CN110734429B - Usnea nicotinamide compound and preparation method and application thereof - Google Patents
Usnea nicotinamide compound and preparation method and application thereof Download PDFInfo
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- CN110734429B CN110734429B CN201911159723.5A CN201911159723A CN110734429B CN 110734429 B CN110734429 B CN 110734429B CN 201911159723 A CN201911159723 A CN 201911159723A CN 110734429 B CN110734429 B CN 110734429B
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Abstract
The invention relates to a preparation method and application of usnea nicotinamide 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 is characterized in that usnamine and nicotinic acid are used as substrates, N' -diisopropyl carbodiimide is used as a dehydrating agent and 4-dimethylamino pyridine is used as a catalyst in an organic solvent medium, and acylation reaction is carried out at room temperature to prepare the compound with remarkable anticancer activity. The synthesis method has the advantages of easily available raw materials, simple and quick steps and easy purification of products. The acute toxicity of the usnea/nicotinamide mouse after oral gavage is classified into non-toxic, and the toxicity is tested on the survival, weight increase, organ development of the animal,The liver and kidney tissues, blood biochemistry and blood routine indexes have no obvious toxicity. The compound has remarkable anti-tumor effect, can be used for preparing anti-tumor chemotherapeutic drugs and auxiliary anti-tumor health care products, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and relates to an usnea nicotinamide compound, a preparation method and an application thereof, wherein the structure of the compound is N- [1- (6-acetyl-7,9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9 b-dihydro-1H-diphenylfuran-2-ethyl) -ethyl]-isonicotinamide (English structure name: N- [1- (6-ethyl-7, 9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9b-dihydro-1H-dibenzofuran-2-yliden) -ethyl]-isonicoyinamide) of formula C24H20N2O7And a molecular weight of 448.
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 published by Globocan of the international cancer institute of the world health organization show that 1266.1 ten thousand new cancer cases and 756.4 ten thousand deaths occur worldwide in 2008. In 2012, the number of newly added cancer cases is 1410 ten thousand, the death is 820 ten thousand, and 3260 thousands of people live with tumors. In 2015, 1750 ten thousand new cancer cases and 870 ten thousand deaths occur worldwide. 2008. Cancer morbidity and mortality present an increasing trend compared to 2012 and 2015. The number of new cancer cases worldwide will reach 1900 ten thousand in 2025 years and 2400 ten thousand in 2035 years. 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 disadvantages of great toxic and side effects, uncertain curative effect and selectivityPoor targeting, weak cancer cell resistance and the like, so that the clinical application and effect of cancer chemical drug therapy 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. Our earlier studies found that usnamine (C)18H17NO6) Has strong in vitro and in vivo anticancer activity and has important application prospect in the aspect of the development of chemotherapy drugs for cancer. Whether the usnamine can be structurally modified to form a new compound with anticancer activity or not has important value for research and development of new anticancer drugs.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an usnea nicotinamide anticancer active compound and a preparation method and application thereof. The structure of the compound is N- [1- (6-acetyl-7,9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9 b-dihydro-1H-diphenyl furan-2-ethyl) -ethyl ] -isonicotinamide, and the chemical synthesis method has the advantages of easily obtained raw materials, simple and rapid synthesis steps, easy purification of products, higher 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 and health products for adjuvant anti-tumor.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
an usnea nicotinamide compound, the structural formula of which is shown in formula (I),
the name of Chinese is: usnea nicotinamide. The Chinese structural formula is: n- [1- (6-acetyl-7,9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9 b-dihydro-1H-diphenylfuran-2-ethyl) -ethyl]-isonicotinamide. The English name is: usenicoyinamide. The English structural formula is named as: n- [1- (6-ethyl-7, 9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9b-dihydro-1H-dibenzofuran-2-yliden) -et-hydroxy-isonicoyinamide. Light yellow solid powder with molecular formula of C24H20N2O7And a molecular weight of 448.
