CN113304151A - Application of nitrofuran small-molecular compound in preparation of drug for inducing iron death and/or slowing down chemotherapy drug resistance of gastric cancer - Google Patents
Application of nitrofuran small-molecular compound in preparation of drug for inducing iron death and/or slowing down chemotherapy drug resistance of gastric cancer Download PDFInfo
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Abstract
The invention discloses application of a nitrofuran micromolecule compound in preparation of a medicament for inducing iron death and/or relieving chemotherapy drug resistance of gastric cancer. The nitrofuran micromolecule compound has a structure shown as a formula (I):
the nitrofuran micromolecule compound provided by the invention has a good effect of inducing iron death (especially gastric cancer iron death), also has a function of reversing gastric cancer drug resistance, and has wide application in preparing drugs for inducing iron death and drugs for slowing down gastric cancer chemotherapy drug resistance.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to application of a nitrofuran small molecular compound in preparation of medicines for inducing iron death and/or relieving gastric cancer chemotherapy drug resistance.
Background
Gastric cancer is the fifth largest malignancy and also the leading cause of cancer-related death worldwide. China is a country with high incidence of gastric cancer, the number of new gastric cancer cases is about 67.9 ten thousand in 2015, and the number of death cases is about 49.8 ten thousand. The disease burden of gastric cancer is heavy in China, the prognosis is poor, the life and health of people are seriously threatened, and the method is the key point of tumor prevention and treatment. Gastric cancer patients often have a late diagnosis, often in the late stage of diagnosis, and lose the chance of radical cure. At present, the treatment method of the gastric cancer mainly comprises operation treatment, chemotherapy, radiotherapy, immunotherapy and molecular targeted therapy. Surgical resection remains the only method for treating the local gastric cancer, however, the survival rate of a single operation is low, the 5-year survival rate is about 20-50%, and the postoperative recurrence rate is 50% -70%. Chemotherapy remains one of the most important therapeutic modalities in the treatment of gastric cancer. Pentafluorouracil (5-FU) is a first-line drug for treating gastric cancer as an antimetabolite. However, in clinical practice, chemotherapy resistance often occurs in 5-FU, which limits its clinical efficacy. Most gastric cancer patients have extensive invasion, lymph node metastasis and chemotherapy resistance at the time of diagnosis, which are major factors leading to poor prognosis and low survival rate of gastric cancer. Although many studies have been made to investigate the action mechanism affecting chemotherapy resistance, the regulation factors and specific mechanism of chemotherapy resistance of gastric cancer are not completely clear. Chemotherapy resistance to gastric cancer has been a great obstacle that plagues the success of clinical gastric cancer therapy.
Iron death is an iron-dependent lipid peroxidation-driven cell death pattern proposed by Brent r.stockwell in 2012 and is associated with the pathophysiological processes of various diseases. Studies have shown that iron death and other types of programmed cell death depend on different cell signaling pathways, and thus the defense mechanisms of tumor apoptosis do not affect the development of iron death inducer lethal animals. Therefore, the iron death mechanism is likely to become an ideal scheme for killing malignant tumor cells of different tissue sources and pathological types. There is increasing evidence that iron death is closely associated with tumor resistance. The drug-resistant tumor cells can perform intracellular signal network reconstruction under the toxic pressure of the drug, and can resist the killing of chemotherapeutic drugs. However, cells after signal network reconstitution may be more susceptible to iron death. Therefore, small molecule compounds induce iron death, which can enhance chemotherapeutic drug sensitivity. Current studies show that there are many key metabolites and enzymes in the iron death pathway. One aspect is the regulation of Cystine (Cys) import by glutamate (Glu) levels, where SLC7a11 is an important transporter of the xCT system, its primary function is to transport Cystine (Cystine), which is a synthetic substrate for Glutathione (GSH), which promotes the synthesis of glutathione peroxidase (GPX 4). GPX4 is a key protein in iron death, which is a very central protein that inhibits iron death by reducing membrane phospholipid peroxides. It was found that inhibition of GPX4 induced iron death in the cells. Another aspect is the regulation of lipid metabolism during iron death. In addition, iron metabolism and iron-catalyzed free radical-mediated lipid oxidation chain reactions are also important links in the regulation of iron death, and some key molecules affecting iron ion production, transport and storage are involved, such as TFRC, IREB2, FTH1, FTL, DMT1, and the like. Wherein, FTH1 is ferritin heavy chain polypeptide 1, and the main function is to mediate the storage of ferrous ions; studies have shown that if FTH1 is inhibited in cells, it will cause accumulation of ferrous ions in the cells and thus induce iron death. Currently, there are some key small molecule regulators of iron death, such as iron death inducers Erastin and RSL4, iron death inhibitors Ferrostatin 1(Fer-1) and Liproxstatin-1. In addition, there are also many reports of iron death inhibitors such as CN111870613A, CN109748884A, etc., but they have not been studied on whether or not chemotherapy resistance for gastric cancer can be alleviated.
