WO2024031970A1 - 一种具有抗肿瘤活性的化合物及其制备方法与它的用途 - Google Patents
一种具有抗肿瘤活性的化合物及其制备方法与它的用途 Download PDFInfo
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- WO2024031970A1 WO2024031970A1 PCT/CN2023/079217 CN2023079217W WO2024031970A1 WO 2024031970 A1 WO2024031970 A1 WO 2024031970A1 CN 2023079217 W CN2023079217 W CN 2023079217W WO 2024031970 A1 WO2024031970 A1 WO 2024031970A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
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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
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- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
Definitions
- the invention belongs to the field of medicine. More specifically, the present invention relates to a compound with anti-tumor activity, a method for preparing the compound, and a use of the compound.
- Cancer also known as malignant tumor, is one of the major diseases that seriously threatens human life and health. According to 2018 data from the Global Cancer Observatory (GCO) website, the global incidence and mortality of this disease were 10.8 million and 9.56 million respectively.
- Capsaicin its compound name: trans-8-methyl-N-vanillyl-6-nonenamide, has the following chemical formula structure:
- capsaicin It is a vanillamide alkaloid with multiple biological activities isolated from Capsicum plants of the Solanaceae family.
- the anti-tumor activity of capsaicin has become a hot research topic in recent years.
- a large number of in vivo and in vitro activity studies have shown that capsaicin can effectively inhibit the growth of a variety of tumors, such as breast cancer, bladder cancer, liver cancer, prostate cancer, endometrial cancer, non-small cell lung cancer and colon cancer. It is a broad-spectrum Antitumor active compounds.
- An object of the present invention is to provide a compound with anti-tumor activity.
- Another object of the present invention is to provide a method for preparing the compound with anti-tumor activity.
- Another object of the present invention is to provide the use of the compound with anti-tumor activity.
- the present invention relates to a compound with anti-tumor activity.
- R 1 is selected from hydroxyl, carboxyl, methyl, methoxy or hydrogen
- R 2 is selected from vinyl, methyl, monochloromethyl or phenyl
- R 3 is selected from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, hydroxyl, methyl or hydrogen;
- R 4 is selected from hydrogen, hydroxyl, chlorine, methyl, bromine, acetyl, methoxyformyl or chloroacetamidomethyl;
- R 5 is selected from hydroxyl, methyl or hydrogen
- R 6 is selected from hydroxyl, acrylamidemethyl, acetamidomethyl, chloroacetamidomethyl, methyl or hydrogen.
- R 2 is vinyl; R 1 is carboxyl; R 6 is acrylamide methyl.
- R 2 is vinyl; R 1 is carboxyl; R 6 is acrylamide methyl; R 3 and R 5 are hydroxyl groups.
- R 2 is vinyl; R 1 is carboxyl; R 6 is acrylamide methyl; R 3 and R 5 are hydroxyl; R 4 is hydroxyl or bromine.
- R 2 is methyl; R 1 is methyl; R 6 is hydrogen.
- R 2 is methyl; R 1 is methyl; R 6 is hydrogen; R 3 and R 5 are hydroxyl or methyl.
- R 2 is methyl; R 1 is methyl; R 6 is hydrogen; R 3 and R 5 are hydroxyl or methyl; R 4 is methyl.
- R 2 is monochloromethyl
- R 3 is methoxycarbonyl, hydroxyl or methyl.
- R 2 is monochloromethyl
- R 3 is methoxycarbonyl, hydroxyl or methyl
- R 6 is selected from hydroxyl, chloroacetamidomethyl or hydrogen.
- R 2 is monochloromethyl;
- R 3 is methoxycarbonyl, hydroxyl or methyl;
- R 6 is selected from hydroxyl, chloroacetamidomethyl or hydrogen;
- R 5 is hydroxyl or methyl.
- R 2 is monochloromethyl;
- R 3 is methoxycarbonyl, hydroxyl or methyl;
- R 6 is selected from hydroxyl, chloroacetamidemethyl or hydrogen;
- R 5 is hydroxyl or methyl;
- R 4 is selected from hydrogen, chlorine or methyl.
- R 2 is monochloromethyl;
- R 3 is methoxycarbonyl, hydroxyl or methyl;
- R 6 is selected from hydroxyl, chloroacetamidemethyl or hydrogen;
- R 5 is hydroxyl or methyl;
- R 4 is selected from hydrogen, chlorine or Methyl;
- R 1 is selected from hydroxyl, methyl, methoxy or hydrogen.
- the compound is a compound selected from the following compounds:
- the invention also relates to methods for the preparation of said compounds.
- the aromatic compound is gallic acid, methyl gallate, propyl gallate, 2,6-dihydroxytoluene, 3,5-dimethylanisole, 2 ,3,5-trimethylphenol, 4-chloro-3,5-dimethylphenol, 2,6-dihydroxyacetophenone, 2,4-dihydroxyacetophenone, 4-bromo-3,5 - Dihydroxybenzoic acid or methyl 3,4-dihydroxybenzoate.
- the amide compound is N-hydroxymethylacrylamide, N-hydroxymethylacetamide, N-hydroxymethylchloroacetamide or N-hydroxymethylbenzamide.
- the catalyst is concentrated sulfuric acid or anhydrous aluminum trichloride.
- the solvent is methylene chloride, chloroform, acetone or ethanol.
- the washed solid matter is dried at a temperature of 50 to 60° C. for 360 to 420 minutes, so that the water content of the dried solid matter is less than 5% by weight.
- the present invention also relates to the use of the compound of chemical formula (I) and the compound of chemical formula (I) prepared by the preparation method as an anti-tumor drug.
- the compound of chemical formula (I) is used to prepare anti-tumor drugs for treating lung cancer, liver cancer, colon cancer, leukemia, cervical cancer or breast cancer.
- the present invention relates to a compound with anti-tumor activity.
- R 1 is selected from hydroxyl, carboxyl, methyl, methoxy or hydrogen
- R 2 is selected from vinyl, methyl, monochloromethyl or phenyl
- R 3 is selected from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, hydroxyl, methyl or hydrogen;
- R 4 is selected from hydrogen, hydroxyl, chlorine, methyl, bromine, acetyl, methoxyformyl or chloroacetamidomethyl;
- R 5 is selected from hydroxyl, methyl or hydrogen
- R 6 is selected from hydroxyl, acrylamidemethyl, acetamidomethyl, chloroacetamidomethyl, methyl or hydrogen.
- the compound is a compound selected from the following compounds:
- the invention also relates to methods for the preparation of said compounds.
- the aromatic compounds are gallic acid, methyl gallate, propyl gallate, 2,6-bis gallate Hydroxytoluene, 3,5-dimethylanisole, 2,3,5-trimethylphenol, 4-chloro-3,5-dimethylphenol, 2,6-dihydroxyacetophenone, 2, 4-dihydroxyacetophenone, 4-bromo-3,5-dihydroxybenzoic acid or methyl 3,4-dihydroxybenzoate.
- the aromatic compounds used in the present invention are products currently on the market, such as gallic acid sold by Sinopharm Chemical Reagent Co., Ltd. under the trade name gallic acid, and gallic acid sold by Sinopharm Chemical Reagent Co., Ltd. under the trade name methyl gallate.
- gallic acid sold by Sinopharm Chemical Reagent Co., Ltd. under the trade name gallic acid
- gallic acid sold by Sinopharm Chemical Reagent Co., Ltd. under the trade name methyl gallate.
- the amide compound is N-hydroxymethylacrylamide (abbreviated as N-1), N-hydroxymethylacetamide (abbreviated as N-2), N-hydroxymethylchloroacetamide (abbreviated as N- 3) or N-hydroxymethylbenzamide (referred to as N-4).
- the amide compounds used in the present invention are all products currently sold on the market, such as N-hydroxymethylacrylamide sold by Sinopharm Chemical Reagent Co., Ltd. under the trade name N-methylolacrylamide, sold by Shanghai Yaxing Biomedical Technology Co., Ltd. sells N-hydroxymethylacetamide under the trade name N-hydroxymethylacetamide, and N-hydroxymethylethyl chloride is sold by Shanghai Yaxing Biomedical Technology Co., Ltd. under the trade name chloroacetamide-N-methanol. Amide, N-hydroxymethylbenzamide sold by Sinopharm Chemical Reagent Co., Ltd. under the trade name N-hydroxymethylbenzamide.
- the catalyst is concentrated sulfuric acid or anhydrous aluminum trichloride, which are chemical products currently sold on the market and commonly used in the field of chemical technology.