A preparation method of usnea nicotinamide compound comprises the following steps:
according to the following reaction formula, using usnamine (C)18H17NO6) With nicotinic acid (C)6H5NO2) Performing acylation synthesis reaction in an organic solvent medium under the action of a N, N' -Diisopropylcarbodiimide (DIC) (CAS:693-13-0) dehydrating agent and a 4-Dimethylaminopyridine (DMAP) (CAS:1122-58-3) catalyst at room temperature to obtain the usnamide compound shown in the formula (I). The usnamine and isonicotinic acid can not form usnic acid amide under the same condition, and can not perform acylation reaction or reaction products have no obvious anticancer activity with organic acids such as ascorbic acid, benzoic acid, o-methylbenzoic acid, 3-phenylpropionic acid, cinnamic acid and the like under the same condition.
Further, it is preferable that the organic solvent is dichloromethane.
Further, the mol ratio of the usnamine to the nicotinic acid is preferably 1: 1-2; the volume ratio of the organic solvent to the usnamine is 5000ml:1-2 mol.
Further, preferably, the specific steps are as follows: adding usnamine into an organic solvent, fully shaking and carrying out ultrasound for 10min at room temperature, then sequentially adding nicotinic acid, DIC and DMAP, shaking and stirring, standing at room temperature for 48-96 h, then adding 0.5-1% of water (volume ratio) to neutralize unreacted DIC (stirring for 30min), filtering, evaporating the solvent to dryness, and then purifying the obtained product to obtain the usnea amide compound shown in the formula (I).
Further, preferably, the specific steps of purifying the obtained product are as follows: and (3) evaporating the filtrate obtained after the reaction solution is filtered to dryness, and repeatedly washing the obtained evaporated substance by using an organic solvent for purification.
The purification method comprises the following specific steps: filtering the reaction solution, evaporating the organic solvent in the filtrate, adding the organic solvent for purification, fully stirring, standing for precipitation, discarding the supernatant, repeating for multiple times, filtering again, washing the filter residue with the organic solvent for purification, tracking and detecting by TLC (developing agent V (trichloromethane): V (acetone): 20:1) under an ultraviolet lamp of 254nm for observing the existence of other impurities, developing with sulfuric acid for further observing the existence of impurity points, and when the impurity points do not exist, completing the purification.
Further, it is preferable that the organic solvent for purification used in the washing purification is ethanol or methanol.
The invention also provides application of the usnea nicotinamide compound in preparation of antitumor drugs or auxiliary antitumor health-care products.
Further, preferably, the pharmaceutical dosage form is injection, tablet, capsule, soft capsule, oral liquid, granule or electuary. In the medicine, the effective amount of the usnea nicotinamide compound can be 0.1-100%, preferably 0.5-95%, and more preferably 10-90% of the weight of the medicine.
The dosage form of the auxiliary anti-tumor health product is as follows: tablet, oral liquid, capsule, soft capsule, granule or granule.
Further, preferably, the tumor is any one of the following human tumors: gastric cancer, colorectal cancer, esophageal cancer, lung cancer, liver cancer, nasopharyngeal cancer, glioma, breast cancer, bladder cancer, cervical cancer, skin cancer, kidney cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, endometrial cancer, leukemia, lymphoma, sarcoma, prostate cancer.
The DMAP is 4-Dimethylaminopyridine (4-dimethylamino pyridine), and the DIC is N, N '-Diisopropylcarbodiimide (N, N' -diamipropylcarbodiimide).
Compared with the prior art, the invention has the beneficial effects that:
the compound N- [1- (6-Acetyl-7,9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9 b-dihydro-1H-diphenyl furan-2-ethyl) -ethyl ] -isonicotinamide (English structure name: N- [1- (6-Acetyl-7,9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9b-dihydro-1H-dibenzofuran-2-yliden) -ethyl ] -isonicotinamide with the structure of the formula (I) is a new structure compound and can be artificially 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 and high yield.
