CN107286123B - Preparation method and application of diphenyl furan compound - Google Patents
Preparation method and application of diphenyl furan compound Download PDFInfo
- Publication number
- CN107286123B CN107286123B CN201710388136.8A CN201710388136A CN107286123B CN 107286123 B CN107286123 B CN 107286123B CN 201710388136 A CN201710388136 A CN 201710388136A CN 107286123 B CN107286123 B CN 107286123B
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- dibenzofuran
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Abstract
The invention relates to a preparation method and application of a diphenyl furan compound, belonging to the technical field of pharmaceutical chemistry. The structure of the compound is shown as the formula (I):
formula (I); the preparation method takes dextro-lichenin and hexamethyl disilazane as substrates, and the dextro-lichenin and hexamethyl disilazane are subjected to amination synthesis reaction in an organic solvent medium at room temperature to prepare the product. The compound has no toxicity to mice due to acute toxicity caused by oral gavage, has no obvious toxic effect on animal weight growth, organ development, blood biochemistry and blood routine indexes under the effective anticancer dose, and can remarkably increase the levels of total serum protein and albumin. The compound has the anti-tumor effect and the anti-tumor effect combined with clinical anti-tumor drugs, can be used for preparing anti-tumor chemotherapeutic drugs, anti-tumor drug compositions and auxiliary anti-tumor health care products, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a preparation method and application of a dibenzofuran compound, wherein the compound is 6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1, 3-diketone (English structure name: 6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1, 3-dione).
Background
Malignant tumor is a serious disease seriously threatening human health and life safety, and is now the main cause of death of human beings and seriously threatening human health and life safety. Data issued by Globocan of the international cancer institute of the world health organization shows that 1266.1 ten thousand new cancer cases and 756.4 ten thousand deaths are worldwide in 2008; wherein, the new cases of cancer in China are 281.6 ten thousand cases and death is 195.8 ten thousand cases. In 2012, the number of newly added cancer cases is 1410 ten thousands, the number of newly added cancer cases is 820 ten thousands, and 3260 thousands of people live with tumors; among them, the number of newly added cancer cases in 2012 in china is 306.5 ten thousand (22% worldwide), 220.6 ten thousand deaths (27% worldwide), and 504.5 ten thousand tumor-bearing survival patients (15% worldwide). Compared with 2008, the number of cancer cases and the number of death cases are increased in 2012, the number of new cancer cases is estimated to reach 1900 ten thousand in 2025, 2400 ten thousand in 2035, and the number of new cancer cases and death cases in China are the top of the world. According to data published by' 2012 annual report of tumor registration in China, published by national tumor registration center of Ministry of health, 312 ten thousand new cancer cases are newly issued in 2012 of China, 8550 new cancer cases are newly added every day on average, and 6 persons per minute on average are confirmed as malignant tumors and 5 dead persons; wherein the population over 50 years old accounts for over 80 percent of the total number of the patients, and the incidence rate of the population over 60 years old is more than 1 percent. Chenwanqing estimates that 429.2 ten thousands of new cancer cases and 281.4 ten thousands of deaths occur in 2015 years in China. The cancers with the highest incidence in China are lung cancer, gastric cancer and liver cancer, 1/3 are newly increased in lung cancer cases in the world, and 1/2 is increased in liver cancer and esophageal cancer in China. Data from the information statistics center of the ministry of health in China show that malignant tumors account for the third leading cause of death of people in China in the 70 th century, and account for the second leading cause of death from the 80 th to the 90 th, and account for the first leading cause of death of people in China since 1997. The data show that the incidence of malignant tumors is rapidly increasing with the aging population, the aggravation of environmental pollution and the change of life patterns.
Cancer is still an incurable disease in the world at present. Chemotherapy for cancer plays an important role in cancer treatment as a systemic therapeutic measure, and is also a promising approach to the future treatment of cancer.
Most of the clinically used cancer chemotherapy drugs have the problems of great toxic and side effects, uncertain curative effect, poor selectivity, weak targeting property, cancer cell drug resistance and the like, so that the clinical application and effect of cancer chemotherapy drug treatment are greatly limited. Therefore, the development of the chemotherapy drugs with definite curative effect, low toxicity, safety, selective and/or targeted anticancer effect is an important direction and urgent task for the research of new anticancer drugs. The content of natural active compounds in animal and plant resources is often very low, the resource sources are limited, the extraction and separation are complex, and the cost is high, so that the natural active compounds are the biggest obstacles for development and application. The solution to the problem of raw material source of natural active compounds in large-scale applications relies mainly on chemical synthesis of the compounds. Therefore, how to overcome the defects of the prior art is a problem to be solved urgently in the technical field of medicinal chemistry.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method and application of a diphenyl furan compound. The compound is 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone, and the chemical synthesis method has the advantages of easily obtained raw materials, simple and rapid synthesis steps, easy purification of products, high yield and low cost. The compound has strong anti-tumor effect, low toxicity and clear action mechanism, and can be used for preparing anti-tumor chemotherapeutic drugs, anti-tumor drug compositions and health products for assisting anti-tumor.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of diphenyl furan compounds, the structural formula of which is shown in formula (I),
formula (I); the name of Chinese is: 6-acetyl-2- (1-amino-ethylene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenylfuran-1, 3-dione; the English name is: 6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1, 3-dione; molecular formula C18H17NO6The molecular weight is 343;
the method comprises the following steps:
according to the following reaction formula, dextro-lichenic acid (CAS:7562-61-0) and hexamethyldisilazane (CAS:999-97-3) are used as substrates, and amination synthesis reaction is carried out in an organic solvent medium at room temperature to prepare the diphenyl furan compound shown in the formula (I);
further, it is preferable that the organic solvent is chloroform, ethyl acetate, acetone, methanol or ethanol.