- the solvent is methylene chloride, chloroform, acetone or ethanol, which are chemical products currently sold on the market and commonly used in the field of chemical technology.
- the molar ratio of the aromatic compound to the amide compound is 1:1.2 to 2.4. If the molar ratio of aromatic compounds to amide compounds is greater than 1:1.2, the aromatic compounds cannot react completely, which is not conducive to the purification of the product and cannot achieve the desired yield; if the molar ratio of aromatic compounds to amide compounds is less than 1 :2.4, the yield will not be improved and the amide compound will be wasted; therefore, the molar ratio of aromatic compounds to amide compounds is 1:1.2 ⁇ 2.4 is reasonable;
- the molar ratio of the aromatic compound to the catalyst is 1:1.8-1.9; if the molar ratio of the aromatic compound to the catalyst is greater than 1:1.8, the reaction will be incomplete and the ideal yield will not be achieved; if If the molar ratio of aromatic compounds to catalyst is less than 1:1.9, the yield will decrease slightly. This may be because excess concentrated sulfuric acid will oxidize some of the products; therefore, the molar ratio of aromatic compounds to catalyst is 1:1.8 ⁇ 1.9 is appropriate;
- Aromatic compounds and amide compounds are substituted in an organic solvent in the presence of a catalyst at a temperature of 25 to 55°C. Reaction takes 48 to 96 hours.
- the substitution reaction time is within the stated range, if the substitution reaction temperature is lower than 25°C, the reaction time will be too long and the ideal yield may not even be achieved; if the substitution reaction temperature is high At 55°C, side reactions will occur, which is not conducive to obtaining the desired compound; therefore, the substitution reaction temperature is suitable for 25 to 55°C, preferably 35 to 40°C; similarly, the substitution reaction temperature is between 25 and 55°C.
- the substitution reaction time is 48 to 96 hours, preferably 60 to 84 hours;
- the washed solid matter is dried at a temperature of 50 to 60° C. for 360 to 420 minutes, so that the water content of the dried solid matter is less than 5% by weight.
- the water content of the dry solid matter is detected according to the GB 5009.3---85 standard method. It is not advisable for the water content of the dry solid to exceed the stated range, because it will cause inaccurate dosage of the compound in subsequent anti-tumor experiments, thereby affecting the measurement results of the anti-tumor activity of the compound.
- m product is the mass of the compound of formula (I), in grams
- M product is the molar mass of the compound of formula (I) in grams/mole
- nAromatic compounds are the amounts of aromatic compounds, in moles
- the amide compound was in excess, so the amount of substance in the product was equal to the amount of substance in the aromatic compound.
- the present invention also relates to the use of the compound of chemical formula (I) prepared by the compound and the preparation method as an anti-tumor drug.
- the compound of chemical formula (I) is used for preparing anti-tumor drugs for treating lung cancer, liver cancer, colon cancer, leukemia, cervical cancer or breast cancer.
- the present invention has the following beneficial effects:
- the preparation method adopted by the present invention has mild reaction conditions, low toxicity of reagents used, easy availability of raw materials, convenient post-processing and high yield. According to pharmacological experiments, the compound of the present invention has excellent anti-tumor activity, good stability, low toxicity and broad-spectrum properties. It can be used as an anti-tumor drug and provides a theoretical basis for subsequent research and development of patent drugs.
- Figure 1 shows the inhibitory effects of compound (I) at different concentrations on tumor cell lines
- Figure 2 is a trend chart of the average body weight of mice transplanted with tumor cell lines after administration of Compound (I);
- Figure 3 is a graph showing the growth trend of the average tumor volume in mice transplanted with tumor cell lines after administration of Compound (I);
- Figure 4 is a statistical diagram of the average tumor weight of tumors in mice transplanted with tumor cell lines after administration of Compound (I);
- Figure 5 is a visual diagram of tumors in mice transplanted with tumor cell lines after administration of Compound (I);
- Figure 6 is a statistical graph showing the average tumor weight inhibition rate of tumors in mice transplanted with tumor cell lines after administration of Compound (I).
- Example 2 The implementation of this example is the same as that of Example 1, except that in this example, 3,5-dimethylanisole is used to replace gallic acid, and N-hydroxymethyl chloroacetamide is used to replace N-hydroxymethylpropylene. Amide, a white solid product was obtained, and the yield was 58.29%;
- Example 2 The implementation of this example is the same as that of Example 1, except that in this example 2,3,5-trimethylphenol is used to replace gallic acid, and N-hydroxymethylacetamide is used to replace N-hydroxymethylacrylamide. , and the molar ratio of 2,3,5-trimethylphenol and N-hydroxymethylacetamide is 1:1.2, a white solid product is obtained, and the yield is 56.35%;
- Example 2 The implementation of this example is the same as that of Example 1, except that in this example, 4-chloro-3,5-dimethylphenol is used to replace gallic acid, and N-hydroxymethyl chloroacetamide is used to replace N-hydroxymethyl. acrylamide, and the molar ratio of 4-chloro-3,5-dimethylphenol and N-hydroxymethyl chloroacetamide is 1:1.2, a white solid product is obtained, and the yield is 79.26%;
- Example 2 The implementation of this example is the same as that of Example 1, except that in this example propyl gallate is used to replace gallic acid, and the molar ratio of propyl gallate to N-methylol acrylamide is 1:1.2, obtaining White solid product, the yield is 85.92%;
- Example 2 The implementation of this example is the same as that of Example 1, except that this example replaces gallic acid with methyl gallate, replaces N-hydroxymethylacrylamide with N-hydroxymethylacetamide, and methyl gallate
- the molar ratio to N-hydroxymethylacetamide is 1:1.2, and a white solid product is obtained, with a yield of 91.36%;
- Example 2 The implementation of this example is the same as that of Example 1, except that this example replaces gallic acid with propyl gallate, replaces N-methylol acrylamide with N-hydroxymethylacetamide, and propyl gallate
- the molar ratio to N-hydroxymethylacetamide is 1:1.2, and a white solid product is obtained, with a yield of 89.68%;
- Example 2 The implementation of this example is the same as that of Example 1, except that in this example, gallic acid is replaced by methyl gallate, N-hydroxymethylacrylamide is replaced by N-hydroxymethylchloroacetamide, and propyl gallate is used.
- the molar ratio of ester to N-hydroxymethyl chloroacetamide is 1:1.2, and a white solid product is obtained, with a yield of 58.52%;
- Example 2 The implementation of this example is the same as that of Example 1, except that this example replaces gallic acid with propyl gallate, replaces N-methylol acrylamide with N-hydroxymethyl chloroacetamide, and propyl gallate
- the molar ratio of ester to N-hydroxymethyl chloroacetamide is 1:1.2, and a white solid product is obtained, with a yield of 43.18%;
- Example 2 The implementation of this example is the same as that of Example 1, except that in this example, gallic acid is replaced by methyl gallate, N-hydroxymethylacrylamide is replaced by N-hydroxymethylbenzamide, and methyl gallate is used.
- the molar ratio of ester to N-hydroxymethylbenzamide is 1:1.2, and a white solid product is obtained, with a yield of 83.14%;
- Test Example 1 In vitro tumor cell proliferation inhibitory ability test
- SRB method Sulforhodamine B colorimetric method
- MTT method tetramethylazolium blue colorimetric method
- the compound prepared by the present invention existing doxorubicin is used as a positive control sample;
- PBS phosphate buffer from Solarbio life sciences; Fetal bovine serum (FBS) (FND500) from Ecosei Biotechnology (Taicang) Co., Ltd.; L-glutamine (G8230) and penicillin-streptomycin sulfate from Solarbio life sciences Anti-mixture (100 ⁇ ) (P1400); RPMI.1640 culture medium (1 ⁇ ) (GNM31800) and DMEM high-glucose culture medium (1 ⁇ ) (GNM12800) from Gino Biomedical Technology Co., Ltd.; Gibco from Invitrogen, USA 0.05% trypsin-EDTA (25300-054); Tris (T8060) and SDS (S8010) from Solarbio life sciences; SRB (S1402) and MTT from Sigma life sciences, Solarbio life sciences.
- FBS Fetal bovine serum
- FND500 Fetal bovine serum
- L-glutamine G8230
- penicillin-streptomycin sulfate from Solarbio life sciences Anti-mixture
- A549, HepG2, HCT116, HT-29, K562, hela and MCF-7 cell lines were placed in a medium containing 10% heat-inactivated FBS (fetal bovine serum), 2mM L-glutamine, 100U/mL penicillin and Culture in 1640, DMEM, 5A, 5A, 1640, DMEM and 1640 medium with 100 mg/mL streptomycin in a cell culture incubator at a temperature of 37°C and a concentration of 5% CO2 by volume. The medium is changed every two days.