The compound of the invention is used for preparing anti-tumor chemotherapeutic drugs and health products for assisting anti-tumor. The usnea nicotinamide can remarkably kill and/or inhibit various human tumor cells in vitro, such as gastric cancer cell SGC-7901, colon cancer cell HCT-116, esophageal cancer cell CaEs-17, nasopharyngeal cancer cell CNE2, glioma cell U-251, Xuanwei lung cancer cell XWLC-05, non-small cell lung cancer cell A-549, lung cancer SPC-A1, lung cancer NCI-H460, lung cancer NCI-H157, breast cancer cell MCF-7 and MDA-MB-231, bladder cancer cell T-24, cervical cancer cell Hela, leukemia cell K-562, lymphoma L-428 and BJAB, liver cancer cell QGY-7703 and HepG2, bile duct cancer cell QBC-939, prostate cancer cell PC-3, kidney cancer cell ACHN, ovarian cancer SKOV-3, endometrial cancer-952, pancreatic cancer PANC-1-952, pancreatic cancer cell PANC-1, Melanoma A-375, and the like. The in vitro anti-tumor effect of the usnea nicotinamide compound is superior to that of common clinical anti-tumor drugs such as cisplatin, 5-fluorouracil and the like.
The usnea nicotinamide compound can remarkably promote the apoptosis of tumor cells, influence the growth cycle distribution of the tumor cells and reduce the migration and invasion capacity of the tumor cells.
In the mouse oral acute toxicity test of the usnamide compound, no obvious toxicity to animals is found when the maximum gavage dose is 15g/kg, and the acute toxicity is classified into non-toxic. The usnea nicotinamide compound is repeatedly administrated for 30 days in a short period under the dosage of 0.625, 1.25 and 2.5g/kg, and has no significant adverse effect on mouse survival, weight increase, organ development, liver and kidney tissues, blood biochemistry and blood conventional indexes; the usnea nicotinamide compounds of the invention showed no genotoxicity at the tested doses.
Usnamines are known compounds and are almost insoluble in water. The usnic nicotinamide of the invention is a compound with a new structure; the chemical polarity of the compound is greater than that of usnamine; the solubility in aqueous methanol and aqueous ethanol is higher than that of usnamine; when the nano liposome medicine is prepared, the drug loading capacity of the liposome is obviously larger than that of usnamine.
Drawings
FIG. 1 is a mass spectrum of usnamide compounds;
FIG. 2 is a nuclear magnetic hydrogen spectrum of usnamide compounds;
FIG. 3 is a nuclear magnetic carbon spectrum and DEPT spectrum of usnea amide compound;
FIG. 4 is a dose-effect relationship curve diagram of the in vitro anti-tumor effect of usnea nicotinamide compound on part of human tumor cell lines (the abscissa is the dose of the compound);
FIG. 5 is a graph showing the time-effect and dose-effect relationship of the anti-tumor effect of usnamide compounds in vitro (the abscissa represents the dose of the compound);
FIG. 6 is a graph of the effect of usnamide compounds on apoptosis of cancer cells;
FIG. 7 is a graph of the effect of usnamide compounds on the distribution of the cancer cell cycle;
FIG. 8 is a graph showing the effect of usnamide compounds on cancer cell invasion and migration;
FIG. 9 shows the body weight changes of male mice at various time points of the short-term repeat dosing test;
FIG. 10 is a graph of the change in body weight of female mice at various time points of a short-term repeat dosing trial;
fig. 11 shows organ coefficients of each group of 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 materials or equipment used are not indicated by manufacturers, and all are 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 usnea amide compound of the present invention can be produced by artificial synthesis in a chemical reaction form using other chemical substrates as raw materials.
The term "pharmaceutical dosage form" as used herein refers to different pharmaceutical preparations prepared from the usnea amide compound of the present invention in different "pharmaceutically acceptable carriers".
As used herein, "pharmaceutical composition" refers to a formulation of the usnamide compounds of the present invention, used in conjunction with a vehicle commonly accepted in the art for delivery of biologically active compounds to mammals such as humans. 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 "treatment" means administration of the usnea amide compound or the formulation of the present 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 invention discloses an usnea nicotinamide compound: chemical synthesis and structural identification of N- [1- (6-Acetyl-7,9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9 b-dihydro-1H-diphenylfuran-2-ethyl) -ethyl ] -isonicotinamide (English name: N- [1- (6-Acetyl-7,9-dihydroxy-8,9-dimethyl-1,3-dioxo-3,9b-dihydro-1H-dibenzofuran-2-yliden) -ethyl ] -isonicotinoylamide).