Therefore, the research and development of the medicine which can increase the sensitivity of cancer cells to chemotherapeutic drugs and slow down the chemotherapeutic drug resistance of gastric cancer have important research significance and medical application value.
Disclosure of Invention
The invention aims to overcome the defect or deficiency of chemotherapy resistance of the existing stomach cancer chemotherapy drugs (such as the pentafluorouracil), and provides application of a nitrofuran micromolecule compound in preparing drugs for inducing iron death and/or relieving the chemotherapy resistance of gastric cancer. The research of the invention finds that the nitrofuran micromolecule compound has a good effect of inducing iron death (especially gastric cancer iron death), has a function of reversing gastric cancer drug resistance, and has wide application in preparing drugs for inducing iron death and drugs for slowing down gastric cancer chemotherapy drug resistance.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
the application of a nitrofuran small molecular compound in preparing a medicament for inducing iron death and/or slowing down chemotherapy resistance of gastric cancer is disclosed, wherein the nitrofuran small molecular compound has a structure shown as a formula (I):
the research of the invention discovers that the nitrofuran micromolecule compound (a micromolecule compound with the molecular formula of C) with a specific structure23H19N5O4Molecular weight of 429.43) has good effect of inducing iron death (especially gastric cancer iron death), also has effect of reversing gastric cancer drug resistance, and has wide application in preparing drugs for inducing iron death and drugs for relieving gastric cancer chemotherapy drug resistance.
Researches show that the nitrofuran micromolecule compound can inhibit invasion, infiltration, growth, proliferation and cloning of gastric cancer cells.
Preferably, the nitrofuran small molecular compound is applied to preparation of a medicine for inhibiting gastric cancer cell cloning.
Preferably, the nitrofuran small molecular compound is applied to preparation of a medicine for inhibiting gastric cancer cell metastasis infiltration.
Preferably, the nitrofuran small molecular compound is applied to preparation of a medicine for inhibiting the growth of gastric cancer cells.
Preferably, the nitrofuran small molecule compound is applied to the preparation of a medicine for reducing the mRNA and/or protein expression of the iron death key proteins GPX4, SLC7A11 and/or FTH 1.
Preferably, the nitrofuran small molecular compound is applied to preparing a medicine for inducing iron death of gastric cancer.
Preferably, the drug for relieving the gastric cancer chemotherapy resistance is a drug for relieving 5-FU resistance.
Preferably, the drug comprises a nitrofuran small molecule compound or a pharmaceutically acceptable salt or solvate thereof and also comprises 5-FU.
The nitrofuran small molecular compound or pharmaceutically acceptable salt or solvate thereof is combined with the pentafluorouracil (5-FU), so that the growth of 5-FU-resistant gastric cancer cells can be inhibited, the cloning formation of the 5-FU-resistant gastric cancer cells can be inhibited, and the 5-FU resistance can be effectively slowed down; and exhibits low toxicity at doses that exert drug efficacy. The invention provides important reference for the development of new drugs for treating gastric cancer by targeting iron death, provides a certain treatment strategy for improving gastric cancer resistance, and has good application prospect.
Specifically, through a nude mouse subcutaneous cell transplantation tumor model experiment, the combination of the nitrofuran small molecular compound and the 5-FU can inhibit the growth of the 5-FU drug-resistant gastric cancer.
The combination of a humanized gastric cancer mouse transplantation tumor model (PDX) nitrofuran micromolecule compound and 5-FU can inhibit the growth of gastric cancer and induce the death of gastric cancer iron.
Preferably, the medicament comprises a nitrofuran small molecule compound or a pharmaceutically acceptable salt or solvate thereof, and also comprises one or more pharmaceutically acceptable carriers, diluents or excipients.