- FBS fetal bovine serum
- A549, HepG2, HCT116, HT-29, hela and MCF-7 cells are confluent, use 0.05% trypsin-EDTA based on mass to volume ratio to digest at 37°C and passage, keeping the cells at Good test logarithmic growth phase.
- K562 suspension cells are not digested or passaged, and the cells are kept in a good logarithmic growth phase.
- A549, HepG2, HCT116, HT-29, K562, hela and MCF-7 cells in the logarithmic growth phase were seeded in 96-well plates at 5000, 5000, 5000, 5000, 6000, 5000 and 5000 cells/well.
- the group is doxorubicin hydrochloride (final concentration is 1 ⁇ M), the solvent control group is an equal volume of DMSO, and the blank control group is an equal volume of culture medium.
- Four duplicate wells are set for each concentration. After A549, HepG2, HCT116, HT-29, hela and MCF-7 cells were treated with drugs for 72 hours, 50% (m/v) cold trichloroacetic acid (TCA) was added to each well to fix the cells, and stained with SRB, and then 150mL was added /well of Tris solution, use a microplate reader to measure the OD value at a wavelength of 540 nm.
- TCA cold trichloroacetic acid
- Tumor cell growth inhibition rate according to the following formula:
- Inhibition rate [(OD 540 control hole - OD 540 administration hole )/OD 540 control hole ] ⁇ 100%
- OD 540 control well is the absorbance of the control group
- OD 540 of the dosing hole is the absorbance of the experimental group.
- the IC 50 value of the test drug (calculated by GraphPad Prism 5 software) is the average of three repeated experimental results.
- Table 2 IC 50 values of some tested compounds against A549, HepG2, HCT116, HT-29, K562, hela and MCF-7 cell lines
- Table 3 IC 50 values of test compounds against A549, HepG2, HCT116, HT-29, K562, hela and MCF-7 cell lines
- the inhibitory rates of doxorubicin (1 ⁇ M) on A549, HepG2, HCT116, HT-29, K562, hela and MCF-7 cell lines were tested in the same way as above. They were 88.81%, 78.10%, 60.92%, and 95.34% respectively. , 40.75%, 44.26% and 69.08%.
- compounds I-3, I-4, I-5, I-6, I-7 and I-17 showed broad spectrum and showed good inhibitory effects on 7 types of cells, and their IC 50 values were lower than 35.50 ⁇ M.
- compound I-5 has the best anti-cancer effect, with IC 50 values of 7 types of cells below 9.40 ⁇ M.
- Test Example 2 Anti-tumor efficacy test of the compound of the present invention
- Solvent control group 2% DMSO + physiological saline solution + sodium carbonate with a compound molar ratio of 1:2 (compound: sodium carbonate);
- 5-fluorouracil control group 5-fluorouracil injection (20mg/kg);
- Compound experimental group 1 mg of compound is fully dissolved in 40 ⁇ L of DMSO, then normal saline is added to adjust the volume to 0.5 mg/mL, 2 mL each time, and the mixture is ready for use on the same day.
- mice Each group was tested with 8 mice.
- the dosage volume of the solvent control group and the compound experimental group was 10 mL/kg (each dosage was calculated according to the body weight of the day), tail vein injection, 5 times a week, 15 times in total; finally The animals were euthanized after one administration.
- the 5-fluorouracil control group was administered twice a week for a total of 6 administrations.
- the body weight and tumor diameter were measured twice a week. After euthanasia, the tumors and spleens were removed and the weights of the tumors and spleens were measured. Calculate tumor volume, relative tumor volume RTV, relative tumor proliferation rate T/C%, tumor volume inhibition rate IR TV %, and tumor weight inhibition rate IR TW %. Data on animals that died accidentally are only listed and are not included in the statistics.
- the volume and weight of tumor cells were measured and intuitive pictures were obtained.
- the results are shown in Figures 3 to 5.
- the tumors in the solvent control group maintained stable growth.
- the average tumor volumes of A549, HCT116 and HT-29 were 831.80, 771.76 and 1188.29mm 3 respectively.
- the tumors in the 5-fu group grew relatively slowly after administration, and the tumor volume measured in the experiment was significantly lower than that in the solvent control group.