Adopts usnamine (C)18H17NO6) With nicotinic acid (C)6H5NO2) As a substrate, a chemical synthesis reaction is carried out in an organic solvent medium under the action of a dehydrating agent DIC and a catalyst DMAP. The results of orthogonal experiments show that the concentration of usnamine in methylene chloride solvent is as follows: niacin 1:1.5 (molar ratio), usnamine: DMAP ═ 1:0.2 (molar ratio), usnamine: DIC is 1:0.1 (molar ratio), the reaction is carried out at room temperature, the reaction time is 96 hours, the product yield is high, impurities are few, and the purification is easy. The yield of the product in other organic solvent media is low or no usnic nicotinamide can be formed, or a plurality of impurity byproducts are formed. Under the same conditions, usnamine and isonicotinic acid can not react to form usnic nicotinamide, and can not perform acylation reaction with other organic acids or form a product with anticancer activity. The mol ratio of the usnamine to the nicotinic acid is preferably 1: 1-2; the preferable proportion of the usage amount of the organic solvent (ml) and the usnamine (mol) is 5000ml:1-2 mol; usnamine: DMAP ═ 1:0.1-0.2 (molar ratio), usnamine: DIC is 1:0.1 to 0.2 (molar ratio), and the reaction is carried out at room temperature, preferably for 48 to 96 hours.
The specific synthesis steps are as follows:
1. chemical synthesis and purification
34.3g of usnamine with the purity of 99.8 percent is put into a 1000ml reaction bottle, 500ml of dichloromethane is added, the mixture is shaken fully and mixed evenly and is subjected to ultrasonic treatment for 10min at room temperature, then 18.5g of analytically pure nicotinic acid (the molar ratio is 1:1.5), 1.3g of DIC and 1.2g of DMAP are added, the mixture is stirred for about 5 minutes and is kept stand at room temperature for reaction for 96 hours. The reaction solution was filtered through a filter paper, and the filter residue was rinsed dropwise with 100ml of analytical dichloromethane. And combining the filtrates, and volatilizing the solvent by using a rotary evaporator to obtain the usnea nicotinamide compound product. Suspending the product with a small amount of methanol (or ethanol), standing for precipitation, removing supernatant, washing the precipitate repeatedly, filtering and purifying. The product yield is more than 30 percent, and the purity is more than 99.8 percent.
2. Structural identification
A mass spectrum of the compound usnic nicotinamide (shown in figure 1);
nuclear magnetic hydrogen spectrum of compound usnic acid amide (as shown in figure 2);
nuclear magnetic carbon spectrum and DEPT spectrum of compound usnitamide (shown in figure 3).
ESI(+)MS:449(M+H)+,471(M+Na)+，487(M+K)+，919(2M+Na)+。
1H NMR(500MHz,CDCl3)δ12.12(s,1H),11.97(s,1H),9.40(s,1H),8.90(d,J＝4.3Hz,1H),8.56(d,J＝8.0Hz,1H),7.59(dd,J＝7.9,5.1Hz,1H),7.06(d,J＝15.1Hz,1H),5.78(s,1H),2.60(s,3H),2.46(s,3H),2.09(s,4H),1.73(s,4H)。
13C NMR(126MHz,CDCl3)δ197.96(C),194.17(C),190.20(C),175.41(C),173.64(C),163.91(C),156.25(C),155.31(C),152.59(CH),150.33(CH),148.83(C),139.13(CH),126.10(C),124.16(CH),116.42(C),113.15(C),108.65(C),102.79(CH),101.57(C),56.89(C),32.61(CH3),31.69(CH3),26.07(CH3),8.83(CH3)。
Example 2:
an usnea nicotinamide compound, the structural formula of the usnea nicotinamide is shown as a formula (I),
the preparation method of the usnea nicotinamide compound comprises the following steps:
adding usnamine into an organic solvent, fully shaking, performing ultrasonic treatment at room temperature for 10min, sequentially adding nicotinic acid, DIC and DMAP, stirring, standing at room temperature for 48h, adding distilled water, stirring for 30min to fully neutralize unreacted DIC, and purifying a reaction product to obtain the usnea amide compound shown in the formula (I). The reaction formula is as follows:
wherein the molar ratio of usnamine to nicotinic acid is 1: 1; the volume of the used organic solvent and the usnamine are in a ratio of 5000ml to 1.5 mol; the molar ratio of usnamine to DMAP was 1: 0.15.