Further, it is preferable that the molar ratio of dextro-orcinic acid to hexamethyldisilazane is 1: 1.7-2.1; the mass ratio of the volume of the used organic solvent to the dextro-rotatory coating acid is 5-6:1 ml/g.
Further, it is preferable that the specific steps are as follows: adding dextro-lichenin into an organic solvent, sufficiently shaking at room temperature to form a suspension state, adding hexamethyldisilazane, continuously shaking until the reaction solution appears unchanged by naked eyes, standing for more than 10h, and purifying the obtained product to obtain the diphenyl furan compound shown in the formula (I).
Further, it is preferable that the specific steps of purifying the obtained product are: and filtering or evaporating the reaction solution to dryness, and purifying the obtained filter residue or evaporated substance by adopting a washing or column chromatography separation method.
Further, it is preferable that the solvent used for the washing is chloroform or methanol; the elution solvent adopted by the column chromatography separation is a mixed solvent of ethyl acetate and acetone in a volume ratio of 100:1, or pure chloroform.
The invention also provides application of the diphenyl furan compound in preparing anti-tumor drugs or auxiliary anti-tumor health care products.
Further, the preferred dosage form is injection, tablet, capsule, soft capsule, oral liquid, granule or electuary. In the medicament, the effective amount of the diphenyl furan compound can be 0.1-100%, preferably 0.2-95%, and more preferably 0.5-90% of the weight of the composition.
The dosage form of the auxiliary anti-tumor health product is as follows: tablet, oral liquid, capsule, soft capsule, granule or granule.
Further, it is preferred that said tumor is any one of the following human tumors: lung cancer, human breast cancer, bladder cancer, nasopharyngeal carcinoma, cervical cancer, renal cancer, gastric cancer, colon cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, endometrial cancer, leukemia, glioma, sarcoma, and prostate cancer.
The invention also claims an anti-tumor pharmaceutical composition, the active ingredients of which comprise the above dibenzofuran compound and at least one of cisplatin, paclitaxel, 5-fluorouracil and cyclophosphamide.
Compared with the prior art, the invention has the beneficial effects that:
the compound 6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone (6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1,3-dione) with the structure shown in the formula (I) can be extracted and separated from the plant usnea longissima and can also be artificially and chemically synthesized through chemical reaction. The chemical synthesis method has the advantages of easily available raw materials, simple and quick synthesis steps, easy purification of products, high yield and low cost.
The compound of the invention is used for preparing anti-tumor chemotherapeutic drugs and health products for assisting anti-tumor. 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenylfuran-1, 3-dione can remarkably kill and/or inhibit various human tumor cells in vitro, such as Xuanwei lung cancer cell XWLC-05, lung cancer cell A-549, lung cancer NCI-H460, lung cancer NCI-H157, breast cancer cell MCF-7, nasopharyngeal cancer cell CNE, bladder cancer cell T-24, cervical cancer cell Hela, leukemia cell K-562, liver cancer cell QGY-7703, bile duct cancer cell QBC-939, glioma cell U-251, prostate cancer cell PC-3, renal cancer cell ACHN, stomach cancer cell SGC-7901, colon cancer cell HCT-116, Ovarian cancer SKOV-3, endometrial cancer RL-952, pancreatic cancer PANC-1, etc. The compound has obvious growth inhibition effect on human liver cancer HepG2 transplanted to balb/c nude mice in vivo.
Researches also find that the compound has combined synergistic or additive antitumor effect with clinically used antitumor chemotherapeutic drugs such as cisplatin, 5-fluorouracil, taxol and cyclophosphamide, and the in vitro antitumor effect of the dibenzofuran compound is superior to that of clinically used antitumor drugs such as cisplatin, 5-fluorouracil and taxol.
The diphenyl furan compound has a cell targeting anticancer effect, the sensitivity of different cancer cell strains is greatly different, and human Xuanwei lung cancer cells XWLC-05, lung cancer cells A-549, liver cancer cells HepG2, breast cancer cells MCF-7, bladder cancer cells T-24 and the like are very sensitive to the diphenyl furan compound.
The diphenyl furan compound also has selective anti-tumor effect, and the killing and/or inhibiting effect on tumor cells is more significant than the killing/inhibiting effect on normal cells of a human body under the same dosage.
The diphenyl furan compound can remarkably promote the apoptosis of tumor cells, influence the growth cycle and differentiation of the tumor cells, regulate the gene expression of the tumor cells, influence the metabolism of the tumor cells and inhibit the proliferation of the tumor cells.
Mouse oral acute toxicity test LD of diphenyl furan compounds50>10g/kg, and grading acute toxicity into non-toxic; the diphenyl furan compound is repeatedly administered in a short period under the effective antitumor dose, has no significant adverse effect on the weight growth, organ development, blood biochemistry and blood routine indexes of mice, and can significantly increase the content of total serum protein and albumin; the inventive dibenzofuran compounds show no genetic toxicity at the tested dosage.