The term "pharmaceutically acceptable" means that the carrier, diluent or excipient, and/or the salt formed, is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form, and is physiologically compatible with the recipient.
The term "acceptable salts" refers to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
More preferably, the pharmaceutically acceptable salt is a pharmaceutically acceptable inorganic salt or organic salt.
Specifically, pharmaceutically acceptable salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate (methanesulfonate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate; or ammonium salts (e.g., primary amine salts, secondary amine salts, tertiary amine salts, quaternary ammonium salts), metal salts (e.g., sodium salts, potassium salts, calcium salts, magnesium salts, manganese salts, iron salts, zinc salts, copper salts, lithium salts, aluminum salts).
Preferably, the medicament is in the form of injection, capsule, tablet, pill or granule.
Compared with the prior art, the invention has the following advantages and effects:
the nitrofuran micromolecule compound provided by the invention has a good effect of inducing iron death (especially gastric cancer iron death), also has a function of reversing gastric cancer drug resistance, and has wide application in preparing drugs for inducing iron death and drugs for slowing down gastric cancer chemotherapy drug resistance.
Drawings
FIG. 1 is a graph showing the result of W1131 inducing gastric cancer cells to cause iron death; FIG. 1A shows the morphology of gastric cancer cells treated with W1131 under an electron microscope, which is characterized by a decrease in mitochondria, a decrease or even disappearance of mitochondrial cristae, and an increase in mitochondrial membrane density; FIG. 1B shows that W1131 can increase Fe2+ production in gastric cancer cells; FIG. 1C shows that W1131 can increase the production of gastric cancer cell lipid ROS; FIG. 1D shows that W1131 can increase the production of gastric cancer cell lipid peroxide MDA;
FIG. 2 is a graph of the effect of W1131 on iron death-related molecules; FIG. 2A shows the effect of W1131 on mRNA of an iron death-related gene in gastric cancer cells; FIG. 2B shows the effect of W1131 on iron death-related proteins in gastric cancer cells;
FIG. 3 is a graph showing the results of inhibition of proliferation and metastasis of gastric cancer cells by W1131; FIG. 3A shows that the inhibition of gastric cancer cell proliferation by W1131 is partially reversed by the iron death inhibitor, Fer-1; FIG. 3B is a graph showing the formation of a clone of gastric cancer cells by W1131 with an increase in the concentration of the drug; FIG. 3C is a graph showing a statistical analysis of the cloning efficiency of gastric cancer cells with increasing drug concentration of W1131; FIG. (3D) W1131 is a graph of the invasion of gastric cancer cells with increasing drug concentration; FIG. 3E is a statistical graph showing the invasion of gastric cancer cells by W1131 with increasing drug concentration.
FIG. 4 is a graph showing the results of inhibition of tumor growth in 5-FU resistant strains of gastric cancer by the combination of W1131 and 5-FU; FIG. 4A shows sensitivity of MGC803 and drug-resistant MGC803/5-FU, which are gastric cancer cells, to 5-FU; FIG. 4B shows that W1131 and 5-FU can exert a synergistic effect to inhibit the cell viability of drug-resistant cells; FIG. 4C shows that W1131 and 5-FU act synergistically to inhibit clonogenic development of resistant cells;
FIG. 5 is a graph showing the results of inhibition of drug-resistant tumor growth in an in vivo model of W1131 in combination with 5-FU; FIG. 5A is a graph showing a statistical graph of tumor volumes of nude mice in a drug-resistant gastric cancer mouse graft tumor model during 25 days of administration to each group; FIG. 5B is a graph showing the appearance of subcutaneous gastric carcinoma tumors obtained by sacrifice of mice 25 days after administration to each group; FIG. 5C shows a statistical weight chart of subcutaneous gastric cancer tumors obtained by sacrifice of mice 25 days after administration to each group.
Detailed Description
The present invention will be further explained with reference to the following examples and drawings, but the examples are not intended to limit the present invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the present invention are commercially available.