And (3) evaporating the filtrate obtained after the reaction solution is filtered to dryness, and repeatedly washing the obtained evaporated substance by using ethanol for purification.
Example 3:
an usnea nicotinamide compound, the structural formula of the usnea nicotinamide is shown as a formula (I),
the preparation method of the usnea nicotinamide compound comprises the following steps:
adding usnamine into an organic solvent, fully shaking, performing ultrasonic treatment at room temperature for 10min, sequentially adding nicotinic acid, DIC and DMAP, stirring, standing at room temperature for reaction for 60 h, adding distilled water, stirring for 30min to fully neutralize unreacted DIC, and purifying a reaction product to obtain the usnea amide compound shown in the formula (I). The reaction formula is as follows:
wherein the molar ratio of the usnamine to the nicotinic acid is 1: 2; the volume of the organic solvent and the usnamine are in a ratio of 5000ml to 2 mol; the molar ratio of usnamine to DMAP was 1: 0.2.
The filtrate after the reaction solution was filtered was evaporated to dryness, and the resulting evaporated material was purified by repeatedly washing with methanol.
Example 4:
the following part of specific experimental examples shows that the usnea nicotinamide compound of the formula (I) has significant and cell-targeted anti-tumor effects.
1. The usnea nicotinamide compound of the invention has the functions of inhibiting and killing human cancer cells in vitro:
in vitro anti-tumor assay methods: the usnea nicotinamide compound is dissolved in analytically pure DMSO, and the preparation concentration is 0, 0.625, 1.25, 2.5, 5.0 and 10.0 mmol/L. 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 (cancer cell density is 5-6 × 10 per well)3Cell density of 1X 10 cells per well, breast cancer MCF-74Individual 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 culture plates is sucked, and then 200 mul of culture medium containing the usnea nicotinamide compound of the invention with corresponding concentration is respectively added according to the design (1 mul of the prepared usnea nicotinamide compound solution of the invention is added in each ml of culture medium, and the final test concentration of usnea nicotinamide is 0.625, 1.25, 2.5, 5.0 and 10.0 mul/l). A DMSO solvent control and an anti-cancer drug positive control (cisplatin, PBS dissolved, using concentration of 2. mu.g/ml) were also set, and each concentration and control group were made into 3 groups in parallel. The cells are put at 37 ℃ and 5% CO after the medicine is added2Continuously 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 usnea nicotinamide compound and the dose-effect relation of each time point, and calculating the half Inhibitory Concentration (IC) by adopting SPSS software50) Statistically analyzing the significant difference. 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 for solvent control-corrected OD value for usnea amide compound group of the present invention)/corrected OD value for 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 usnic nicotinamide has obvious in-vitro anti-cancer effect on human cancer cell strains such as human gastric cancer cell SGC-7901, liver cancer HepG2, human glioma cell U-251, human colon cancer cell HCT-116, nasopharyngeal cancer cell CNE2, lung cancer cell SPC-A1, non-small cell lung cancer cell A-549, Xuanwei lung cancer cell XWLC-05 and the like, and the in-vitro anti-cancer effect has obvious dose-effect and/or time-effect relation. In an in vitro anticancer activity screening test, after cancer cells are treated by the compound shown in the formula (I) for 72 hours, under a microscope, the compound also has very obvious in vitro inhibition or killing effects on human cervical cancer cells Hela, human leukemia cells K-562, lymphoma cells L-428 and BJAB, lung cancer cells NCI-H460 and NCI-H157, liver cancer cells QGY-7703, esophageal cancer cells CaEs-17, breast cancer cells MCF-7 and MDA-MB-231, bladder cancer cells T-24, human bile duct cancer cells QBC-939, human prostate cancer cells PC-3, human renal cancer cells ACHN, human ovarian cancer cells SKOV-3, endometrial cancer RL-952, human pancreatic cancer PANC-1, melanoma cells A-375 and the like. The in vitro anticancer dose-effect relationship of the usnea nicotinamide compound on partial cancer cells is shown in figure 4, and the time-effect and dose-effect relationship result on in vitro anticancer of gastric cancer SGC-7901 is shown in figure 5.