Drawings
FIG. 1 is a mass spectrum of a dibenzofuran compound;
FIG. 2 is a nuclear magnetic hydrogen spectrum of a dibenzofuran compound;
FIG. 3 is a nuclear magnetic carbon spectrum and a DEPT spectrum of a diphenyl furan compound;
FIG. 4 is a graph showing the dose-effect relationship of the in vitro anti-tumor effect of dibenzofuran compounds on different human tumor cell lines (the abscissa represents the dose of the compound)
FIG. 5 is a graph showing the relationship between time-effect and dose-effect of the in vitro antitumor effect of dibenzofuran compounds (the abscissa represents the dose of the compound)
FIG. 6 shows the inhibitory effect of dibenzofuran compounds on cancer cells and normal cells (dose of compound on abscissa)
FIG. 7 is a graph showing the dose-effect relationship of paclitaxel on the anti-cancer effect of cancer cell lines in vitro (the abscissa represents the dose of the compound)
FIG. 8 is the Relative Tumor Volumes (RTV) at different time points of the in vivo anticancer assay in nude mice;
FIG. 9 is the tumor Relative Proliferation Rate (RPR) at different time points of the in vivo anticancer assay in nude mice;
FIG. 10 shows Tumor Weights (TW) at the end of the anticancer test in nude mice;
FIG. 11 is a cluster plot of mRNA from MCF-7 cells significantly affected; wherein GCS175157 is a solvent control group, and GCS175163 is a diphenyl furan compound group;
FIG. 12 is a cluster map of ncRNA significantly affecting MCF-7 cells; wherein GCS175157 is a solvent control group, and GCS175163 is a diphenyl furan compound group;
FIG. 13 is a cancer significantly affected by pathways in cancer;
FIG. 14 shows the body weight of mice at each time point of the short-term repeat dose administration test;
fig. 15 shows the organ coefficients of the mice at the end of the short-term repeated dose administration test.
Detailed Description
The present invention will be described in further detail with reference to examples.
It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available by purchase.
Unless otherwise indicated, the terms used herein have the following meanings:
the term "chemical synthesis" as used herein means that the dibenzofuran compounds of the present invention can be artificially synthesized by chemical reaction using other chemical substrates as raw materials.
The term "pharmaceutical dosage form" as used herein refers to different pharmaceutical preparations made from the dibenzofuran compounds of the present invention in different "pharmaceutically acceptable carriers".
As used herein, "pharmaceutical composition" refers to a formulation of a dibenzofuran-like compound of the invention, together with a vehicle commonly accepted in the art for delivery of biologically active compounds to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers.
As used herein, "pharmaceutically acceptable carrier" is intended to include, but is not limited to, any adjuvant, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, disintegrating agent, solvent, or emulsifying agent that has been recognized by the united states Food and Drug Administration (FDA) as being useful in humans or animals in a variety of forms that have no adverse effects on the resulting pharmaceutical composition.
The term "treating" means administering a benzfuran-like compound or formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;
(ii) inhibiting the disease or disease state, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.
The auxiliary anti-tumor health product is used for the auxiliary treatment of tumor patients in the treatment process of the tumor patients, and may have sensitization and synergy effects on the treatment of the tumor patients, but is not a health product for treatment.
Example 1
The diphenyl furan compound of the invention: chemical synthesis and structural identification of 6-Acetyl-2- (1-amino-ethylene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1,3-dione (6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1, 3-dione).
Using d-orcylic Acid (CAS:7562-61-0, (+) -Usic Acid) and hexamethyldisilazane (CAS:999-97-3, C)6H19NSi2Or (Me)3Si)2NH) as substrate in different solvent media. The result shows that chloroform or ethyl acetate is the best solvent medium, the product yield is high, the purification is easy, the purity is high, and the process is simple. The product yield in methanol and ethanol media is low, a plurality of impurity byproducts can be formed in acetone media, and the synthetic reaction can not be carried out in petroleum ether and grease media. The mol ratio of the dextro-lichenin to the hexamethyldisilazane is preferably 1: 1.7-2.1; the optimal ratio of the solvent (ml) to the d-lichenin (g) is 5-6: 1; the reaction was carried out at room temperature. The specific synthesis steps are as follows:
1.1 100g of 98% pure d-lichenic acid was taken in a 1000ml reaction flask, 500ml of chloroform was added and shaken well to a suspension state, and then 80ml of analytically pure hexamethyldisilazane (molar ratio 1:1.7) was added and shaken vigorously for about 5 minutes, whereby a large amount of creamy yellow powdery suspension appeared in the solution, and the reaction solution generated heat and generated air bubbles. After the reaction solution is cooled, the reaction solution is kept stand at room temperature for more than 18 hours. The reaction solution is filtered by filter paper, and the milk yellow powdery filter residue is leached by dropwise adding 300-500ml of analytically pure chloroform. Naturally drying the milky yellow powdery filter residue in a cool, dry and ventilated place, volatilizing the residual solvent, and grinding into powder to obtain the diphenyl furan compound 6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1,3-dione (6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1, 3-dione). The product yield is more than 92 percent, and the purity is more than 99.5 percent.