- A549, The average tumor volumes of HCT116 and HT-29 were 322.03, 599.83 and 658.02mm 3 respectively.
- the volume of the compound I-4 experimental group was lower than that of the control group, with a volume of 574.36mm 3 .
- the volume of the compound I-7 experimental group was slightly larger than the control group. Group, volume is 624.48mm 3 ;
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Abstract
本发明涉及一种具有化学式(I)的化合物,还涉及它的制备方法与它的用途。药理实验结果表明,本发明化合物抗肿瘤活性优良、稳定性好、毒性小且具有广谱的特性,可作为抗肿瘤药物应用,为后续的成药研发提供了理论基础。
Description
本发明属于医药领域。更具体地,本发明涉及一种具有抗肿瘤活性的化合物,还涉及所述化合物的制备方法,还涉及所述化合物的用途。
癌症,亦称恶性肿瘤,是目前严重威胁人类生命健康的主要疾病之一。据全球癌症观察站(GCO)网站2018年数据显示,全球该病发生率和死亡率分别为1080万例和956万例。
天然产物由于其来源广泛、结构多样,可以提供多种具有潜在抗癌作用的活性成分,已成为治疗癌症药物的宝库。目前,已有多种天然活性成分被证实具有抗肿瘤活性,但已上市的活性良好的天然抗癌药物较少。因此,开发活性优异的天然产物已经成为癌症治疗的迫切需求。
辣椒素(Capsaicin),其化合物名称:反式-8-甲基-N-香草基-6-壬烯酰胺,它具有下述化学式结构:
它是一种从茄科辣椒属植物中分离出来的具有多种生物活性的香草酰胺类生物碱。辣椒素的抗肿瘤活性已成为近年来研究的热点。大量体内外活性研究表明,辣椒素可以有效抑制多种肿瘤的生长,如乳腺癌、膀胱癌、肝癌、前列腺癌、子宫内膜癌、非小细胞肺癌及结肠癌等,是一种广谱的抗肿瘤活性化合物。
但是,它还不能满足抗癌实际需要,也存在一些技术问题。鉴于现有技术存在的缺陷,本发明人在总结现有技术基础之上,通过大量实验研究工作与总结分析,终于完成了本发明。
发明内容
本发明的一个目的是提供一种具有抗肿瘤活性的化合物。
本发明的另一个目的是提供所述具有抗肿瘤活性的化合物的制备方法。
本发明的再一个目的是提供所述具有抗肿瘤活性的化合物的用途。
本发明是通过下述技术方案实现的:
本发明涉及一种具有抗肿瘤活性的化合物。
所述具有抗肿瘤活性化合物的结构式如下:
式中:
R1选自羟基、羧基、甲基、甲氧基或氢;
R2选自乙烯基、甲基、一氯甲基或苯基;
R3选自甲氧羰基、乙氧羰基、丙氧羰基、羟基、甲基或氢;
R4选自氢、羟基、氯、甲基、溴、乙酰基、甲氧甲酰基或氯乙酰胺甲基;
R5选自羟基、甲基或氢;
R6选自羟基、丙烯酰胺甲基、乙酰胺甲基、氯乙酰胺甲基、甲基或氢。
根据本发明的一种实施方式,其中,
R2为乙烯基;R1为羧基;R6为丙烯酰胺甲基。
根据本发明的一种实施方式,其中,
R2为乙烯基;R1为羧基;R6为丙烯酰胺甲基;R3和R5为羟基。
根据本发明的一种实施方式,其中,
R2为乙烯基;R1为羧基;R6为丙烯酰胺甲基;R3和R5为羟基;R4为羟基或溴。
根据本发明的一种实施方式,其中,
R2为甲基;R1为甲基;R6为氢。
根据本发明的一种实施方式,其中,
R2为甲基;R1为甲基;R6为氢;R3和R5为羟基或甲基。
根据本发明的一种实施方式,其中,
R2为甲基;R1为甲基;R6为氢;R3和R5为羟基或甲基;R4为甲基。
根据本发明的一种实施方式,其中,
R2为一氯甲基;R3为甲氧羰基、羟基或甲基。
根据本发明的一种实施方式,其中,
R2为一氯甲基;R3为甲氧羰基、羟基或甲基;R6选自羟基、氯乙酰胺甲基或氢。
根据本发明的一种实施方式,其中,
R2为一氯甲基;R3为甲氧羰基、羟基或甲基;R6选自羟基、氯乙酰胺甲基或氢;
R5为羟基或甲基。
根据本发明的一种实施方式,其中,
R2为一氯甲基;R3为甲氧羰基、羟基或甲基;R6选自羟基、氯乙酰胺甲基或氢;R5为羟基或甲基;R4选自氢、氯或甲基。
根据本发明的一种实施方式,其中,
R2为一氯甲基;R3为甲氧羰基、羟基或甲基;R6选自羟基、氯乙酰胺甲基或氢;R5为羟基或甲基;R4选自氢、氯或甲基;R1选自羟基、甲基、甲氧基或氢。
根据本发明的一种实施方式,所述的化合物是一种选自如下化合物的化合物:
本发明还涉及所述化合物的制备方法。
该化合物制备方法的制备步骤如下:
按照芳香族化合物(如下式(II)所示)与酰胺化合物(如下式(III)所示)的摩尔比1:1.2~2.4以及芳香族化合物与催化剂的摩尔比1:1.8~1.9;让芳香族化合物与酰胺化合物在有机溶剂中在催化剂存在下在温度25~55℃下进行取代反应48~96h,接着过滤,得
到的固体物使用去离子水充分洗涤,烘干得到化学式(I)化合物。
根据本发明的另一种实施方式,所述的芳香族化合物是没食子酸、没食子酸甲酯、没食子酸丙酯、2,6-二羟基甲苯、3,5-二甲基苯甲醚、2,3,5-三甲基苯酚、4-氯-3,5-二甲基苯酚、2,6-二羟基苯乙酮、2,4-二羟基苯乙酮、4-溴-3,5-二羟基苯甲酸或3,4-二羟基苯甲酸甲酯。
根据本发明的另一种实施方式,所述的酰胺化合物是N-羟甲基丙烯酰胺、N-羟甲基乙酰胺、N-羟甲基氯乙酰胺或N-羟甲基苯甲酰胺。
根据本发明的另一种实施方式,所述的催化剂是浓硫酸或无水三氯化铝。
根据本发明的另一种实施方式,所述的溶剂是二氯甲烷、三氯甲烷、丙酮或乙醇。
根据本发明的另一种实施方式,洗涤的固体物在温度50~60℃下烘干360~420min,得到烘干固体物的水含量是以重量计5%以下。
本发明还涉及所述化学式(I)化合物与所述制备方法制备得到的化学式(I)化合物作为抗肿瘤药物的用途。
根据本发明的一种实施方式,化学式(I)化合物用于制备治疗肺癌、肝癌、结肠癌、白血病、宫颈癌或乳腺癌的抗肿瘤药物。
下面将更详细地描述本发明。
本发明涉及一种具有抗肿瘤活性的化合物。
所述具有抗肿瘤活性化合物的结构式如下:
式中:
R1选自羟基、羧基、甲基、甲氧基或氢;
R2选自乙烯基、甲基、一氯甲基或苯基;
R3选自甲氧羰基、乙氧羰基、丙氧羰基、羟基、甲基或氢;
R4选自氢、羟基、氯、甲基、溴、乙酰基、甲氧甲酰基或氯乙酰胺甲基;
R5选自羟基、甲基或氢;
R6选自羟基、丙烯酰胺甲基、乙酰胺甲基、氯乙酰胺甲基、甲基或氢。
根据本发明,所述的化合物是一种选自如下化合物的化合物:
本发明还涉及所述化合物的制备方法。
该化合物制备方法的制备步骤如下:
按照芳香族化合物(如下式(II)所示)与酰胺化合物(如下式(III)所示)的摩尔比1:1.2~2.4以及芳香族化合物与催化剂的摩尔比1:1.8~1.9;让芳香族化合物与酰胺化合物在有机溶剂中在催化剂存在下在温度25~55℃下进行取代反应48~96h,接着过滤,得到的固体物使用去离子水充分洗涤,烘干得到化学式(I)化合物。
根据本发明,所述的芳香族化合物是没食子酸、没食子酸甲酯、没食子酸丙酯、2,6-二
羟基甲苯、3,5-二甲基苯甲醚、2,3,5-三甲基苯酚、4-氯-3,5-二甲基苯酚、2,6-二羟基苯乙酮、2,4-二羟基苯乙酮、4-溴-3,5-二羟基苯甲酸或3,4-二羟基苯甲酸甲酯。
本发明使用的芳香族化合物是目前市场上销售的产品,例如由国药集团化学试剂有限公司以商品名没食子酸销售的没食子酸、由国药集团化学试剂公司以商品名没食子酸甲酯销售的没食子酸甲酯、由国药集团化学试剂有限公司以商品名2,6-二羟基甲苯销售的2,6-二羟基甲苯、由国药集团化学试剂有限公司以商品名3,5-二甲基苯甲醚销售的3,5-二甲基苯甲醚、由国药集团化学试剂有限公司以商品名4-氯-3,5-二甲基苯酚销售的4-氯-3,5-二甲基苯酚、由国药集团化学试剂有限公司以商品名2,6-二羟基苯乙酮销售的2,6-二羟基苯乙酮、由国药集团化学试剂有限公司以商品名2,4-二羟基苯乙酮销售的2,4-二羟基苯乙酮、由国药集团化学试剂有限公司以商品名4-溴-3,5-二羟基苯甲酸销售的4-溴-3,5-二羟基苯甲酸、由国药集团化学试剂有限公司以商品名3,4-二羟基苯甲酸甲酯销售的3,4-二羟基苯甲酸甲酯。
根据本发明,所述的酰胺化合物是N-羟甲基丙烯酰胺(简称N-1)、N-羟甲基乙酰胺(简称N-2)、N-羟甲基氯乙酰胺(简称N-3)或N-羟甲基苯甲酰胺(简称N-4)。本发明使用的酰胺化合物都是目前市场上销售的产品,例如由国药集团化学试剂有限公司以商品名N-羟甲基丙烯酰胺销售的N-羟甲基丙烯酰胺、由上海亚兴生物医药科技有限公司以商品名N-羟甲基乙酰胺销售的N-羟甲基乙酰胺、由上海亚兴生物医药科技有限公司以商品名氯乙酰胺-N-甲醇销售的N-羟甲基氯乙酰胺、由国药集团化学试剂有限公司以商品名N-羟甲基苯甲酰胺销售的N-羟甲基苯甲酰胺。
根据本发明,所述的催化剂是浓硫酸或无水三氯化铝,它们都是目前市场上销售的、在化工技术领域里通常使用的化学产品。
根据本发明,所述的溶剂是二氯甲烷、三氯甲烷、丙酮或乙醇,它们都是目前市场上销售的、在化工技术领域里通常使用的化学产品。
在本发明中,芳香族化合物与酰胺化合物的摩尔比是1:1.2~2.4。如果芳香族化合物与酰胺化合物的摩尔比大于1:1.2,则芳香族化合物无法完全反应,既不利于产物的提纯又达不到理想的产率;如果芳香族化合物与酰胺化合物的摩尔比小于1:2.4,则在产率不会提升的同时造成酰胺化合物的浪费;因此,芳香族化合物与酰胺化合物的摩尔比为1:1.2~2.4是合理的;