2. Cell targeting anticancer effect
In vitro anticancer test results show that the inhibition rates of the usnea nicotinamide compound of the invention on different cancer cell strains are obviously different, most human cancer cells are sensitive to the usnea nicotinamide compound of the invention, and the in vitro anticancer effect of the usnea nicotinamide compound of the invention has cell targeting. IC of different cancer cells50(half inhibitory concentration) difference is large, and 72 hours later, the usnea oil amide compound of the invention has IC of SGC-7901, HepG2, CNE2, HCT-116, U-251, SPC-A1, A-549 and XWLC-0550The (median inhibitory concentration) was 1.736, 1.775, 1.934, 1.680, 2.146, 0.723 and 1.509. mu. mol/L. The usnea nicotinamide compound has a cell targeting anticancer effect.
3. The anticancer effect of the usnea nicotinamide is superior to that of common clinical anticancer drugs
Under the same test conditions, the inhibition effect of the usnea nicotinamide compound on the same cancer cell line is remarkably stronger than that of cisplatin and 5-fluorouracil. IC of usnea nicotinamide compound on detected cancer cell strain50The values are all significantly lower than that of cisplatin and 5-fluorouracil which are clinical anticancer drugs, and the results are shown in table 1.
TABLE 1 IC of usnea nicotinamide compound of the invention, cisplatin, 5-fluorouracil on different cancer cell lines50Comparison (μ g/ml)
| Cancer cell line | Usnea nicotinamide | Cis-platinum | 5-Fluorouracil |
| A-549 | 1.31 | 6.73 | 36.89 |
| XWLC-05 | 1.17 | 4.55 | >80 |
| HepG2 | 1.77 | 3.24 | 27.98 |
| CNE2 | 3.63 | 4.15 | >80 |
| HCT-116 | 4.28 | 5.51 | ---- |
| U-251 | 4.44 | ---- | >80 |
Note: "- - - -" indicates that no experimental examination was performed and no data was obtained.
Example 5:
the anticancer action mechanism of the compound usnic acid amide shown in the formula (I) is demonstrated by the following part of specific experimental examples.
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 stomach cancer cells SGC-7901 are treated by usnamide compounds shown in formula (I) (the dosage is 0, 1.25, 2.5 and 5.0 mu mol) for 48 hours, the apoptosis condition is detected by a flow cytometer (FACS). The apoptosis rates (Q2+ Q4) of the groups were 6.79%, 8.06%, 23.62% and 37.00%, respectively, and the cancer cell apoptosis rate of the drug-treated group was significantly increased and had a concentration-effect relationship, and the results are shown in fig. 6. After stomach cancer cells SGC-7901 are treated with usnea nicotinamide compound shown in formula (I) (dosage is 0, 2.5, 5.0 and 10.0 mu mol) for 48h, cell distribution cycle is detected by flow cytometry (FACS). The cycle distribution of each group of cells is shown in table 2 and fig. 7.
As a result: the usnea nicotinamide compound shown in the formula (I) can obviously influence the differentiation and the cycle of cancer cells, block the cells in the S phase, reduce the cells in the G1 phase, and has a concentration-effect relationship.
TABLE 2 different cell cycle percentages for groups SGC 7901: (
n＝3).
Note: denotes p <0.05 compared to solvent control; indicates p <0.01 compared to solvent control.