1.2 100g of 98% purity d-usnic acid was put into a 1000ml reaction flask, 500ml of analytically pure ethyl acetate was added, the mixture was shaken well to a suspension, 80ml of analytically pure hexamethyldisilazane (molar ratio 1:1.7) was added, the mixture was shaken well, the solution became clear, and the mixture was left to stand at room temperature for 10 to 20 hours and then filtered. And evaporating the filtrate to remove the solvent to obtain a milky yellow powder. The creamy yellow powder was suspended in 200ml of analytically pure chloroform and filtered on a filter paper and purified by dropwise elution with 300ml of analytically pure chloroform. Naturally drying the milky yellow powdery filter residue in a cool and dry ventilated place, volatilizing the residual solvent and grinding into powder. The diphenyl furan compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone is obtained. The product yield is more than 94 percent, and the purity is more than 99.5 percent.
1.3 100g of 98% purity d-usnic acid was put into a 1000ml reaction flask, 500ml of analytically pure methanol was added, and the mixture was shaken well to a suspension state, and then 100ml of analytically pure hexamethyldisilazane (molar ratio 1:2.1) was added, and shaken well, whereby a large amount of air bubbles were generated, and a flocculent precipitate and a white powdery precipitate appeared in the solution. Standing the reaction solution at room temperature for 24-48h, then evaporating the volatile solvent in a rotary manner, separating the product by silica gel column chromatography, wherein the eluent is ethyl acetate: acetone (100: 1) gives the synthetic product 6-acetyl-2- (1-amino-ethylene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1,3-dione, formula (I). The product yield is about 60 percent, and the purity is more than 99 percent.
1.4 100g of 98% purity d-usnic acid was put into a 1000ml reaction flask, 500ml of analytically pure methanol was added, and the mixture was shaken well to a suspension state, and then 100ml of analytically pure hexamethyldisilazane (molar ratio 1:2.1) was added, and shaken well, whereby a large amount of air bubbles were generated, and a flocculent precipitate and a white powdery precipitate appeared in the solution. Standing the reaction solution at room temperature for 24-48h, performing rotary evaporation on the volatile solvent, separating the product by silica gel column chromatography, and obtaining the synthetic product, namely the compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone shown in the formula (I) by using pure chloroform as eluent. The product yield is about 60 percent, and the purity is more than 99 percent.
1.5 100g of 98% purity d-usnic acid was put into a 1000ml reaction flask, 500ml of absolute alcohol was added thereto, and the mixture was shaken sufficiently to form a suspension, and then 100ml of analytically pure hexamethyldisilazane (molar ratio 1:2.1) was added thereto, and the mixture was shaken sufficiently to cause a small amount of flocculent precipitate to appear in the solution. Standing the reaction solution at room temperature for 24-48h, then evaporating the volatile solvent in a rotary manner, separating the product by silica gel column chromatography, wherein the eluent is ethyl acetate: acetone to 100:1 (volume ratio) gave the synthetic product 6-acetyl-2- (1-amino-ethylene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1,3-dione, formula (I). The product yield is about 60 percent, and the purity is more than 99 percent.
1.6 100g of 98% purity d-usnic acid was put into a 1000ml reaction flask, 500ml of absolute alcohol was added thereto, and the mixture was shaken sufficiently to form a suspension, and then 100ml of analytically pure hexamethyldisilazane (molar ratio 1:2.1) was added thereto, and the mixture was shaken sufficiently to cause a small amount of flocculent precipitate to appear in the solution. Standing the reaction solution at room temperature for 24-48h, performing rotary evaporation on the volatile solvent, separating the product by silica gel column chromatography, and obtaining the synthetic product, namely the compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone shown in the formula (I) by using pure chloroform as eluent. The product yield is about 60 percent, and the purity is more than 99 percent.
1.7 taking 100g of 98 percent purity dextro-usnic acid into a 1000ml reaction bottle, adding 500ml of analytical pure acetone, fully shaking to obtain a suspension state, then adding 90ml of analytical pure hexamethyldisilazane (the molar ratio is 1:1.9), fully shaking to generate a large amount of bubbles and generate a large amount of heat, wherein the upper layer of the reaction solution is in a clear state, and a small amount of flocculent precipitate appears at the bottom. The reaction solution was allowed to stand at room temperature, and the solution gradually changed from yellow to dark reddish brown, and a granular precipitate appeared. After 72h the solvent was evaporated by rotary evaporation, the product was suspended in methanol and filtered and rinsed with 300-500ml of analytically pure methanol. The obtained yellow granular crystal is the synthesized product of the compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone in the formula (I). The product yield is about 50 percent, and the purity is more than 95 percent.
2. Structural identification
The mass spectrum of the compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1,3-dione (shown in figure 1);
nuclear magnetic hydrogen spectrum of compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1,3-dione (shown in figure 2);
nuclear magnetic carbon spectrum and DEPT spectrum of compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone (shown in figure 3).