EXAMPLE 1 preparation of Nitrofuran Small molecule Compound W1131
The structure and preparation process of 4- (3- (4- (5-nitrofuran-2-carboxamide) phenyl) imidazo [1,2-a ] pyridin-7-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (W1131) are as follows:
the preparation process comprises the following steps:
step 1: preparation of 7-bromoimidazo [1,2-a ] pyridine (W1131a)
A solution of 4-bromopyridin-2-amine (8.0g, 46.2mol) and 2-chloroacetaldehyde (9.07g, 39.1mol) dissolved in 100mL of ethanol. Stirring at 78 ℃ for 4h at rt, filtration, spin-drying of the solvent and column chromatography (dichloromethane/methanol 70:1, V/V) gave the pure product as a brown oil (6.25g, 69.0%).
1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝7.2Hz,1H),7.67(d,J＝2.0Hz,1H),7.46(d,J＝12.8Hz,2H),6.73(dd,J＝7.2,2.0Hz,1H).13C NMR(126MHz,Chloroform-d)δ145.38,134.10,125.99,119.80,118.03,116.10,112.68；MS(EI)m/z 196.96(M+H)+.
Step 2: 7-bromo-3- (4-nitrophenyl) imidazo [1,2-a ] pyridine (W1131b)
W1131b (1500mg, 7.6mmol), potassium carbonate (5244mg, 38mmol) and 1-iodo-4-nitrobenzene (2.85g, 11.48mmol) were added to a clean flask at room temperature, dissolved in 20mL of N, N-dimethylformamide and the catalyst palladium acetate (85mg, 0.38mmol) was added to the reaction under nitrogen. After stirring at 130 ℃ for 12h, the solution was diluted with 100ml of ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The resulting solution was spun dry and purified by silica gel column chromatography (petroleum ether/ethyl acetate 65:1, V/V) to give the desired product ((1200mg, 49.6%) as a red-brown solid.
1H NMR(400MHz,DMSO-d6)δ8.68(dd,J＝7.3,0.8Hz,1H),8.40–8.32(m,2H),8.11–8.03(m,2H),8.02–7.97(m,2H),7.20(dd,J＝7.3,2.1Hz,1H).13C NMR(126MHz,DMSO)δ147.34,146.67,136.07,135.54,128.18,126.26,124.93,124.38,120.15,119.18,117.27；MS(EI)m/z 317.98(M+H)+.
And step 3: preparation of 4- (3- (4-nitrophenyl) imidazo [1,2-a ] pyridin-7-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (W1131c)
Compound W1131b (736mg, 2mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (679.8mg, 2.2mmol) were dissolved in 10mL of a1, 4-dioxane/water (3:1, V/V) solution, and potassium carbonate (424mg, 4mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (81.6mg, 0.1mmol) were added to the above reaction solution at room temperature. After stirring at 110 ℃ for 12h, the reaction was diluted with 100ml of ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The resulting solution was evaporated and purified by silica gel column chromatography (dichloromethane/methanol 50:1, V/V) to give 545mg of a brown solid, yield, 65%.
1H NMR(500MHz,Chloroform-d)δ8.12(d,J＝7.4Hz,1H),7.30(d,J＝9.0Hz,2H),7.26(d,J＝8.0Hz,2H),6.90(d,J＝7.4Hz,1H),6.81(d,J＝7.9Hz,2H),6.21(s,1H),4.11(s,2H),3.56(d,J＝6.0Hz,2H),2.44(s,2H),1.49(s,9H).MS(EI)m/z 421.18(M+H)+.
And 4, step 4: 4- (3- (4-aminophenyl) imidazo [1,2-a ] pyridin-7-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (W1131d)
W1131c (390mg, 1.0mmol) was dissolved in 15mL ethanol and ammonium chloride (534.9mg, 10 mm) was added at room temperatureol) was dissolved in 15mL of water, the two were mixed, and iron powder (392mg, 7mmol) was added thereto. After stirring at 80 ℃ for 4 hours, the solution was filtered through celite to remove iron powder. The resulting solution was evaporated and purified by silica gel column chromatography (dichloromethane/methanol 200:1, V/V) to give the title product as a tan solid (253.5mg, 65%).
1H NMR(500MHz,Chloroform-d)δ8.16(d,J＝7.4Hz,1H),7.55(d,J＝9.0Hz,2H),7.31(d,J＝8.0Hz,2H),6.90(d,J＝7.4Hz,1H),6.81(d,J＝7.9Hz,2H),6.21(s,1H),4.13(s,2H),3.66(d,J＝6.0Hz,2H),2.56(s,2H),1.50(s,9H).MS(EI)m/z 391.21(M+H)+.