在本发明中,芳香族化合物与催化剂的摩尔比是1:1.8~1.9;如果芳香族化合物与催化剂的摩尔比大于1:1.8,则会造成反应不完全进而达不到理想的产率;如果芳香族化合物与催化剂的摩尔比小于1:1.9,则会造成产率稍微下降的现象,这可能是过量的浓硫酸会氧化部分产物;因此,芳香族化合物与催化剂的摩尔比为1:1.8~1.9是恰当的;
芳香族化合物与酰胺化合物在有机溶剂中在催化剂存在下在温度25~55℃下进行取代
反应48~96h。在本发明中,该取代反应时间在所述的范围内时,如果该取代反应温度低于25℃,则会造成反应时间过长,甚至达不到理想的产率;如果该取代反应温度高于55℃,则会造成副反应进行,进而不利于获得需要的化合物;因此,该取代反应温度为25~55℃是合适的,优选地是35~40℃;同样地,该取代反应温度在所述的范围内时,如果该取代反应时间短于48h,则会造成该取代反应不完全,进而达不到理想的产率;如果该取代反应时间长于96h,则在产率不会提升的同时,还会造成能源和时间的浪费;因此,该取代反应时间为48~96h是适当的,优选地是60~84h;
根据本发明,洗涤的固体物在温度50~60℃下烘干360~420min,得到烘干固体物的水含量是以重量计5%以下。在本发明中,烘干固体物的水含量是根据GB 5009.3---85标准方法检测的。烘干固体物的水含量超过所述的范围是不可取的,因为会造成后续抗肿瘤实验中化合物用量不准确,进而影响化合物抗肿瘤活性的测定结果。
根据下述公式计算该制备方法的收率:
收率(%)=m产物/(M产物×n芳香族化合物)×100%
式中:
m产物是式(I)化合物的质量,以克计;
M产物是式(I)化合物的摩尔质量,以克/摩尔计;
n芳香族化合物是芳香族化合物的物质的量,以摩尔计;
合成实验中,酰胺化合物过量,所以产物的物质的量等于芳香族化合物的物质的量。
本发明还涉及所述化合物与所述制备方法制备得到的化学式(I)化合物作为抗肿瘤药物的用途。
根据本发明,化学式(I)化合物用于制备治疗肺癌、肝癌、结肠癌、白血病、宫颈癌或乳腺癌的抗肿瘤药物。
与现有的技术相比,本发明具有如下有益效果:
本发明采用的制备方法反应条件温和、所用试剂低毒、原料易得、后处理方便、产率高。根据药理实验表明,本发明化合物抗肿瘤活性优良、稳定性好、毒性小且具有广谱的特性,可作为抗肿瘤药物应用,为后续的成药研发提供了理论基础。
图1是不同浓度化合物(I)对肿瘤细胞株的抑制作用;
图2是移植肿瘤细胞株小鼠在施用化合物(I)后的平均体重趋势图;
图3是移植肿瘤细胞株小鼠在施用化合物(I)后的肿瘤平均体积增长趋势图;
图4是移植肿瘤细胞株小鼠在施用化合物(I)后的肿瘤平均瘤重统计图;
图5是移植肿瘤细胞株小鼠在施用化合物(I)后肿瘤的直观图;
图6是移植肿瘤细胞株小鼠在施用化合物(I)后肿瘤的平均瘤重抑制率统计图。
以下结合附图及实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
实施例1:制备N-(2,3,4-三羟基-5-丙烯酰胺甲基-6-羧基苄基)丙烯酰胺
该实施例的实施方式如下:
按照芳香族化合物与酰胺化合物的摩尔比1:2.4以及芳香族化合物与催化剂的摩尔比1:1.9;让没食子酸芳香族化合物与N-羟甲基丙烯酰胺化合物在无水乙醇有机溶剂中在浓硫酸催化剂存在下在温度35~40℃下进行取代反应72h,反应液接着过滤,得到的固体物使用去离子水充分洗涤,在温度55℃下烘干400min烘干,根据本申请说明书描述的方法检测,烘干产物的水含量为以重量计4.5%,它为白色固体粉末,按照本申请说明书描述的方法计算收率为84.26%。
这种烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:819.05,985.89,1118.34,1588.12,1618.13,1656.18,1711.79,3142.38,3313.61,3441.67cm-1。
1H NMR(DMSO,600MHz)δ:4.59(s,2H,CH2),4.67(s,1H,CH2),4.68(s,12H,CH2),5.67(m,1H,=CH),5.95(m,1H,=CH),6.18(m,1H,=CH2),6.38(d,J=6.00Hz,1H,=CH2),6.42(m,1H,=CH2),7.66(m,1H,=CH2),9.07(t,J=6.00Hz,1H,NH),9.47(s,1H,OH),9.52(s,1H,OH),10.43(s,1H,OH)。
13C NMR(DMSO,150MHz)δ:32.89,45.52,116.01,118.13,122.56,127.32,130.05,130.68,140.19,141.07,146.17,165.16,167.48,168.47。
HR-ESI-MS:m/z 337.1036([M+H]+,C15H17N2O7的计算值为337.3117),359.0852([M+Na]+,C15H16N2O7Na的计算值为359.3038)。
由此可见,该产物是N-(2,3,4-三羟基-5-丙烯酰胺甲基-6-羧基苄基)丙烯酰胺(I-1),它的化学结构式如下:
实施例2:制备N-(2,3,4-三羟基-5-乙酰胺甲基-6-羧基苄基)乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用N-羟甲基乙酰胺替换N-羟甲基丙烯酰胺,得到白色固体产物,其收率是65.37%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:815.39,934.66,1122.73,1570.56,1600.56,1677.40,1707.40,3112.38,3334.83,3441.67cm-1。
1H NMR(DMSO,600MHz)δ:1.89(s,3H,CH3),4.56(s,1H,CH2),4.57(s,1H,CH2),4.49(s,2H,CH2),8.96(t,J=6.00Hz,1H,NH),9.38(s,1H,OH),9.43(s,1H,OH),10.60(s,1H,OH),12.39(s,1H,COOH)。
13C NMR(DMSO,150MHz)δ:22.08,24.93,32.88,45.20,116.15,118.13,122.15,140.11,140.81,146.12,168.44,170.27,173.29。
HR-ESI-MS:m/z 314.0673([M+H]+,C13H17N2O7的计算值为313.2897),335.0809([M+Na]+,C13H16N2O7Na的计算值为335.2818)。
由此可见,该产物是N-(2,3,4-三羟基-5-乙酰胺甲基-6-羧基苄基)乙酰胺(I-2),它的化学结构式如下:
实施例3:制备N-(2,4-二羟基-3-甲基-5-氯乙酰胺甲基苄基)氯乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用2,6-二羟基甲苯替换没食子酸,用N-羟甲基氯乙酰胺替换N-羟甲基丙烯酰胺,得到米白色固体产物,其收率是66.25%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:778.50,1123.23,1262.88,1449.61,1543.78,1625.17,2950.64,3154.92,3324.10cm-1。
1H NMR(DMSO,600MHz)δ:2.02(s,3H,CH3),4.13(s,4H,CH2),4.15(s,2H,CH2),4.15(s,2H,CH2),6.80(s,1H,PhH),8.76(t,J=6.00Hz,2H,NH),8.89
(s,2H,OH)。
13C NMR(DMSO,150MHz)δ:10.01,39.41,42.84,113.11,116.54,128.58,153.85,167.59。
HR-ESI-MS:m/z 358.0407([M+Na]+,C13H16N2O4Cl2Na的计算值为358.1818)。
由此可见,该产物是N-(2,4-二羟基-3-甲基-5-氯乙酰胺甲基苄基)氯乙酰胺(I-3),它的化学结构式如下:
实施例4:制备N-(2-甲醚-3-氯乙酰胺甲基-4,6-二甲基苄基)氯乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用3,5-二甲基苯甲醚替换没食子酸,用N-羟甲基氯乙酰胺替换N-羟甲基丙烯酰胺,得到白色固体产物,其收率是58.29%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:591.13,1052.83,1140.20,1389.50,1462.56,1543.15,1638.05,2831.83,2956.10,3285.24cm-1。
1H NMR(DMSO,600MHz)δ:2.24(t,J=6.00Hz,3H,CH3),2.27(s,3H,CH3),3.70(s,2H,CH2),3.77(d,J=12.00Hz,2H,CH2),4.02(t,J=6.00Hz,3H,CH3),4.24(d,J=6.00Hz,1H,CH2),4.26(d,J=6.00Hz,1H,CH2),4.28(d,J=6.00Hz,1H,CH2),4.32(d,J=6.00Hz,1H,CH2),6.625(s,1H,PhH),8.06(t,J=6.00Hz,1H,NH),8.18(d,J=6.00Hz,1H,NH)。
13C NMR(DMSO,150.92MHz)δ:15.56,20.12,34.86,37.59,42.99,43.01,55.37,109.87,111.06,113.75,123.51,126.85,139.16,158.66,166.02。
HR-ESI-MS:m/z 370.0778([M+Na]+,C15H20N2O3Cl2Na的计算值为370.2352)。
