KR101721665B1 (en) Amide-based derivative compound, preparing method and use thereof
WO1998049895A1 (en) Selectively cytotoxic acetogenin compounds
WO2004078764A1 (en) Gm-95-containing antitumor effect potentiator, combined antitumor preparation and antitumor agent
JP4844955B2 (en) Antitumor agent
US11286273B2 (en) Rhamnolipid compounds and use thereof
CN101307041B (en) Novel taxane halogenation derivates with anti-tumor activity
CN112778393B (en) Oleandrin derivatives, and preparation method, pharmaceutical composition and application thereof
KR101372887B1 (en) Anti-cancer composition comprising dipeptide isolated from microorganism
KR101876450B1 (en) Novel 5-hydroxyindole compound and pharmaceutical compositions for prevention or treatment of cancer comprising the same
Amrine Studies on Epipolythiodioxopiperazine Alkaloids
KR101283895B1 (en) Composotion comprising 5-hydroxyindole compound or the extract of Scalarispongia sp. for preventing and treating cancer
Chan Natural Products from New Zealand Ascidians Pseudodistoma opacum and Aplidium scabellum
EP2703410B1 (en) Jagaricin, derivatives, and uses thereof
WO2022018430A1 (en) Zinc complexes and their uses

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant