CN110963905A - Anti-tumor compound aiming at Fyn-CD147 signal channel target spot and preparation method and application thereof - Google Patents
Anti-tumor compound aiming at Fyn-CD147 signal channel target spot and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an anti-tumor compound aiming at Fyn-CD147 signal channel targets, and a preparation method and application thereof. The anti-tumor compound is prepared by reacting 1- (5-bromo-2-hydroxyphenyl) ethanone and 4-hydroxy-3-methoxybenzaldehyde under the catalysis of piperidine at high temperature. The antitumor compound can effectively inhibit the proliferation of skin tumor cells, colon cancer cells, liver cancer cells and lung cancer cells, wherein the half inhibition concentration of human skin malignant melanoma cells SK-Mel-28 is 5.8 mu M, which indicates that the antitumor compound inhibits the growth and proliferation of tumors and induces the tumor cellsHas strong apoptosis ability, and can be used for preparing antitumor drugs.
Description
Technical Field
The invention relates to the field of medicines, in particular to an anti-tumor compound aiming at Fyn-CD147 signal channel targets, and a preparation method and application thereof.
Background
A tumor is a cell proliferative disease, and the tumor cells have three significant basic characteristics: immobility, migration and loss of contact inhibition. On a cellular level, carcinogenesis is a very rare event. Genetically, cancer develops from a cell and from a cell that has lost control of proliferation. The human body has millions of cells, and billions of cells divide every day, and theoretically almost any cell may be cancerated by the change of genetic components, but this is not true in practice. Malignant transformation of a cell requires multiple genetic changes, i.e., multiple genetic mutations in a cell. Tumorigenesis is thus a progressive process involving multiple stages of reaction and accumulation of mutations. In this process, the more cancerous cell lines are, the less under the control of regulatory mechanisms within the receptor, and are progressively invaded towards normal tissues. After malignant transformation of the cells, the cancer cells continue to accumulate mutations, which confer new properties on the mutated cells and make the cancer cells more dangerous. At present, the anti-tumor medicines are still few and expensive, and other anti-tumor compounds need to be further searched.
Disclosure of Invention
Based on the situation, the anti-tumor compound aiming at Fyn-CD147 signal channel targets and the preparation method and application thereof are needed.
An anti-tumor compound directed against a Fyn-CD147 signaling pathway target, said anti-tumor compound having a structure represented by structural formula I:
the invention also provides a preparation method of the anti-tumor compound, which comprises the following steps:
mixing 1- (5-bromo-2-hydroxyphenyl) ethanone and 4-hydroxy-3-methoxybenzaldehyde, heating to 140-180 ℃, adding piperidine for reaction for 5-15 min, mixing with an alkali solution, adjusting the pH value to 1-2, and filtering to obtain the anti-tumor compound.
In one embodiment, the molar ratio of the 1- (5-bromo-2-hydroxyphenyl) ethanone to the 4-hydroxy-3-methoxybenzaldehyde is (1-1.3): 1.
In one embodiment, the ratio of the amount of the substance of the 1- (5-bromo-2-hydroxyphenyl) ethanone to the volume of the piperidine is (20-24) mmol:1 ml.
In one embodiment, the mass concentration of the alkali solution is 10% -30%, and the temperature of the alkali solution is 0-10 ℃.
In one embodiment, the method further comprises the following steps: and recrystallizing the anti-tumor compound by using a mixed solution of ethyl acetate and petroleum ether, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1 (12-18).
In one embodiment, the adjusting the pH specifically includes the following steps: and (3) adjusting the pH value to 1-2 by using saturated hydrochloric acid.
The invention also provides an application of the anti-tumor compound in preparing anti-tumor drugs.
The invention also provides an anti-tumor drug aiming at the Fyn-CD147 signal channel target spot, which comprises the anti-tumor compound, wherein the mass ratio of the anti-tumor compound in the anti-tumor drug is not more than 99%.
In one embodiment, the dosage form of the antitumor drug is injection, tablet, paste or suppository.
The anti-tumor compound is prepared by reacting 1- (5-bromo-2-hydroxyphenyl) ethanone and 4-hydroxy-3-methoxy benzaldehyde under the catalysis of piperidine at high temperature, and the chemical reaction formula is as follows:
the anti-tumor compound can effectively inhibit the proliferation of skin tumor cells, colon cancer cells, liver cancer cells and lung cancer cells, wherein the semi-inhibition concentration of human skin malignant melanoma cells SK-Mel-28 is 5.8 mu M, the semi-inhibition concentration of colon cancer cells is 5.3 mu M, the semi-inhibition concentration of liver cancer cells is 5.56 mu M, and the semi-inhibition concentration of lung cancer cells is 6.87 mu M, which shows that the anti-tumor compound has strong capacity of inhibiting the growth and proliferation of tumors and inducing the apoptosis of tumor cells. The antitumor compound can weaken phosphorylation of FYN kinase on CD147 tyrosine, is an antitumor compound aiming at Fyn-CD147 signal channel targets, can be applied to preparation of antitumor drugs, provides new theoretical and experimental bases for prevention and treatment of tumors, and can be widely used as a tool molecule in tumor-related research.
Drawings
FIG. 1 is a photograph showing the results of a colony formation inhibition experiment of the antitumor compound of example 1;
FIG. 2 is a graph showing the results of CCK-8 experiments on human skin malignant melanoma cells SK-Mel-28 at various concentrations of the antitumor compound of example 1;
FIG. 3 is a graph showing the results of CCK-8 experiments on colon cancer cells HT29 at various concentrations of the anti-tumor compound of example 1;
FIG. 4 is a graph showing the results of CCK-8 experiments on hepatoma cells HepG2 with the anti-tumor compound of example 1 at different concentrations;
FIG. 5 is a graph showing the results of the CCK-8 assay for lung cancer cell A549 with the anti-tumor compound of example 1 at various concentrations;
FIG. 6 is a diagram showing the results of CCK-8 experiments on human skin malignant melanoma cells SK-Mel-28 at different concentrations of chalcone;
FIG. 7 is a diagram showing the results of CCK-8 experiments on human malignant melanoma cells SK-Mel-28 at different concentrations for compounds of structural formula II;
FIG. 8 is a diagram showing the results of CCK-8 experiments on human malignant melanoma cells SK-Mel-28 at different concentrations for compounds of structural formula III;
FIG. 9 is a diagram showing the results of an experiment for detecting the inhibition of CD147 phosphorylation by an anti-tumor compound by carrying out an in vitro phosphorylation reaction of FYN kinase and prokaryotic expression purified CD 147.
Detailed Description
In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The anti-tumor compound aiming at the Fyn-CD147 signal channel target of one embodiment of the invention has a structure represented by the following structural formula I:
the preparation method of the antitumor compound provided by the embodiment of the invention comprises the following steps: mixing 1- (5-bromo-2-hydroxyphenyl) ethanone and 4-hydroxy-3-methoxybenzaldehyde, heating to 140-180 ℃, adding piperidine for reaction for 5-15 min, mixing with an alkali solution, adjusting the pH value to 1-2, and filtering to obtain the anti-tumor compound.
In a specific example, the molar ratio of 1- (5-bromo-2-hydroxyphenyl) ethanone to 4-hydroxy-3-methoxybenzaldehyde is (1-1.3): 1.
In a specific example, the ratio of the amount of the substance of 1- (5-bromo-2-hydroxyphenyl) ethanone to the volume of piperidine is (20-24) mmol:1 ml.
In a specific example, the mass concentration of the alkali solution is 10% -30%, the temperature of the alkali solution is 0-10 ℃, and the precooled low-temperature alkali solution is adopted for dissolving, so that the excessive heat release during mixing can be prevented. Alternatively, the alkali solution is a 10% by mass sodium hydroxide solution.
In one specific example, the method further comprises the following steps: the anti-tumor compound is recrystallized by using a mixed solution of ethyl acetate and petroleum ether, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1 (12-18), so that the purity of the anti-tumor compound is effectively improved.
In a specific example, adjusting the pH value specifically comprises the steps of: and (3) adjusting the pH value to 1-2 by using saturated hydrochloric acid. It is to be understood that the adjustment method is not limited thereto, and may be selected as desired.
The invention provides an application of the anti-tumor compound in preparing anti-tumor drugs. The anti-tumor compound is tested by experiments, and has inhibiting effect on other skin tumors such as basal cell carcinoma, squamous cell carcinoma, colon cancer cell, liver cancer cell, lung cancer cell, etc. besides skin malignant melanoma.
The invention also provides an anti-tumor drug aiming at the Fyn-CD147 signal channel target spot, which comprises the anti-tumor compound, wherein the mass percentage of the anti-tumor compound in the anti-tumor drug is not more than 99%. Optionally, the anti-tumor drug is in the form of injection, tablet, paste or suppository.
The anti-tumor compound is prepared by reacting 1- (5-bromo-2-hydroxyphenyl) ethanone and 4-hydroxy-3-methoxy benzaldehyde under the catalysis of piperidine at high temperature, and the chemical reaction formula is as follows:
the anti-tumor compound can effectively inhibit the proliferation of skin tumor cells, colon cancer cells, liver cancer cells and lung cancer cells, wherein the semi-inhibition concentration of human skin malignant melanoma cells SK-Mel-28 is 5.8 mu M, the semi-inhibition concentration of colon cancer cells is 5.3 mu M, the semi-inhibition concentration of liver cancer cells is 5.56 mu M, and the semi-inhibition concentration of lung cancer cells is 6.87 mu M, which shows that the anti-tumor compound has strong capacity of inhibiting the growth and proliferation of tumors and inducing the apoptosis of tumor cells. The antitumor compound can weaken phosphorylation of FYN kinase on CD147 tyrosine, is an antitumor compound aiming at Fyn-CD147 signal channel targets, can be applied to preparation of antitumor drugs, provides new theoretical and experimental bases for prevention and treatment of tumors, and can be widely used as a tool molecule in tumor-related research.
The following are specific examples.
Example 1
Respectively adding 1- (5-bromo-2-hydroxyphenyl) ethanone (9.56mmol,2.03g) and 4-hydroxy-3-methoxybenzaldehyde (8.60mmol,1.31g) into a 25mL single-neck bottle, heating to 160 ℃ to enable reactants to be in a molten state, then rapidly adding piperidine (0.43mL), stirring for 10min, pouring the mixture into a beaker containing 10% of ice NaOH solution, washing residues in the bottle with absolute ethyl alcohol to the beaker, then adjusting the pH of the solution in the beaker to 1-2 with saturated hydrochloric acid, separating out orange yellow solids, stirring for 2h, filtering, recrystallizing the crude product with a mixed solution of ethyl acetate and petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1:15) to obtain a pure product (E) -1- (5-bromo-2-hydroxyphenyl) -3- (4-hydroxy-3-methoxyphenyl) -2-methoxyphenyl) -1 2.07g of-propen-1-one, giving a yield of 68% based on the actual yield divided by the theoretical yield.
Example 2
Respectively adding 1- (5-bromo-2-hydroxyphenyl) ethanone (9.56mmol,2.03g) and 4-hydroxy-3-methoxybenzaldehyde (8.60mmol,1.31g) into a 25mL single-neck bottle, heating to 140 ℃ to enable reactants to be in a molten state, then rapidly adding piperidine (0.43mL), stirring for 5min, pouring the mixture into a beaker containing 30% of ice NaOH solution, washing residues in the bottle with absolute ethyl alcohol to the beaker, then adjusting the pH of the solution in the beaker to 1-2 with saturated hydrochloric acid, separating out orange yellow solids, stirring for 2h, filtering, recrystallizing the crude product with a mixed solution of ethyl acetate and petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1:12) to obtain a pure product (E) -1- (5-bromo-2-hydroxyphenyl) -3- (4-hydroxy-3-methoxyphenyl) -2-methoxyphenyl) -1 1.88g of p-propen-1-one.
Comparative example 1
1- (5-bromo-2-hydroxyphenyl) ethanone (9.56mmol,2.03g) and 4-hydroxy-3-methoxybenzaldehyde (8.60mmol,1.31g) were added to a 25mL single-neck flask, heated to 80 ℃ and then piperidine (0.43mL) was added rapidly, and after stirring and reacting for 10min, the mixture was poured into a beaker containing ice 10% NaOH solution, the residue in the flask was washed into the beaker with anhydrous ethanol, and then the pH of the solution in the beaker was adjusted to 1-2 with saturated hydrochloric acid, and no orange-yellow solid precipitated.
Comparative example 2
1- (5-bromo-2-hydroxyphenyl) ethanone (9.56mmol,2.03g) and 4-hydroxy-3-methoxybenzaldehyde (8.60mmol,1.31g) were added to a 25mL single-neck flask, heated to 160 ℃, followed by the rapid addition of N-methylpiperidine (0.43mL) and stirred for reaction for 10min, the mixture was poured into a beaker containing ice 10% NaOH solution, the flask residue was washed into the beaker with anhydrous ethanol, and then the pH of the solution in the beaker was adjusted to 1-2 with saturated hydrochloric acid, and no orange-yellow solid precipitated.
The anti-tumor compound obtained in example 1 was used to perform a colony formation inhibition assay: taking human skin malignant melanoma cells SK-Mel-5 and SK-Mel-28 in logarithmic growth phase, digesting with 0.25% pancreatin, blowing into single cells, preparing single cell suspension with culture medium containing 10% fetal calf serum, and counting. Inoculating 700 cells into a 6cm culture plate, adding antitumor compounds (0 μ M, 5 μ M and 10 μ M) with different concentrations, culturing in an incubator for 10 days, discarding the old culture solution after the experiment is finished, washing with PBS for 2-3 times, fixing with methanol for 15min, staining with crystal violet for 5min, washing with distilled water for several times, air drying naturally, and taking a picture. As shown in FIG. 1, it can be seen that for the two SK-Mel-5 and SK-Mel-28 cell lines, the antitumor compound only needs 5uM to significantly inhibit the formation of single clone, and the number of single clones is significantly reduced.
The anti-tumor compound obtained in example 1 was used for the CCK-8 test: preparing a single-cell suspension from human skin malignant melanoma cells SK-Mel-28 by using a culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells per well to a 96-well plate, wherein the volume of each well is 100ul, adding anti-tumor compounds (0 mu M, 1 mu M, 5 mu M, 10 mu M and 20 mu M) with different concentrations after adherence, adding the maximum corresponding volume of the drugs into a DMSO group, performing determination in 0h, 24h, 48h and 72h, adding 10ul CCK-8 before determination, incubating for 2 hours, determining the absorption value of each well on a microplate reader at a wavelength of 450nm, recording the result, and drawing a cell growth curve by using time as a horizontal coordinate and the absorption value as a vertical coordinate. The results are shown in FIG. 2, and it can be seen that the antitumor compound has a good inhibitory effect on SK-Mel-28, and the half inhibitory concentration is 5.8 μ M. Taking colon cancer cells HT29, liver cancer cells HepG2 and lung cancer cells A549 respectively, preparing single cell suspension by using a culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells in each hole to a 96-hole plate, wherein each hole is 100ul, adding anti-tumor compounds (1 mu M, 5 mu M, 10 mu M and 20 mu M) with different concentrations after adherence, adding a maximum corresponding volume of a drug into a DMSO group, carrying out determination at 0h, 24h, 48h and 72h, adding 10ul of CCK-8 before the determination, measuring the absorption value of each hole at a wavelength of 450nm on an enzyme labeling instrument after incubation for 2 hours, recording the result, and drawing a cell growth curve by taking time as a horizontal coordinate and the absorption value as a vertical coordinate. The results are shown in fig. 3-5 respectively, and it can be seen that the antitumor compound also has certain inhibitory effects on colon cancer, liver cancer and lung cancer, and the half inhibitory concentrations are 5.3 μ M, 5.56 μ M and 6.87 μ M respectively.
CCK-8 testing was performed using the backbone compound chalcone: taking human skin malignant melanoma cells SK-Mel-28, preparing single cell suspension with culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells per well to 96-well plate, each well volume being 100ul, adding chalcone (1 uM, 5uM, 10 uM and 20 uM) with different concentrations after adherence, adding maximum corresponding volume of the drug into DMSO group, measuring at 0h, 24h, 48h and 72h, adding 10ul CCK-8 before measuring, incubating for 2 hours, measuring absorption value of each well at 450nm wavelength on a microplate reader, recording the result, and drawing cell growth curve with time as abscissa and light absorption value as ordinate. The results are shown in FIG. 6, where the half inhibitory concentration was 6.7. mu.M, and the effect and stability were inferior to those of the antitumor compound of the present invention.
CCK-8 testing was performed using a compound of formula II: taking human skin malignant melanoma cells SK-Mel-28, preparing single cell suspension with culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells per well to 96-well plate, each well volume being 100ul, adding the above compounds (1 uM, 5uM and 20 uM) with different concentrations after adherence, adding maximum corresponding volume of the drug into DMSO group, performing determination in 0h, 24h, 48h and 72h, adding 10ul CCK-8 before determination, incubating for 2h, determining absorption value of each well at 450nm wavelength on enzyme labeling instrument, recording result, and drawing cell growth curve with time as abscissa and absorption value as ordinate. As shown in FIG. 7, the half inhibitory concentration was 20.1. mu.M, which is far less effective than the antitumor compound of the present invention.
CCK-8 testing was performed using the compound of formula III below: taking human skin malignant melanoma cells SK-Mel-28, preparing single cell suspension with culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells per well to 96-well plate, each well volume being 100ul, adding the above compounds (5 μ M, 10 μ M and 20 μ M) with different concentrations after adherence, adding maximum corresponding volume of the drug into DMSO group, performing determination in 0h, 24h, 48h and 72h, adding 10ul CCK-8 before determination, incubating for 2h, determining absorption value of each well at 450nm wavelength on enzyme labeling instrument, recording result, and drawing cell growth curve with time as abscissa and absorption value as ordinate. As shown in FIG. 8, the half inhibitory concentration was 20.7. mu.M, which is far less effective than the antitumor compound of the present invention.
In vivo experiments: in order to further explore the in vivo effect of the antitumor compound, a xenograft model is established by using nude mice of 5-6 weeks old, melanoma cells SK-Mel-5 with high proliferation speed are selected as inoculation cells, cells with good growth state, no pollution and strong activity are selected for amplification, and subcutaneous tumorigenesis is carried out on 40 nude mice. Continuously observing 7-10 days after inoculation until the size of the tumor reaches 50mm3～100mm3Selecting the nude mice meeting the above standard, and randomly dividing the nude mice into 3 groups: a control group, a 20mg/kg dose group and a 40mg/kg dose group,feeding the group of 6 animals in cages after grouping, continuously injecting the anti-tumor compound into the abdominal cavity for treatment, and measuring the tumor volume every other day until the tumor size of the control group reaches 1000mm3The experiment was terminated at this time, and the tumor bodies of the mice were removed for immunohistochemistry and Ki67 expression was detected.
The experimental results are as follows: after treatment, no mortality occurred in each group of nude mice, and the body weight average increased with the treatment time. The growth of tumors was significantly inhibited in the 20mg/kg dose group compared to the control group, whereas the 40mg/kg dose group was more significantly inhibited than the 20mg/kg dose group. The above results can demonstrate that the anti-tumor compound of the present invention can effectively inhibit the growth of melanoma in vivo.
The invention further researches and screens the action mechanism of the anti-tumor compound, and finds that the anti-tumor compound mainly plays a role in aiming at Fyn-CD147 signal channel targets. By reacting Fyn kinase with purified CD147, the reaction system: fyn 1uL (100ng), CD147(5uL), 10 XKinase Buffer (2uL), ATP (1mM 1uL), an antitumor compound (5. mu.M 2. mu.L), and reacted at 30 ℃ for 40 minutes, followed by Western Blot and Coomassie staining. The results are shown in fig. 9 (wherein anti-p is tyrosine phosphorylation antibody), which illustrates that the antitumor compound of the present invention can reduce phosphorylation of FYN kinase on CD147 tyrosine, thereby proving that the antitumor compound is an antitumor compound aiming at FYN-CD147 signal pathway target, providing new theory and experimental basis for prevention and treatment of tumor, and can be widely used as a tool molecule in tumor-related research.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. An anti-tumor compound directed to a Fyn-CD147 signal pathway target, wherein the anti-tumor compound has a structure represented by the following structural formula I:
2. a process for the preparation of an anti-neoplastic compound of claim 1, comprising the steps of:
mixing 1- (5-bromo-2-hydroxyphenyl) ethanone and 4-hydroxy-3-methoxybenzaldehyde, heating to 140-180 ℃, adding piperidine for reaction for 5-15 min, mixing with an alkali solution, adjusting the pH value to 1-2, and filtering to obtain the anti-tumor compound.
3. The method according to claim 2, wherein the molar ratio of the 1- (5-bromo-2-hydroxyphenyl) ethanone to the 4-hydroxy-3-methoxybenzaldehyde is (1-1.3): 1.
4. The method according to claim 2, wherein the ratio of the amount of the substance of 1- (5-bromo-2-hydroxyphenyl) ethanone to the volume of the piperidine is (20-24) mmol:1 ml.
5. The preparation method according to claim 2, wherein the mass concentration of the alkali solution is 10-30%, and the temperature of the alkali solution is 0-10 ℃.
6. The method of claim 2, further comprising the steps of: and recrystallizing the anti-tumor compound by using a mixed solution of ethyl acetate and petroleum ether, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1 (12-18).
7. The method according to claim 2, wherein the adjusting the pH specifically comprises the steps of: and (3) adjusting the pH value to 1-2 by using saturated hydrochloric acid.
8. Use of the anti-tumor compound of claim 1 in the preparation of an anti-tumor medicament.
9. An anti-tumor drug against Fyn-CD147 signal pathway targets, comprising the anti-tumor compound of claim 1, wherein the anti-tumor compound accounts for no more than 99% of the anti-tumor drug by mass.
10. The antitumor drug as claimed in claim 9, wherein the dosage form of the antitumor drug is injection, tablet, paste or suppository.
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| US20020040029A1 (en) * | 1999-12-23 | 2002-04-04 | Bowen J. Phillip | Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states |
| CN106831375A (en) * | 2016-12-28 | 2017-06-13 | 哈尔滨医科大学 | A kind of Chalcone Compounds with antitumor activity and its production and use |
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| US20020040029A1 (en) * | 1999-12-23 | 2002-04-04 | Bowen J. Phillip | Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states |
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