由此可见,该产物是N-(2-甲醚-3-氯乙酰胺甲基-4,6-二甲基苄基)氯乙酰胺(I-4),它的化学结构式如下:
实施例5:制备N-(2,3,6-三甲基-4-羟基-5-氯乙酰胺甲基苄基)氯乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用2,3,5-三甲基苯酚替换没食子酸,用N-羟甲基氯乙酰胺替换N-羟甲基丙烯酰胺,得到白色固体产物,其收率是43.29%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:780.93,1101.03,1232.09,1405.32,1455.78,1543.90,1641.06,2919.20,3054.77,3269.42cm-1。
1H NMR(DMSO,600MHz)δ:2.11(s,3H,CH3),2.16(s,3H,CH3),2.27(s,3H,CH3),4.04(s,2H,CH2),4.17(s,2H,CH2),4.26(s,1H,CH2),4.27(s,1H,CH2),4.28(s,1H,CH2),4.29(s,1H,CH2),8.24(t,1H,NH),9.32(s,1H,OH),9.37(t,1H,NH)。
13C NMR(DMSO,150MHz)δ:13.23,15.92,16.42,36.74,38.72,45.52,42.99,121.84,122.48,126.20,134.93,137.09,153.43,165.97,168.36。
HR-ESI-MS:m/z 370.0776([M+Na]+,C15H20N2O3Cl2Na的计算值为370.2352)。
由此可见,该产物是N-(2,3,6-三甲基-4-羟基-5-氯乙酰胺甲基苄基)氯乙酰胺(I-5),它的化学结构式如下:
实施例6:制备N-(2,3,6-三甲基-4-羟基苄基)乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用2,3,5-三甲基苯酚替换没食子酸,用N-羟甲基乙酰胺替换N-羟甲基丙烯酰胺,并且2,3,5-三甲基苯酚与N-羟甲基乙酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是56.35%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:852.49,1088.98,1308.16,1556.70,1464.06,1417.37,1624.49,2855.93,2927.48,3303.31cm-1。
1H NMR(DMSO,600MHz)δ:1.78(s,3H,CH3),2.02(s,3H,CH3),2.12(s,3H,CH3),2.17(s,3H,CH3),4.14(s,1H,CH2),4.15(s,1H,CH2),6.53(s,1H,
PhH),7.70(s,1H,NH),9.12(s,1H,OH)。
13C NMR(DMSO,150MHz)δ:12.36,16.05,20.10,22.80,37.83,114.51,120.35,125.62,134.91,137.33,154.50,169.17。
HR-ESI-MS:m/z 208.1333([M+H]+,C12H18NO2的计算值为208.2798),230.1153([M+Na]+,C12H17NO2Na的计算值为230.2720)。
由此可见,该产物是N-(2,3,6-三甲基-4-羟基苄基)乙酰胺(I-6),它的化学结构式如下:
实施例7:制备N-(2,4-二甲基-3-氯-6-羟基苄基)氯乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用4-氯-3,5-二甲基苯酚替换没食子酸,用N-羟甲基氯乙酰胺替换N-羟甲基丙烯酰胺,并且4-氯-3,5-二甲基苯酚与N-羟甲基氯乙酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是79.26%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:844.20,1067.89,1168.82,1543.90,1455.78,1400.80,1637.29,2936.52,3277.71,3358.30cm-1。
1H NMR(DMSO,600MHz)δ:2.24(s,3H,CH3),2.29(s,3H,CH3),4.04(s,1H,CH2),4.31(d,J=6.00Hz,1H,CH2),6.70(s,1H,PhH),8.25(s,1H,NH),9.71(s,1H,OH)。
13C NMR(DMSO,150.92MHz)δ:17.03,21.11,35.77,42.93,115.77,122.40,124.56,135.98,136.33,154.67,166.30。
HR-ESI-MS:m/z 262.0403([M+H]+,C11H14NO2Cl2的计算值为263.1375),284.0221([M+Na]+,C11H13NO2Cl2Na的计算值为285.1296)。
由此可见,该产物是N-(2,4-二甲基-3-氯-6-羟基苄基)氯乙酰胺(I-7),它的化学结构式如下:
实施例8:制备N-(2,3,4-三羟基-6-甲酸甲酯苄基)丙烯酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用没食子酸甲酯替换没食子酸,并且没食子酸甲酯与N-羟甲基丙烯酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是93.27%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:633.91,1100.04,1217.85,1442.50,1538.37,1593.98,1689.84,2964.56,3183.36,3402.89cm-1。
1H NMR(DMSO,600MHz)δ:3.78(s,3H,CH3),4.51(d,2H,CH2),5.64(m,1H,CH=),6.15(m,1H,=CH2),6.43(m,1H,=CH2),6.98(s,1H,PhH),8.67(t,J=6.00Hz,1H,NH),9.04(s,1H,OH),9.27(s,1H,OH),10.18(s,1H,OH)。
13C NMR(DMSO,150.92MHz)δ:36.03,52.21,110.55,118.92,119.70,126.90,131.05,139.10,144.96,145.71,166.96,167.41。
HR-ESI-MS:m/z 268.0813([M+H]+,C12H14NO6的计算值为268.2427),290.0633([M+Na]+,C12H13NO6Na的计算值为290.2247)。
由此可见,该产物是N-(2,3,4-三羟基-6-甲酸甲酯苄基)丙烯酰胺(I-8),它的化学结构式如下:
实施例9:制备N-(2,3,4-三羟基-6-甲酸丙酯苄基)丙烯酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用没食子酸丙酯替换没食子酸,并且没食子酸丙酯与N-羟甲基丙烯酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是85.92%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:637.57,1089.80,1230.29,1442.50,1541.29,1600.56,1689.83,2971.15,3370.68cm-1。
1H NMR(DMSO,600MHz)δ:0.97(t,J=6.00Hz,3H,CH3),1.70(d,2H,CH2),
4.16(t,J=6.00Hz,2H,CH2),4.53(d,J=6.00Hz,2H,CH2),5.64(m,1H,CH=),6.15(m,1H,=CH2),6.44(m,1H,=CH2),7.02(s,1H,PhH),8.64(t,J=6.00Hz,1H,NH),9.05(s,1H,OH),9.29(s,1H,OH),10.10(s,1H,OH)。
13C NMR(DMSO,150.92MHz)δ:10.96,22.09,36.01,66.13,110.43,118.88,119.96,126.74,131.13,138.99,144.92,145.73,166.85,166.95。
HR-ESI-MS:m/z 296.1130([M+H]+,C14H18NO6的计算值为296.2976),318.0950([M+Na]+,C14H17NO6Na的计算值为318.2796)。
由此可见,该产物是N-(2,3,4-三羟基-6-甲酸丙酯苄基)丙烯酰胺(I-9),它的化学结构式如下:
实施例10:制备N-(2,3,4-三羟基-6-甲酸甲酯苄基)乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用没食子酸甲酯替换没食子酸,用N-羟甲基乙酰胺替换N-羟甲基丙烯酰胺,并且没食子酸甲酯与N-羟甲基乙酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是91.36%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:686.9,1043.79,1214.76,1540.89,1595.12,1626.00,1688.51,2953.84,3233.27,3380.89cm-1。