And 5: preparation of tert-butyl 4- (3- (4- (5-nitrofuran-2-carboxamide) phenyl) imidazo [1,2-a ] pyridin-7-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (W1131e)
W1131d (252mg, 0.65mmol) was dissolved in 15mL of N, N-dimethylformamide and 5-nitrofuran-2-carboxylic acid (151.1mg, 0.975mmol), HATU (494mg, 1.3mmol) and N, N-diisopropylethylamine (251.55mg, 1.95mmol) were added thereto at room temperature. After stirring at room temperature for 4 hours, the solution was diluted with 100ml of ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The resulting solution was evaporated and purified by silica gel column chromatography (dichloromethane: methanol ═ 5:1, V/V) to give the desired product as a tan solid (80mg, 61.1%)
1H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.25(d,J＝7.3Hz,1H),7.79(d,J＝8.2Hz,2H),7.67(s,1H),7.63(s,1H),7.52(s,1H),7.47(d,J＝8.1Hz,2H),7.24(d,J＝3.2Hz,1H),7.14(d,J＝7.1Hz,1H),6.54(s,1H),6.31(s,1H),4.11(s,2H),3.62(s,2H),2.50(s,2H),1.48(s,9H).MS(EI)m/z 530.19(M+H)+；HRMS(ESI)calcd for C28H28N5O6(M+H)+:530.1968；found530.1964.
Step 6: preparation of 5-nitro-N- (4- (7- (1,2,3, 6-tetrahydropyridin-4-yl) imidazo [1,2-a ] pyridin-3-yl) phenyl) furan-2-carboxamide (W1131)
Compound W1131d (80mg, 0.151mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added dropwise to the above reaction solution at room temperature. After stirring at room temperature for 1 hour, the solution was diluted with 50mL of dichloromethane. A saturated sodium bicarbonate solution was added while cooling on ice and the pH was adjusted to 7. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The resulting solution was evaporated and purified by silica gel column chromatography (dichloromethane/methanol 50:3, V/V) to give the desired product (42.1mg, 65%) as a yellow-brown solid.
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),9.62(s,1H),8.56(d,J＝7.4Hz,1H),8.06(m,3H),7.85(d,J＝3.9Hz,1H),7.80(s,1H),7.70(d,J＝8.5Hz,2H),7.67(s,1H),7.21(d,J＝7.0Hz,1H),6.48(s,1H),3.83–3.72(m,2H),3.05–2.59(m,2H),2.51(s,2H).13C NMR(126MHz,DMSO-d6)δ155.13,152.29,148.30,146.47,137.93,136.52,133.39,132.60,128.20,125.43,125.37,125.21,123.99,121.68,117.21,113.97,111.85,110.48,45.01,42.59,25.99.MS(EI)m/z430.14(M+H)+；HRMS(ESI)calcd for C23H20N5O4(M+H)+:430.1437；found 430.1435.
Example 2W 1131 Induction of pig iron death in gastric cancer cells
(1) Cell culture
AGS and MGC803 cells used in the present invention are cultured in RPIM-1640 medium containing 10% fetal bovine serum and 1% double-resistant penicillin and streptomycin, and placed in a cell culture box at 37 ℃ and 5% CO 2. MGC803/5-FU cells are MGC803 cells, which are induced to generate drug resistance to 5-FU by adopting an in-vitro low-concentration gradient increasing method, so as to obtain MGC803 cell strains with drug resistance to 5-FU, and the MGC803/5-FU cells are continuously maintained and cultured in a complete culture medium containing 5-FU.
(2) Transmission electron microscopy inspection
1) Collecting stomach cancer cells in logarithmic growth phase, digesting the cells, counting, and measuring by (20-40) × 104A hole is inoculated in a 60mm culture dish with the density of 4mL per hole, and the culture dish is placed in a constant temperature incubator to be cultured until cells adhere to the wall;
2) after adherence, adding corresponding DMSO into a control group, adding W1131(1 mu M) into an administration group, and continuously culturing for 24 h;
3) discarding the culture medium of the cultured cells, adding 2.5% of a fixing solution for a normal-temperature electron microscope, fixing at normal temperature for about 5min, and slightly scraping the cells along one direction by using a cell scraper to avoid scraping the cells;
4) then sucking the cell sap into a centrifugal tube by using a pipette, putting the centrifugal tube into a centrifugal machine, rotating the centrifugal machine at 2000rpm, and centrifuging for 2min, wherein the cell should have the size of mung bean;
5) removing the fixing solution, adding a new electron microscope fixing solution, gently picking up the cell clusters, and suspending the cell clusters in the fixing solution;
6) the cells were fixed at room temperature in the dark for 30min, and then transferred to 4 ℃ for storage and examination (electron microscopy was performed by Wuhanseville Biotech).
