CN114149347A - Novel anthraquinone derivative and synthesis method and application thereof - Google Patents
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- 150000004056 anthraquinones Chemical class 0.000 title claims abstract description 27
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 claims abstract description 7
- BOCJQSFSGAZAPQ-UHFFFAOYSA-N 1-chloroanthracene-9,10-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2Cl BOCJQSFSGAZAPQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
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- KHUFHLFHOQVFGB-UHFFFAOYSA-N 1-aminoanthracene-9,10-dione Chemical class O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2N KHUFHLFHOQVFGB-UHFFFAOYSA-N 0.000 description 1
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- VMDWTZZCNDEKIO-CBNJBKGYSA-N [(2s,3s,4s,6r)-6-[[(1s,3s)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-2,4-dihydro-1h-tetracen-1-yl]oxy]-4-(aziridin-1-yl)-2-methyloxan-3-yl] methanesulfonate Chemical compound N1([C@H]2C[C@@H](O[C@H]([C@H]2OS(C)(=O)=O)C)O[C@@H]2C3=C(O)C=4C(=O)C5=CC=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(C)=O)CC1 VMDWTZZCNDEKIO-CBNJBKGYSA-N 0.000 description 1
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- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/66—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to halogen atoms or to nitro or nitroso groups
- C07C275/68—N-nitroso ureas
-
- 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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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the field of drug design and synthesis, in particular to a novel anthraquinone derivative and a synthesis method and application thereof, wherein the chemical general formula of the novel anthraquinone derivative is as follows:
Description
Technical Field
The invention relates to the field of drug design and synthesis, in particular to a novel anthraquinone derivative and a synthesis method and application thereof.
Background
Anthraquinone antibiotics are important powerful anticancer agents, can effectively inhibit the growth and reproduction of cancer cells, and are often used for treating malignant cancers such as breast cancer, solid tumors of children, acute lymphocytic leukemia and the like in clinic. However, anthraquinone antibiotics also face the side effect of dose-accumulating chronic cardiotoxicity while exerting strong anticancer capability, and the clinical application range of the anthraquinone antibiotics is limited to a greater extent. Therefore, the research and innovation of the structural modification and the targeted delivery mechanism of the anthraquinone antibiotics become a new idea for improving the drugs.
Mitoxantrone is a chemically synthesized atypical anthraquinone derivative, has stronger anticancer efficiency than that of traditional anthraquinone anticancer drugs such as adriamycin and remarkably reduced cardiotoxicity, is a first-line drug for replacing adriamycin for clinical treatment, and still shows chronic cardiotoxicity in anticancer treatment of clinical relapsing and remitting multiple sclerosis patients.
Based on the fact that the anthraquinone derivative anticancer drugs applied in the existing clinic still have certain toxic and side effects on the heart, a novel anticancer agent with high-efficiency anticancer efficacy and the effect of remarkably reducing the toxicity on the heart needs to be developed.
Disclosure of Invention
The invention provides a novel anthraquinone derivative anticancer agent AD-NU and a synthesis method thereof, which realizes powerful anticancer and obviously reduces the cardiotoxicity effect by modifying nitrosourea groups on an amino alkyl chain substituted anthraquinone ring.
A novel anthraquinone derivative AD-NU has the following structural general formula:
the invention is synthesized by the following technical scheme:
s1: 1-chloroanthraquinone and N, N-dimethylethylenediamine are used as raw materials, mixed and heated to 80 ℃, stirred and refluxed for 1 hour, and the mixture is cooled after the reaction is finishedThen diluted with ice water, the reaction was extracted with chloroform and the organic layer was washed, and Na was added2SO4Drying overnight, concentrating the organic solution in vacuum, and separating and purifying the product by using eluent 1 through column chromatography to obtain a compound 2;
s2: dissolving the compound 2 in methanol, dropwise adding the methanol solution dissolved with chloroethyl isocyanate, stirring for reacting for 40 minutes, removing the methanol in vacuum, and separating and purifying the product by using eluent 2 through column chromatography to obtain a compound 3;
s3: dissolving compound 3 in formic acid, adding NaNO in 1 hour2Solid, reaction temperature below 10 deg.c, extracting the mixture with ether, and saturated NaHCO solution for the organic phase3Washing with Na2SO4Drying overnight, removing formic acid in vacuum, and separating and purifying the product by using eluent 2 through column chromatography to obtain a final product;
the reaction equation is as follows:
wherein the ratio of the eluent 1 is ethyl acetate: petroleum ether 1:1 (1% triethylamine); the ratio of the eluent 2 is ethyl acetate: petroleum ether-5: 2 (1% triethylamine).