1H NMR(DMSO,600MHz)δ:1.90(s,3H,CH3),3.79(s,3H,CH3),4.42(d,2H,CH2),6.97(s,1H,PhH),8.54(t,J=6.00Hz,1H,NH),9.00(s,1H,OH),9.20(s,1H,OH),10.37(s,1H,OH)。
13C NMR(DMSO,150.92MHz)δ:22.20,36.08,52.19,110.60,119.27,119.53,139.22,144.88,145.66,167.43,172.73。
HR-ESI-MS:m/z 256.0816([M+H]+,C11H14NO6的计算值为256.2319),278.0634([M+Na]+,C11H13NO6Na的计算值为278.2139)。
由此可见,该产物是N-(2,3,4-三羟基-6-甲酸甲酯苄基)乙酰胺(I-10),它的化学结构式如下:
实施例11:制备N-(2,3,4-三羟基-6-甲酸丙酯苄基)乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用没食子酸丙酯替换没食子酸,用N-羟甲基乙酰胺替换N-羟甲基丙烯酰胺,并且没食子酸丙酯与N-羟甲基乙酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是89.68%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:722.94,1110.82,1213.26,1550.68,1579.30,1623.74,1689.26,2970.41,3281.21,3402.73cm-1。
1H NMR(DMSO,600MHz)δ:0.97(t,J=6.00Hz,3H,CH3),1.70(m,2H,CH2),1.88(s,3H,CH3),4.15(t,J=6.00Hz,2H,CH2),4.40(d,J=6.00Hz,2H,CH2),6.99(s,1H,PhH),8.49(t,J=6.00Hz,1H,NH),8.99(s,1H,OH),9.20(s,1H,OH),10.28(s,1H,OH)。
13C NMR(DMSO,150.92MHz)δ:10.96,22.11,36.02,66.09,100.00,110.47,119.30,119.76,139.12,144.84,145.68,166.95,172.58。
HR-ESI-MS:m/z 284.1130([M+H]+,C13H18NO6的计算值为284.2868),306.0947([M+Na]+,C13H17NO6Na的计算值为306.2688)。
由此可见,该产物是N-(2,3,4-三羟基-6-甲酸丙酯苄基)乙酰胺(I-11),它的化学结构式如下:
实施例12:制备N-(2,3,4-三羟基-6-甲酸甲酯苄基)氯乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用没食子酸甲酯替换没食子酸,用N-羟甲基氯乙酰胺替换N-羟甲基丙烯酰胺,并且没食子酸丙酯与N-羟甲基氯乙酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是58.52%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果
如下:
IR(KBr)ν:767.38,1052.83,1213.26,1543.15,1594.36,1638.05,1689.36,2948.57,3402.73cm-1。
1H NMR(DMSO,600MHz)δ:3.77(s,3H,CH3),4.12(s,2H,CH2),4.50(d,J=6.00Hz,2H,CH2),6.97(s,1H,PhH),8.36(t,J=6.00Hz,1H,NH),9.18(s,1H,OH),9.32(s,1H,OH),9.43(s,1H,OH)。
13C NMR(DMSO,150.92MHz)δ:35.94,42.75,52.23,110.23,118.15,120.12,138.53,144.96,145.64,167.27,167.49。
HR-ESI-MS:m/z 290.0427([M+H]+,C11H13NO6Cl的计算值为290.6767),312.0244([M+Na]+,C11H12NO6ClNa的计算值为312.6587)。
由此可见,该产物是N-(2,3,4-三羟基-6-甲酸甲酯苄基)氯乙酰胺(I-12),它的化学结构式如下:
实施例13:制备N-(2,3,4-三羟基-6-甲酸丙酯苄基)氯乙酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用没食子酸丙酯替换没食子酸,用N-羟甲基氯乙酰胺替换N-羟甲基丙烯酰胺,并且没食子酸丙酯与N-羟甲基氯乙酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是43.18%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:657.41,1045.30,1242.83,1543.15,1586.83,1638.05,1668.48,2963.63,3182.81,3410.26cm-1。
1H NMR(DMSO,600MHz)δ:0.96(t,J=6.00Hz,3H,CH3),1.70(m,2H,CH2),4.11(s,2H,CH2),4.14(t,J=6.00Hz,2H,CH2),4.49(d,J=6.00Hz,2H,CH2),7.00(s,1H,PhH),8.32(t,J=6.00Hz,1H,NH),9.18(s,1H,OH),9.27(s,1H,OH),9.44(s,1H,OH)。
13C NMR(DMSO,150.92MHz)δ:10.96,22.07,36.98,42.76,66.23,110.14,118.06,120.41,138.42,144.93,146.86,167.09,167.11。
HR-ESI-MS:m/z 318.0738([M+H]+,C13H17NO6Cl的计算值为318.7316),340.0555
([M+Na]+,C13H16NO6ClNa的计算值为340.7136)。
由此可见,该产物是N-(2,3,4-三羟基-6-甲酸丙酯苄基)氯乙酰胺(I-13),它的化学结构式如下:
实施例14:制备N-(2,3,4-三羟基-6-甲酸甲酯苄基)苯甲酰胺
该实施例的实施方式与实施例1的实施方式相同,只是该实施例用没食子酸甲酯替换没食子酸,用N-羟甲基苯甲酰胺替换N-羟甲基丙烯酰胺,并且没食子酸甲酯与N-羟甲基苯甲酰胺的摩尔比是1:1.2,得到白色固体产物,其收率是83.14%;
得到的烘干产物进行了常规IR、1H NMR、13C NMR与HR-ESI-MS分析,其分析结果如下:
IR(KBr)ν:3443.00,3227.54,2957.02,1687.42,1591.66,1531.81,1490.31,1252.51,1096.10,725.03cm-1。
1H NMR(DMSO,600MHz)δ:3.77(d,J=18.00Hz,3H,CH3),4.68(s,1H,CH2),4.69(s,1H,CH2),6.96(s,1H,PhH),7.45(t,J=6.00Hz,2H,PhH),7.53(t,J=6.00Hz,1H,PhH),7.83(s,1H,PhH),7.85(s,1H,PhH),8.63(t,J=6.00Hz,1H,NH),9.08(s,1H,OH),9.33(s,1H,OH),9.78(s,1H,OH)。
13C NMR(DMSO,150.92MHz)δ:52.25,36.30,108.96,110.43,118.58,120.43,127.94,128.76,131.98,134.00,138.64,144.87,145.77,146.05,153.50,167.73,168.11。
HR-ESI-MS:m/z 318.0974([M+H]+,C16H16NO6的计算值为318.0978),340.0789([M+Na]+,C16H15NO6Na的计算值为340.2921)。
由此可见,该产物是N-(2,3,4-三羟基-6-甲酸甲酯苄基)苯甲酰胺(I-14),它的化学结构式如下:
试验实施例1:体外肿瘤细胞增殖抑制能力测试
该试验实施例的实施方式如下:
I、试验方法:
磺酰罗丹明B比色法(SRB法)与四甲基氮唑蓝比色法(MTT法)
II、试验样品:
本发明制备的化合物;现有阿霉素作为阳性对照样品;
III、试验设备:
苏净集团安泰公司的超净工作台(SW-CJ-2F);美国Millipore公司的Milli-Q超纯水系统(AdvantageA 5);日本Olympus公司的显微镜(CX41);Thermo公司的二氧化碳细胞培养箱(Heracell150i);上海一恒科技有限公司的电热恒温水浴锅(HWS-24);美国Molecular Devices的多功能酶标仪(I3);美国Millipore公司的细胞自动计数仪(MuseTM cell analyzer)。
IV、试验材料与试剂:
依科赛生物科技(太仓)有限公司的96孔细胞培养板与25cm2细胞培养瓶。
Solarbio life sciences的PBS磷酸盐缓冲液;依科赛生物科技(太仓)有限公司的胎牛血清(FBS)(FND500);Solarbio life sciences的左旋谷氨酰胺(G8230)与青霉素-硫酸链霉素双抗混合液(100×)(P1400);吉诺生物医药技术有限公司的RPMI.1640培养液(1×)(GNM31800)与DMEM高糖培养液(1×)(GNM12800);美国Invitrogen公司的Gibco 0.05%胰酶-EDTA(25300-054);Solarbio life sciences的Tris(T8060)与SDS(S8010);Sigma life science的SRB(S1402)与MTT,Solarbio life sciences。