2. Effect on migration and invasion of SGC7901 cells
Compared with a solvent control group, the usnic acid amide with the concentration of 2.5, 5 and 10 mu mol/L can obviously reduce the invasion and migration capacity of SGC-7901 gastric cancer cells. The scratch of the solvent control group becomes narrow, SGC-7901 cells migrate to the middle of the scratch area towards the inside of the scratch, and the scratch gaps of the drug groups of 2.5, 5 and 10 mu mol/L are obviously wider than those of the control group. The results are shown in FIG. 8.
Example 6:
the toxicological safety of usnic acid amide, a compound of formula (I), is demonstrated below by a partial illustration of specific experiments.
1. Acute toxicity test
In the acute toxicity test, the test was carried out by the Kouyn method. Kunming mice are administrated by oral gavage. The usnea nicotinamide compound is dissolved into suspension (mass percentage concentration) by 0.5 percent sodium carboxymethyl cellulose solution, and is administrated for 4 times within 24 hours, and the interval between every two times is 6 hours. The animals were closely observed for toxic reactions after dosing. When the highest dose group is administered with the total dose of 15g/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 when the maximum gavage dosage of the usnea nicotinamide compound through oral gavage is 15g/kg, animals do not have any toxic reaction, and the usnea nicotinamide compound through oral acute toxicity tests belong to non-toxic classes according to acute toxicity grading.
2. Short term repeat dosing test
In a short-term repeated administration test of 30 days, the usnea nicotinamide compound is dissolved into a suspension by a sodium carboxymethylcellulose solution with the mass percentage concentration of 0.5 percent, and oral gavage administration is adopted; the dose for each administration was 0.625, 1.25 and 2.5g/kg, respectively. The preparation is administered by gavage for 1 time and 30 times (the same amount of sodium carboxymethylcellulose solution with a mass percentage concentration of 0.5% as that of the control group). Observing whether the animals have obvious toxic reaction during the test period, and regularly measuring the weight and the feed consumption of the animals; at the end of the test, after measuring the weight, taking blood to carry out blood routine and blood biochemical index detection, dissecting and observing the organ condition, stripping the liver, the kidney, the spleen and the testis, weighing, and calculating the coefficient of each organ. The liver and kidney of the high dose group and negative control group animals were extracted for pathological section examination. As a result: no animal death occurs during the administration period, no obvious abnormal toxicity is shown in the animal, no significant adverse effect is found on the hematopoietic system, the liver function and the kidney function of the animal in blood test, and the blood sugar and the blood fat level of the animal are not influenced. In the administration process, mice with the usnea nicotinamide compound group eat and drink water normally. Compared with a negative control group, the usnea nicotinamide compound has no significant influence on the weight increase and the development of main organs of animals (see fig. 9, 10 and 11), and no obvious abnormal pathological changes are seen in liver and kidney tissue sections.
Example 7:
the solubility of usnic acid amide, a compound represented by formula (I), is illustrated below by a part of specific experimental examples.
TABLE 5 solubility comparison of usnic acid amide and usnamine in different solutions (mg/ml)
Note: n (usnic nicotinamide), M (usnamine)
Therefore, the solubility of usnic nicotinamide in analytically pure methanol and absolute ethanol is lower than that of usnic amine; but the solubility of the usnic nicotinamide in the water-containing alcohol is obviously higher than that of the usnic amine, which shows that the solubility of the usnic nicotinamide in the water is increased compared with that of the usnic amine after structural modification. The results of TLC also showed that the polarity of the usnic nicotinamide, the product after structural modification, was more polar than usnamine.
Example 8
0.5g of usnea nicotinamide, 4.0g of soybean phospholipid and 0.8g of cholesterol which are compounds shown in the formula (I) are dissolved in 30ml of ethyl acetate, and then the organic solvent is evaporated by a rotary evaporator to form a film on a rotary bottle. Blowing off residual organic solvent gas in the bottle by using a blower, adding 50ml of normal saline, fully washing the membrane, carrying out common ultrasonic treatment for 30 minutes, and carrying out ultrasonic treatment for 3 times by using an ultrasonic crusher on ice bath for 5 minutes/time. Coarse filtering with 1000nm filter head to obtain nanometer oral liquid; filtering with 450nm filter head, filtering with 220nm sterile filter head, and making into nanometer injection. The drug-loading rate of usnic acid amide in the nano oral liquid can reach 6-8 mg/ml; the drug-loading rate of usnea nicotinamide in the nano injection can reach 3-6 mg/ml.