Wherein the mixing ratio of the 1-chloroanthraquinone to the N, N-dimethylethylenediamine is 1: 11.
Wherein the mixing ratio of the compound 2 to the chloroethyl isocyanate is 1: 1.
Wherein, the compound 3 is reacted with NaNO2The mixing ratio of the solids was 1: 5.
The idea of the invention is as follows:
the alkylating group is modified on the basis of the structure of a natural anthraquinone drug, so that the synergistic anticancer effect with an anthraquinone ring can be realized, and the anticancer mechanism for inhibiting the TOPII effect is changed, so that the occurrence of chronic cardiotoxicity and even heart failure after the administration and the withdrawal of the drug can be greatly reduced, the anthraquinone drugs PNU-159548 and PNU-159550 which are modified by substituting the alkylating group have already entered the clinical test stage, and the application of the alkylating group has observed the significantly reduced cardiotoxicity effect compared with the traditional anthraquinone anticancer drugs; nitrosourea drugs refer to a biological alkylating agent with chloroethyl nitrosourea structure and spectrum antitumor activity, and mainly rely on the metabolism in human environment to generate electrophilic reagents, so as to alkylate DNA molecules and play the role of antitumor.
Based on the above drug structure improvement optimization mechanism, we have adopted the amino alkyl chain and chloroethyl nitrosourea structure in the Mitoxantrone (MTZ) drug structure, designed a series of novel nitrosourea substituted aminoanthraquinone derivatives AD-NU and Med-1-5, and optimized and screened the series of molecules by combining DNA acceptor (PDB:2DES) in the molecular docking software MOE, the candidate compounds and their DNA docking energy are shown in the following tables 1 and 2,
TABLE 1 docking candidate Compounds
TABLE 2 DNA docking energy of candidate Compounds
A3D-binding mode diagram of AD-NU and double-stranded DNA is shown in figure 1, in a molecular docking software MOE, according to the characteristics of interaction between an embedded organic small molecule and a DNA receptor, firstly, the series of small molecule structures are processed into an optimal conformation, structure preparation and energy minimization processing are carried out on the DNA receptor, in the docking process, a flexible docking mode between the small molecule and a biological macromolecule is selected, the embedding posture is continuously adjusted to achieve the most stable binding form, the interaction between a ligand and the receptor is analyzed and determined by comparing a docking energy value and an analysis binding mode diagram, and the optimal molecule represented by energy is AD-NU by combining the optimal conformation in figure 1 and the energy docking result in a table 2.
The invention has the beneficial effects that:
(1) the novel anthraquinone derivative anticancer agent AD-NU synthesized by the invention has stronger DNA damage and cancer cell killing effects, and particularly in the treatment process of a non-small cell lung cancer cell line A549 cell line, the AD-NU has a median lethal dose IC of 3 mu M50Compared with 15.6 mu M of mitoxantrone, the composition shows stronger anticancer effect;
(2) compared with the traditional anthraquinone anticancer drugs, the novel anthraquinone derivative AD-NU can obviously reduce the cardiotoxicity effect by modifying a nitrosourea group on an anthraquinone ring substituted by an amino alkyl chain;
(3) the whole synthesis route is simple and convenient, the reaction conditions are mild and controllable, and the target product AD-NU can be efficiently synthesized by three steps by using common and easily-obtained raw materials.
Drawings
FIG. 1 is a graph showing the 3D-binding pattern of AD-NU to double-stranded DNA;
FIG. 2 is an image of AD-NU treated 1% agarose gel electrophoresis.
Detailed Description
The present invention is further illustrated by the following examples.
Example (b):
(1) adding 1.5mmol of 1-chloroanthraquinone into 1.75mL of N, N-dimethylethylenediamine, refluxing for 1 hour at 80 ℃, stopping heating after the basic consumption of raw materials is detected by thin-layer chromatography, cooling the mixture to room temperature, and slowly adding 10mL of ice water prepared in advance into the mixture for dilution; the mixture was then extracted with chloroform (3X 20mL), the organic phase was washed with deionized water to ensure no excess of dimethylethylenediamine was left, and then Na was added2SO4Drying overnight; the chloroform phase was then removed in vacuo and the mixture was passed throughThe red component, compound 2, was collected by flash column chromatography eluting at ethyl acetate: petroleum ether is 1:1 (1% triethylamine) in about 60% yield.