V、试验细胞株:
人肺癌细胞A549、人肝癌细胞HepG2、人结肠癌细胞HCT116、人结肠癌细胞HT-29、人白血病细胞K562、人宫颈癌细胞hela、人乳腺癌细胞MCF-7,均由中国科学院上海细胞库提供。
VI、试验方法:
将A549、HepG2、HCT116、HT-29、K562、hela及MCF-7细胞株分别置于含有以重量计10%热灭活FBS(胎牛血清)、2mM左旋谷氨酰胺、100U/mL青霉素和100mg/mL链霉素的1640、DMEM、5A、5A、1640、DMEM及1640培养基中,在温度37℃与浓度为以体积计5%CO2的细胞培养箱中进行培养。每两天换液一次,A549、HepG2、HCT116、HT-29、hela及MCF-7细胞汇合后,使用以质量体积比计0.05%胰酶-EDTA在温度37℃下消化,传代,保持细胞在良好的受试对数生长期。K562悬浮细胞不进行消化,传代,保持细胞在良好的受试对数生长期。处于对数生长期的A549、HepG2、HCT116、HT-29、K562、hela及MCF-7细胞,以5000、5000、5000、5000、6000、5000、5000个/孔接种于96孔板中,在温度37℃下培养24h,接着加入不同浓度的试验样品,阳性对照
组为盐酸阿霉素(终浓度为1μM),溶剂对照组为等体积的DMSO,空白对照组为等体积的培养液,每个浓度设4个复孔。A549、HepG2、HCT116、HT-29、hela及MCF-7细胞药物作用72h后,每孔加入50%(m/v)的冷三氯乙酸(TCA)固定细胞,并以SRB染色,再加入150mL/孔的Tris溶液,使用酶标仪测定在波长540nm处的OD值。K562细胞药物作用肿瘤细胞72h后加入20mL 5mg/mL的MTT,在温度37℃下温育4h,接着加入100mL三联液(10%SDS、5%异丁醇、12mM盐酸)继续温育12~20h,使用酶标仪测定在波长570nm处的OD值。
按照下述公式肿瘤细胞生长抑制率:
抑制率=[(OD540对照孔-OD540给药孔)/OD540对照孔]×100%
式中:
OD540对照孔是对照组的吸光度;
OD540给药孔是实验组的吸光度。
试验药物的IC50值(GraphPad Prism 5软件计算)是3次重复实验结果的均值。
VII、试验结果
试验结果列于表1-表3与附图1中。
表1:试验化合物(10μM)对A549、HepG2及HCT116细胞株的抑制率
表2:部分受试化合物对A549、HepG2、HCT116、HT-29、K562、hela及MCF-7细胞株的IC50值
表3:试验化合物对A549、HepG2、HCT116、HT-29、K562、hela及MCF-7细胞株的IC50值
按照上述同样方式检测了阿霉素(1μM)对A549、HepG2、HCT116、HT-29、K562、hela及MCF-7细胞株的抑制率,它们分别是88.81%、78.10%、60.92%、95.34%、40.75%、44.26%及69.08%。
表1-表3列出的数据以及阿霉素数据表明,尽管本发明化合物的抗肿瘤效果差于阿霉素,但大多数化合物仍然对肿瘤细胞表现出良好的抑制活性,且与化合物的浓度密切相关,随浓度增加,其抑制效果也逐渐增强,如图1所示。在12.5μM之后,本发明化合物的抑制率基本保持不变,且均未达到100%,表明化合物是抑制肿瘤细胞而不是致死细胞,本发明化合物表现出健康的特性。另外,化合物I-3、I-4、I-5、I-6、I-7与I-17表现出广谱性,对7种细胞均表现出良好的抑制效果,其IC50值低于35.50μM。其中,化合物I-5的抗癌效果最佳,对7种细胞的IC50值均低于9.40μM。
试验实施例2:本发明化合物抗肿瘤药效试验
该试验实施例的实施方式如下:
建立A549、HCT116及HT-29细胞BALB/c nude裸小鼠皮下移植瘤模型。
溶剂对照组:2%DMSO+生理盐水溶液+化合物摩尔比1:2的碳酸钠(化合物:碳酸钠);
5-氟尿嘧啶对照组:5-氟尿嘧啶注射液(20mg/kg);
化合物实验组:1mg化合物加40μL DMSO充分溶解后加生理盐水定容至0.5mg/mL,每次2mL,当天使用现用现配。
试验方法:
试验每组8只小鼠。
溶剂对照组和化合物实验组给药容量均为10mL/kg(每次给药均按照当天称量体重计算给药量),尾静脉注射,每周给药5次,总共给药15次;最后一次给药后将动物实施安乐死。
5-氟尿嘧啶对照组每周给药2次,总共给药6次。
在给药期间每周进行2次称量体重和瘤径测量,安乐死后剥取肿瘤和脾脏,称量肿瘤和脾脏重量。计算瘤体积、相对肿瘤体积RTV、相对肿瘤增殖率T/C%、瘤体积抑制率IRTV%、瘤重抑制率IRTW%。意外死亡动物数据仅列出,不参与统计。
在整个实验过程中,动物精神状况良好,各组动物体重有一定增长,但随着肿瘤不断生长,实验后期各组动物体重呈轻微下降趋势。除个别化合物在某天的体重显著低于溶剂对照组外,其他治疗组在实验过程中体重均未显著低于溶剂对照组。5-fu对照组动物体重显著下降的原因可能是由化疗药物的副作用引起的,其结果参见附图2。
在确定肿瘤细胞在小鼠体内正常生长的前提下,测定了肿瘤细胞的体积、重量并获得其直观图片,其结果参见附图3-附图5。由附图3可知,溶剂对照组肿瘤保持稳定增长,实验结束时,A549、HCT116及HT-29平均瘤体积分别为831.80、771.76及1188.29mm3。5-fu组给药后肿瘤生长相对缓慢,实验测得的瘤体积显著低于溶剂对照组,在实验结束时,A549、
HCT116及HT-29平均瘤体积分别为322.03、599.83及658.02mm3。
在A549细胞BALB/c nude裸小鼠皮下移植瘤实验中,所有实验组的体积均高于对照组,其中,化合物I-1、I-6及I-7实验组的体积较小一些,它们分别是539.48、492.12及559.37mm3;
在HCT116细胞BALB/c nude裸小鼠皮下移植瘤实验中,化合物I-4实验组的体积低于对照组,它的体积是574.36mm3,另外,化合物I-7实验组的体积稍大于对照组,体积为624.48mm3;
在HT-29细胞BALB/c nude裸小鼠皮下移植瘤实验中,化合物I-6实验组的体积低于对照组,它的体积为559.37mm3。在其后获得的经辣素衍生物作用后肿瘤的平均瘤重(图4)及其直观照片(图5)可以发现,肿瘤的体积、重量和其直观照片基本是相对应的,一般来说,抑制效果越好,肿瘤的体积及重量越小。
在A549细胞BALB/c nude裸小鼠皮下移植瘤实验中,7种化合物的抑制效果均低于5-fu(43.11%),其中,化合物I-1(33.25%)、I-6(35.19%)及I-7(33.56%)的抑制效果最好,化合物I-4(22.05%)也表现出一定的抑制效果;
在HCT116细胞BALB/c nude裸小鼠皮下移植瘤实验中,本发明化合物的抑制效果均低于5-fu(44.81%),其中,化合物I-1(35.13%)的抑制效果最好,且化合物I-4(29.86%)也表现出一定的抑制效果;
在HT-29细胞BALB/c nude裸小鼠皮下移植瘤实验中,本发明化合物的抑制效果均低于5-fu(44.60%),其中,化合物I-6(32.07%)的抑制效果最好,化合物I-4(23.90%)和I-7(26.52%)也表现出一定的抑制效果。其结果如图6所示。
Claims (10)
- 一种具有抗肿瘤活性的化合物,其特征在于所述化合物的结构式如下:
式中:R1选自羟基、羧基、甲基、甲氧基或氢;R2选自乙烯基、甲基、一氯甲基或苯基;R3选自甲氧羰基、乙氧羰基、丙氧羰基、羟基、甲基或氢;R4选自氢、羟基、氯、甲基、溴、乙酰基、甲氧甲酰基或氯乙酰胺甲基;R5选自羟基、甲基或氢;R6选自羟基、丙烯酰胺甲基、乙酰胺甲基、氯乙酰胺甲基、甲基或氢。 - 根据权利要求1所述的化合物,其特征在于所述的化合物是一种选自如下化合物的化合物:
- 根据权利要求1或2所述化合物的制备方法,其特征在于该制备方法的制备步骤如下:按照芳香族化合物与酰胺化合物的摩尔比1:1.2~2.4以及芳香族化合物与催化剂的摩尔比1:1.8~1.9;让芳香族化合物与酰胺化合物在有机溶剂中在催化剂存在下在温度25~55℃下进行取代反应48~96h,接着过滤,得到的固体物使用去离子水充分洗涤,烘干得到化学式(I)化合物。
- 根据权利要求3所述化合物的制备方法,其特征在于所述的芳香族化合物是没食子酸、没食子酸甲酯、没食子酸丙酯、2,6-二羟基甲苯、3,5-二甲基苯甲醚、2,3,5-三甲基苯酚、4-氯-3,5-二甲基苯酚、2,6-二羟基苯乙酮、2,4-二羟基苯乙酮、4-溴-3,5-二羟基苯甲酸或3,4-二羟基苯甲酸甲酯。
- 根据权利要求3所述化合物的制备方法,其特征在于所述的酰胺化合物是N-羟甲基丙烯酰胺、N-羟甲基乙酰胺、N-羟甲基氯乙酰胺或N-羟甲基苯甲酰胺。
- 根据权利要求3所述化合物的制备方法,其特征在于所述的催化剂是浓硫酸或无水三氯化铝。
- 根据权利要求3所述化合物的制备方法,其特征在于所述的溶剂是二氯甲烷、三氯甲烷、丙酮或乙醇。
- 根据权利要求3所述化合物的制备方法,其特征在于洗涤的固体物在温度50~60℃下烘干360~420min,得到烘干固体物的水含量是以重量计5%以下。
- 根据权利要求1-2中任一权利要求所述化学式(I)化合物与权利要求3-8中任一权利要求所述制备方法制备得到的化学式(I)化合物作为抗肿瘤药物的用途。
- 根据权利要求9所述的用途,其特征在于化学式(I)化合物用于制备治疗肺癌、肝癌、结肠癌、白血病、宫颈癌或乳腺癌的抗肿瘤药物。
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