Example 9
Dissolving usnea nicotinamide shown in formula (I) in a small amount of DMSO, adding castor oil polyoxyethylene ether (cremophor EL) or other pharmaceutically acceptable cosolvent, adding normal saline, fine filtering, bottling, and sterilizing to obtain clear injection. DMSO, DMSO: castor oil polyoxyethylene ether: the volume ratio of the normal saline is 10:10:80, and the final concentration of the usnea nicotinamide compound is 1-5 mg/ml.
Example 10
Adding excipient into usnea nicotinamide compound shown in formula (I) according to the required proportion and dosage requirement of the preparation, granulating, and tabletting to obtain tablets.
Example 11
The usnea nicotinamide compound shown in the formula (I) can be directly packaged into capsules of various specifications according to the requirement of administration dosage.
Example 12
The usnea nicotinamide compound shown in the formula (I) can be partially dissolved in edible vegetable oil, and can be dissolved and filtered 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 13
The usnea nicotinamide compound shown in the formula (I) is prepared into oral liquid according to a conventional oral liquid preparation method.
Example 14
Adding excipient into usnamide compound shown in formula (I) according to the required proportion of the preparation, and preparing into granules or medicinal granules.
Example 15
Adding food or other carriers into the usnea nicotinamide compound shown in the formula (I) according to the required proportion of the product to prepare a health-care product or other functional products.
Example 16
The usnea nicotinamide compound shown in the formula (I) is mixed with other antitumor drugs in proportion according to treatment needs 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 (10)
1. An usnea nicotinamide compound is characterized in that the usnea nicotinamide has a structural formula shown in a formula (I),
2. the method for preparing the usnea amide compound of claim 1, comprising the steps of:
carrying out acylation synthesis reaction at room temperature by using usnamine and nicotinic acid as substrates, DIC as a dehydrating agent and DMAP as a catalyst in an organic solvent medium to obtain an usnamide compound shown in the formula (I); the reaction formula is as follows:
3. the method for preparing usnea amide compounds according to claim 2, wherein the organic solvent is dichloromethane.
4. The method for preparing usnea amide compounds according to claim 2, wherein the molar ratio of usnamine to nicotinic acid is 1: 1-2; the ratio of the volume of the organic solvent to the usnamine is 5000ml to 1-2 mol.
5. The preparation method of the usnea amide compound according to claim 2, comprising the following steps: adding usnamine into an organic solvent, fully shaking, performing ultrasonic treatment at room temperature for 10min, sequentially adding nicotinic acid, DIC and DMAP, stirring, standing at room temperature for 48-96 h, adding distilled water, stirring to fully neutralize unreacted DIC, and purifying a reaction product to obtain the usnic amide compound shown in the formula (I).
6. The method for preparing usnic acid amide according to claim 5, wherein the step of purifying the obtained reaction product comprises: and (3) evaporating the filtrate obtained after the reaction solution is filtered to dryness, and repeatedly washing the obtained evaporated substance by using an organic solvent for purification.
7. The method of claim 6, wherein the organic solvent used for the purification of the reaction product is ethanol or methanol.
8. The use of the usnic acid amide compound of claim 1 in the preparation of an antitumor drug.
9. The use of usnic acid amide compound according to claim 8 in the preparation of antitumor drugs, wherein the drug is in the form of injection, tablet, capsule, oral liquid or granule.
10. The use of usnic acid amide compounds according to claim 8 in the preparation of antitumor drugs, wherein the tumor is any one of the following human tumors: gastric cancer, colorectal cancer, esophageal cancer, lung cancer, liver cancer, nasopharyngeal cancer, glioma, breast cancer, bladder cancer, cervical cancer, kidney cancer, bile duct cancer, pancreatic cancer, ovarian cancer, endometrial cancer, leukemia, lymphoma, skin cancer and prostate cancer.
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