(2) Firstly, dissolving 1mmol of chloroethyl isocyanate and 1mmol of compound 2 in 5mL of methanol respectively, dropwise adding the chloroethyl isocyanate solution into the compound 2 solution under the condition of stirring at room temperature for 40 minutes, after the reaction is confirmed to be finished by thin-layer chromatography, separating and purifying the product by column chromatography to obtain a compound 3, wherein the eluent ratio is ethyl acetate: petroleum ether is 5:2 (1% triethylamine) in about 35% yield.
(3) 0.12mmol of Compound 3 was dissolved in 3mL of formic acid, and 0.6mmol of NaNO was added to the solution in portions at a reaction temperature of 10 deg.C2After the solid is added within 1 hour, continuing to react for 30 minutes; the reaction mixture was then extracted with ether (3X 10mL) and saturated NaHCO3The organic phase was washed with solution (2 × 10mL) and deionized water to further neutralize formic acid; and finally, separating and purifying the product by column chromatography to obtain a compound AD-NU, wherein the eluent ratio is ethyl acetate: petroleum ether is 5:2 (1% triethylamine) in about 30% yield.
As shown in figure 2, the anticancer activity of the prepared final product AD-NU is evaluated, calf thymus double-stranded DNA (cfDNA) is selected, 10, 20, 30 and 250 mu M concentration gradients of AD-NU are set, after incubation for 6 hours at 37 ℃, the calf thymus double-stranded DNA (cfDNA) runs for 30 minutes in 1% agarose gel electrophoresis, EB color development is carried out, and an electrophoresis image figure 2 shows that the brightness of a DNA strip is continuously reduced along with the continuous increase of the action concentration of the AD-NU compound, which indicates the embedding damage and the fracture action of a drug molecule on the DNA molecule; compared with mitoxantrone and AD-NU with the same concentration, the DNA damage effect is stronger, and the molecular basis is provided for the anti-cancer effect;
in order to further verify the anti-cancer effect of the AD-NU molecules, the non-small cell lung cancer cell line A549 and the cervical cancer cell line Hela are selected and treated by different drug concentrations, and the result shows that when the AD-NU concentration reaches 4 mu M, the anti-cancer agent shows obvious killing capability on cancer cells; wherein in A549 is fineDuring the treatment of cell lines, AD-NU was half-lethal IC at 3. mu.M50A stronger anticancer effect was shown compared to 15.6. mu.M of mitoxantrone.
Claims (8)
1. A novel anthraquinone derivative is characterized in that the structural general formula is as follows:
2. the process for producing a novel anthraquinone derivative according to claim 1, which comprises the steps of:
s1: mixing 1-chloroanthraquinone and N, N-dimethylethylenediamine as raw materials, heating to 80 ℃, stirring and refluxing for 1 hour, cooling the mixture after the reaction is finished, diluting the mixture with ice water, extracting reactants, washing an organic layer, and adding Na2SO4Drying overnight, concentrating the organic phase in vacuum, and separating and purifying the product by using eluent 1 through column chromatography to obtain a compound 2;
s2: dissolving the compound 2 in methanol, dropwise adding the methanol solution dissolved with chloroethyl isocyanate, stirring for reacting for 40 minutes, removing the methanol in vacuum after the reaction is finished, and separating and purifying the product by using eluent 2 through column chromatography to obtain a compound 3;
s3: dissolving compound 3 in formic acid, adding NaNO in 1 hour2Solid, reaction temperature below 10 deg.C, extracting the mixture after reaction, washing organic layer, and adding Na2SO4Drying overnight, removing formic acid in vacuum, and separating and purifying the product by using eluent 2 through column chromatography to obtain a final product;
the reaction equation is as follows:
3. the method of claim 2, wherein the ratio of the eluent 1 is ethyl acetate: petroleum ether is 1:1 (1% triethylamine).
4. The method of claim 2, wherein the ratio of eluent 2 is ethyl acetate: petroleum ether-5: 2 (1% triethylamine).
5. The method of claim 2, wherein the ratio of 1-chloroanthraquinone to N, N-dimethylethylenediamine is 1: 11.
6. The method of claim 2, wherein the ratio of compound 2 to chloroethyl isocyanate is 1: 1.
7. The method for producing a novel anthraquinone derivative anticancer agent according to claim 2, wherein said compound 3 is mixed with NaNO2The ratio of solids was 1: 5.
8. Use of the novel anthraquinone derivative according to claim 1 for the preparation of an anticancer agent.
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