ESI(+)MS:344(M+H)+,366(M+Na)+，382(M+K)+，709(2M+Na)+
1H-NMR(CDCL3,500MHZ)δH:5.83(s,H-4),13.36(s,H-7),11.76(s,H-9),1.70(3H,s,H-10),2.62(3H,s,H-12),2.09(3H,s,H-13),2.63(3H,s,H-15),6.45(s,NH2-b),12.29(s,NH2-a)。13C-NMR(CDCL3,125MHZ)δC:198.81(C-1),102.23(C-2),190.66(C-3),102.52(C-4),174.77(C-4a),155.74(C-5a),101.41(C-6),163.56(C-7),108.19(C-8),158.16(C-9),104.87(C-9a),57.28(c-9b),31.78(C-10),174.29(C-11),26.6(C-12),7.51(C-13),200.72(C-14),31.33(C-15)。
Example 2: biological experiment results of antitumor effect, combined antitumor effect, toxicological safety and antitumor action mechanism of 6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1,3-dione (6-Acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9bH-dibenzofuran-1,3-dione) shown as formula (I)
The following is a part of specific experimental illustrations to show that the compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1,3-dione of the formula (I) has significant, selective and cell-targeted antitumor effects, and combined antitumor effect and antitumor effect with clinical antitumor drugs are superior to clinical antitumor drugs, and the toxicological safety and antitumor action mechanism of the compound are demonstrated.
1. The diphenyl furan compound of the invention has the functions of inhibiting and killing human cancer cells in vitro:
in vitro anti-tumor assay methods: the diphenyl furan compound is dissolved in analytically pure DMSO, and the preparation concentration is 0, 0.25, 0.50, 1.0, 2.0 and 4.0 mg/ml. Collecting cultured human cancer cells in logarithmic growth phase by conventional in vitro tumor cell culture test method, suspending with DMEM/F12 complete culture solution, inoculating into 96-well plate, adding 200 μ l cell suspension into each well (cell density of different cancer cell lines is different, and most cancer cells have density of 7 × 10 per well3Individual cells), 8 replicate wells per concentration, per assay time point. The culture plate after cell inoculation is placed at 37 ℃ and 5% CO2Culturing in an incubator, and measuring OD values of 1 96-well plate by adopting an MTT method after 24 hours as 0 hour value of dosing; the culture medium of the rest of the plates was aspirated, and then 200. mu.l of the culture medium containing the dibenzofuran compounds of the invention at the corresponding concentrations (1. mu.l of the prepared dibenzofuran compounds of the invention was added to each ml of the culture medium, and the final test concentrations were 0.25, 0.50, 1.0, 2.0, and 4.0. mu.g/ml) were added, respectively, as designed. A DMSO solvent control and an anti-cancer drug positive control (cisplatin, PBS dissolved, using concentration 3. mu.M) are set at the same time, and each concentration and control group are made into 3 groups in parallel. The cells were incubated at 37 ℃ with 5% CO2Continuously culturing in an incubator, respectively taking a group of cells 24h, 48h and 72h after adding medicine, determining the OD value of each hole by adopting an MTT method, drawing cell growth curves under different time and different doses, determining the time-effect of the in-vitro anticancer effect of the diphenyl furan compound and the dose-effect relation of each time point, and calculating the median Inhibitory Concentration (IC) by adopting SPSS software50). The dose-response relationship after 72 hours of drug action can also be determined, or the effect result can be roughly observed under a microscope by using a screening test for 72 hours. The MTT method calculates the growth inhibition rate of cancer cells according to the following formula:
inhibition (%) - (corrected OD value of solvent control-corrected OD value of diphenyl furan compound group of the present invention)/corrected OD value of solvent control × 100
Corrected OD value-OD value actually measured in experimental group-OD value of cell-free blank control group
As a result: the 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenylfuran-1, 3-dione has significant in-vitro anticancer effect on human cancer cell strains such as Xuanwei lung cancer cell XWLC-05, lung cancer cell A-549, lung cancer NCI-H460, lung cancer NCI-H157, liver cancer cell HepG2, breast cancer cell MCF-7, bladder cancer cell T-24, nasopharyngeal carcinoma cell CNE and the like, and the in-vitro antitumor effect has significant dose-effect and/or time-effect relationship. In an in vitro anticancer activity screening test, after cancer cells are treated by the compound shown in the formula (I) for 72 hours, the compound also has very obvious in vitro inhibition or killing effects on human cervical cancer cells Hela, human leukemia cells K-562, human liver cancer cells QGY-7703, human bile duct cancer cells QBC-939, human glioma cells U-251, human prostate cancer cells PC-3, human kidney cancer cells ACHN, human colon cancer cells HCT-116, human gastric cancer cells SGC-7901, human ovarian cancer cells SKOV-3, endometrial cancer RL-952, human pancreatic cancer PANC-1 and the like under a microscope. The in vitro anticancer dose-effect relationship of the dibenzofuran compounds on partial cancer cells is shown in figure 4, and the time-effect and dose-effect relationship result on lung cancer A-549 is shown in figure 5.
After 72 hours, the diphenyl furan compound of the invention has IC to XWLC-05, A-549, MCF-7, HepG2, T-24, NCI-H157, NCI-H460 and CNE50(half inhibitory concentrations) were 0.525, 0.587, 0.862, 0.654, 0.723, 1.509, 1.151, 1.162. mu.g/ml, respectively.
2. Selective anticancer effect
Under the same dosage and test conditions, the growth inhibition and/or killing effect of the diphenyl furan compound on human normal vascular endothelial cell strains HUVEC and lung epithelial cell strains Beas-2b is lower than that on a plurality of human cancer cell strains. The inventive IC of diphenyl furan compound to Beas-2b50(half inhibitory concentrations) were 1.756. mu.g/ml, respectively, greater than half inhibitory concentrations on most human cancer cells (see FIG. 6).
3. Cell targeting anticancer effect
In vitro anticancer test results show that the inhibitory rates of the dibenzofuran compounds on different cancer cell strains are significantly different, and most people haveThe carcinoid cells are sensitive to the diphenyl furan compounds, and the in vitro anti-cancer effect of the diphenyl furan compounds has cell targeting. IC of different cancer cells50The difference (median inhibitory concentration) is large, wherein XWLC-05, A-549, HepG2, MCF-7 and T-24 are very sensitive to the diphenyl furan compound shown in the formula (I). The diphenyl furan compounds have cell targeting anticancer effect, and the results are shown in figure 4 and table 1.
4. The anticancer effect is superior to that of common clinical anticancer drugs
Under the same test conditions, the inhibitory action of the dibenzofuran compounds on the same cancer cell strains is remarkably stronger than that of cisplatin and 5-fluorouracil and better than that of taxol. IC of diphenyl furan compound on detected cancer cell strain50The values are all significantly higher than that of the clinical anticancer drugs cisplatin and 5-fluorouracil, and the results are shown in Table 1. Despite the IC of paclitaxel50The value is lower than that of the diphenyl furan compound, but the inhibition rate of paclitaxel on most cancer cell strains is not increased along with the increase of the dosage after reaching a certain height, while the inhibition rate of the diphenyl furan compound on cancer cells under higher dosage is higher than that of the paclitaxel under the same dosage, and the results are shown in table 2, figure 4 and figure 7.
TABLE 1 IC of dibenzofuran compounds, cisplatin, 5-fluorouracil and taxol on different cancer cell lines50Comparison (μ g/ml)
| Cancer cell line | Compounds of the invention | Cis-platinum | 5-Fluorouracil | Paclitaxel |
| A-549 | 0.587 | 2.018 | 4.796 | <0.01 |
| XWLC-05 | 0.525 | 1.365 | >10 | <0.01 |
| MCF-7 | 0.862 | 3.564 | ---- | 0.027 |
| NCI-H460 | 1.151 | 1.980 | ---- | 0.020 |
| HepG2 | 0.654 | 0.972 | 3.638 | <0.01 |
| CNE | 1.162 | 1.244 | >10 | ---- |
| T-24 | 0.723 | 1.654 | ---- | ---- |
Note: "- - - -" indicates that no experimental examination was performed and no data was obtained.
TABLE 2 comparison of the inhibition (%) of cancer cell lines by dibenzofuran compounds of the invention and paclitaxel
Note: "M" represents a dibenzofuran compound of the invention; "P" means Paclitaxel (Paclitaxel)
5. Combined action with clinical anticancer medicine
In vitro anticancer test results show that the diphenyl furan compound of the invention is combined with clinical anticancer drugs such as cisplatin, 5-fluorouracil, paclitaxel and the like, and has synergistic or additive anticancer effect on certain cancer cell strains. The diphenyl furan compound can be used as a sensitizing medicament or a combined medicament composition of clinical anticancer medicaments. For example, the in vitro inhibition effect of the combined application of the dibenzofuran compounds and the cisplatin DDP on the Xuanwei lung cancer XWLC-05 is shown in Table 3:
TABLE 3 inhibition of XWLC-05 by the combined use of dibenzofuran compounds of the invention and cisplatin
Note: the Q value is the combined coefficient of action. A Q value of <0.85 indicates that the two are antagonistic; q value is between 0.85 and 1.05, which indicates that the two have additive effect; a Q value >1.05 indicates a synergistic effect.
The squares in table 3 are non-combinatory groups and therefore have no Q value.
6. The inventive diphenyl furan compound can inhibit the growth of transplanted human tumor in animal body
The test method for the in vivo transplantation-resistant human tumor of the nude mice comprises the following steps: preparing HepG2 tumor cell sample by conventional tumor cell culture technology, collecting cells, washing twice with sterile PBS, and adjusting cell concentration to 1 × 10 with sterile FBS-free DMEM/F12 culture solution8Individual cells/ml. Balb/c nude mice (weighing 18-20g) acclimatized for 1 week were each inoculated with 0.1ml of cell suspension by subcutaneous aseptic manipulation on the right back. Nude mice were housed in the SPF laboratory. On day 12 after cell inoculation, most mice have macroscopically visible tumors subcutaneously, and the tumor volume reaches 100-3Left and right, the major diameter (a) and the transverse diameter (b) of the tumor of each tumor-bearing mouse were measured with an automatic reading vernier caliper, using the formula: v ═ a × b2Tumor volume was calculated for each mouse. Dividing tumor-bearing mice into a solvent control group, an anticancer drug cis-platinum positive control group and a test group of the dibenzofuran compound after layering according to tumor volume, wherein each group comprises 6 tumor-bearing mice. The diphenyl furan compound is prepared by using 8% mass spectrum pure DMSO, 12% castor oil polyoxyethylene ether (Cremophor EL) and 80% PBS as solvents (volume ratio), the administration dosage of a mouse is 10mg/kg, intraperitoneal injection administration is adopted, the solvents with the same volume are administered by virtue of intraperitoneal injection of a solvent control group mouse, cisplatin with the dosage of 3mg/kg is administered by virtue of intraperitoneal injection of a positive control group mouse, and the cisplatin is prepared by dissolving in sterile PBS. Mice were dosed starting on the day of grouping, 1 every other day, tumor volume and body weight were measured 1 time every 4 days, and general conditions of the animals were observed and recorded. After 16 times of administration, the weight of the mice was measured, the mice were sacrificed by dislocation after blood sampling, the tumor volume was measured, the tumor, liver, spleen, kidney, heart and testis were completely exfoliated, and the weights of the tumor and each organ were measured with a precision electronic scale.
The relative tumor proliferation rate RPR (%) at each time point was calculated according to the following formula: relative increment rate (%) ═ TRTV/CRTV×100,TRTVFor administration of the drugRelative volume of tumor, CRTVRelative tumor volume for the solvent control group, RTV ═ Vt/V0,V0Is the tumor volume at the time of group administration, VtTumor volume for each measurement.
Tumor weight inhibition was calculated according to the following formula: inhibition (%) - (average tumor weight in solvent control group-average tumor weight in administration group)/average tumor weight in solvent control group × 100
The organ coefficients were calculated as follows: organ coefficient is organ weight/body weight × 100
The relative volumes (RTV) of HepG2 tumor from the liver cancer at each time point are shown in FIG. 8. The tumor volume increasing rate of the animals with the dibenzofuran compound group shown in the formula (I) is obviously lower than that of the solvent control group and the positive medicament cis-platinum group.
The Relative Proliferation Rate (RPR) of HepG2 tumor at each time point is shown in FIG. 9. The national new drug standard, RPR < 60% is considered to have the in vivo anti-tumor effect. The RPR of the dibenzofuran compound group tumor shown in the formula (I) is lower than 60% after the first administration, and is reduced along with the increase of the administration times. The RPR significance of the dibenzofuran compound group tumor shown in the formula (I) at each time point is lower than that of a positive control group, and the growth inhibition effect on liver cancer HepG2 is stronger than that of cisplatin.
The Tumor Weight (TW) of each group at the end of the experiment is shown in FIG. 10. The tumor weight of the diphenyl furan compound group shown in the formula (I) is obviously lower than that of a solvent control group and a cis-platinum positive drug control group, which shows that the diphenyl furan compound shown in the formula (I) can inhibit the growth of tumors and has stronger effect than that of cisplatin.
Example 3: an anticancer action mechanism of a compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone shown as a formula (I)
1. Effect on the growth cycle of cancer cells
The cell culture assay is the same as the in vitro anti-cancer assay described above. After the liver cancer cell HepG2 is treated by the diphenyl furan compound shown in the formula (I) (the dose is 1.0 mu g/ml) for 48 hours, the cell cycle and the apoptosis condition are detected by a flow cytometer (FACS). The positive control group was cisplatin (DDP, 1.5. mu.g/ml) and 5-fluorouracil (5-Fu, 5.0. mu.g/ml). The results are shown in Table 4.
As a result: the dibenzofuran compounds shown in the formula (I) can obviously influence the differentiation and the cycle of cancer cells, block the cells in the G2/M stage, and reduce the cells in the G0/G1 stage and the S stage.
TABLE 4 Effect on cell cycle (HepG2 cells)
2. Effect on Gene expression in cancer cells
The cell culture assay is the same as the in vitro anti-cancer assay described above. The detection result of the gene chip of MCF-7 cells treated by the drug for 48 hours shows that the dibenzofuran compounds shown in the formula (I) can significantly influence the gene expression of the MCF-7 cancer cells, and 1525 obviously changed genes (the difference multiple is more than 1.5 times, p is less than 0.01) appear, wherein 210 mRNAs (the maximum value is 2.0491 times) are up-regulated, and 97 mRNAs (the maximum value is 3.6817 times) are down-regulated, which is shown in figure 11; up-regulated 421 ncRNA (3.7672-fold maximum) and down-regulated 797 ncRNA (3.3150-fold maximum), as shown in FIG. 12. The dibenzofuran compounds shown in the formula (I) can significantly affect 117 cell signal paths, wherein the first 20 cell signal paths are shown in Table 5. The cancers in which the dibenzofurans of formula (I) are affected by pathways in cancer pathway are shown in FIG. 13. Can significantly affect 432 functions of cancer cells and multiple metabolisms of cancer cells.
TABLE 5 significantly affected first 20 cell signaling pathways
Example 4: the toxicological safety of the compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1,3-dione
In the acute toxicity test, the test was carried out by the Kouyn method. Kunming mice are administrated by oral gavage. The diphenyl furan compound is dissolved into suspension by distilled water, and is administrated for 4 times within 8 hours, with 2 hours interval for each time. Close observation of animal toxicity after administrationAnd (4) performing a sexual reaction. When the highest dose group is administered with the total dose of 10g/kg, no obvious toxic reaction and death of the animals are observed within 24 hours. After the animals are continuously raised and observed for 14 days, the animals normally eat and drink water, normally gain weight, and have no death in each group. After the experiment, the animals were sacrificed and dissected, and no obvious organ abnormality was observed by visual observation. Acute toxicity test results show that the diphenyl furan compound oral gavage LD50>10g/kg, and classified according to acute toxicity, the diphenyl furan compound belongs to nontoxic class.
In a 32-day short-term repeated administration test, 8% mass spectrum pure DMSO, 12% castor oil polyoxyethylene ether (Cremophor EL) and 80% PBS are used as solvents for preparation (volume ratio), the administration dose of a mouse is 10mg/kg, and intraperitoneal injection is adopted for administration; the mice in the solvent control group are injected with the solvent with the same volume, the mice in the positive control group are injected with the cisplatin with the dose of 3mg/kg, and the cisplatin is dissolved in PBS. The administration is 1 time every other day, and 16 times in total. And (5) taking blood at the end of the test to carry out blood routine and blood biochemical index detection. No significant abnormal toxicity profile was seen in the animals during the administration period, no significant adverse effects were found in the blood tests on the hematopoietic system, liver function, and kidney function of the animals (see tables 6 and 7), and also significant increases in the levels of total serum protein and albumin were noted. In the administration process, the mice with the dibenzofuran compounds have normal food intake and water drinking. Compared with a solvent control group, the dibenzofuran compound has no significant influence on the weight increase and the development of main organs of animals (see fig. 14 and 15).
TABLE 6 Biochemical index of blood
P <0.05 compared to solvent control
TABLE 7 blood general indices
P <0.05 compared to solvent control
Example 6:
dissolving a compound 6-acetyl-2- (1-amino-ethylidene) -7,9-dihydroxy-8,9b-dimethyl-9 bH-diphenyl furan-1, 3-diketone shown in the formula (I) in a small amount of DMSO, adding castor oil polyoxyethylene ether (cremophor EL) or other cosolvents allowed by medicaments, adding physiological saline, finely filtering, encapsulating and sterilizing to prepare a clear injection. DMSO, DMSO: castor oil polyoxyethylene ether: the volume ratio of the normal saline is 8:10:82, and the final concentration of the diphenyl furan compound is 1-5 mg/ml.
Example 7
Adding excipient into the diphenyl furan compound shown in the formula (I) according to the required proportion and dosage requirement of the preparation, granulating and tabletting to prepare tablets.
Example 8
The diphenyl furan compound shown in the formula (I) can be directly packaged into capsules of various specifications according to the requirement of the administration dosage.
Example 9
The diphenyl furan compound shown in the formula (I) can be dissolved in edible vegetable oil, and can be dissolved into clear liquid to prepare soft capsules by adopting the edible vegetable oil as a solvent according to the requirements of solubility and administration dosage.
Example 10
The diphenyl furan compound shown in the formula (I) is prepared into oral liquid according to a conventional oral liquid preparation method.
Example 11
Adding excipient into the dibenzofuran compound shown in formula (I) according to the required proportion of the preparation, and preparing into granules or medicinal granules.
Example 12
The diphenyl furan compound shown in the formula (I) is added with food or other carriers according to the required proportion of the product to prepare health products or other functional products.
Example 13
The diphenyl furan compound shown in the formula (I) is mixed with other antitumor drugs in proportion according to the treatment requirement to prepare various preparations, or is temporarily combined for application in clinical use to form a combined antitumor drug composition.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (6)
1. A preparation method of diphenyl furan compounds, the structural formula of which is shown in formula (I),
formula (I); the method is characterized by comprising the following steps:
according to the following reaction formula, dextro-lichenin and hexamethyldisilazane are taken as substrates, and amination synthesis reaction is carried out in an organic solvent medium at room temperature to prepare the diphenyl furan compound shown in the formula (I);
2. the method for preparing dibenzofuran compounds of claim 1, wherein the organic solvent is chloroform, ethyl acetate, acetone, methanol or ethanol.
3. The method for producing dibenzofuran compounds of claim 1, wherein the molar ratio of dextro-usnic acid to hexamethyldisilazane is 1: 1.7-2.1; the mass ratio of the volume of the used organic solvent to the dextro-rotatory coating acid is 5-6:1 mL/g.
4. The method for preparing the dibenzofuran compound of claim 1, wherein the method comprises the following steps: adding dextro-lichenin into an organic solvent, sufficiently shaking at room temperature to form a suspension state, adding hexamethyldisilazane, continuously shaking until the reaction solution appears unchanged by naked eyes, standing for more than 10h, and purifying the obtained product to obtain the diphenyl furan compound shown in the formula (I).
5. The method for preparing dibenzofuran compounds of claim 4, wherein the purification of the obtained product comprises the following steps: and filtering or evaporating the reaction solution to dryness, and purifying the obtained filter residue or evaporated substance by adopting a washing or column chromatography separation method.
6. The method for producing a dibenzofuran compound of claim 5, wherein the solvent used for washing is chloroform or methanol; the elution solvent adopted by the column chromatography separation is a mixed solvent of ethyl acetate and acetone in a volume ratio of 100:1, or pure chloroform.
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| Chemistry of hexarnethyldisilazane. SiEylation of P-diketones and amination of P-triketones;DANIELT. W. CHU，et al;《CAN. J. CHEM.》;19801231;第58卷;第138-142页 * |
| 于学龙.长松萝的化学成分及其生物活性研究.《中国优秀硕士学位论文全文数据库 医药卫生科技辑》.2016,(第08期),第E057-121页. * |
| 长松萝的化学成分及其生物活性研究;于学龙;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20160716(第08期);第E057-121页 * |
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