(3) MDA detection assay
1) Preparation of samples cells were lysed with cell lysate RIPA, centrifuged at 10000g-12000g for 10min at 4 ℃ and the supernatant taken for subsequent assays.
2) BCA quantification
After the sample preparation was completed, the protein concentration was measured using the BCA protein concentration measurement kit.
3) Preparation of the kit
Weighing a proper amount of TBA, preparing TBA storage solution with the concentration of 0.37% by using TBA preparation solution, and storing at room temperature in a dark place;
secondly, according to the number of samples to be measured, according to the TBA diluent used in 1 part of samples: TBA stock solution: preparing a formula of 150 mu L of antioxidant, 50 mu L of antioxidant and 3 mu L of antioxidant, wherein a proper amount of MDA detection working solution is prepared freshly before detection, and the prepared MDA detection working solution is only used in the same day;
③ taking a proper amount of standard substance, diluting the standard substance to 1,2,5, 10, 20 and 50 mu M with distilled water, and using the diluted standard substance to make a standard curve subsequently.
4) Sample assay
Firstly, 100 mu L of standard substances with different concentrations are added into a centrifuge tube 100 mu LPBS as a blank control for preparing a standard curve, and 100 mu L of sample is added for determination; then adding 200 mu of LMDA detection working solution;
② after mixing, heating for 15min at 100 ℃ or in boiling water bath;
③ cooling to room temperature in water bath, and centrifuging for 10min at room temperature of 1000 g. Adding 200 mu L of supernatant into a 96-well plate, and then measuring the absorbance at 532nm by using an enzyme-linked immunosorbent assay;
and fourthly, substituting the measurement result of the sample solution into the standard curve, calculating the MDA content in the sample solution, and then combining the BCA quantification result to express the MDA content in the initial sample through the protein content of unit weight.
(4) Ferrooorange probe fluorescence imaging assay
Ferrooorange is a novel fluorescent probe, and can carry out fluorescence imaging on Fe2+ in living cells.
1) Cells were seeded in Confocol dishes and cultured overnight in a 5% CO2 incubator at 37 ℃;
2) the supernatant was removed and the cells were washed 3 times with HBSS;
3) replacing the culture medium containing the medicine, and culturing in a 5% CO2 incubator at 37 ℃ for 24 h;
4) preparation of Ferrooorange working solution
To a tube containing 24. mu.g of Ferrooorange was added 35. mu.L of DMSO, and the mixture was pipetted and mixed to prepare a 1mmol/L Ferrooorange solution, which was stored at-20 ℃. A1. mu. mol/l Ferro orange working solution was prepared by diluting a 1mmol/l Ferro orange solution with HBSS solution just before use and was ready for use.
5) Adding Ferrooorange working solution with the concentration of 1 mu mol/l into the cells, and culturing for 30min in a 5% CO2 incubator at 37 ℃;
6) cells were observed under a fluorescent confocal microscope.
(5) Liperfluor probe fluorescence imaging assay
The Liperfluor is a derivative of Spy-LHP (a lipid hydrogen peroxide probe), can be used for detecting Lipid Peroxide (LPO), can be specifically oxidized by the lipid peroxide to emit strong fluorescence when a lipid oxidation process occurs in an organic solvent such as ethanol and the like, and is suitable for fluorescence imaging of the lipid peroxide in living cells.
1) Cells were seeded in Confocol dishes and cultured overnight in a 5% CO2 incubator at 37 ℃;
2) replacing the culture medium containing the medicine, and culturing in a 5% CO2 incubator at 37 ℃ for 24 h;
3) preparation of Liperfluor working solution
Adding 60 mu L of DMSO into a tube containing 50 mu g of Liperfluoro, blowing and beating the DMSO by a pipette uniformly to prepare a 1mmol/L Liperfluoro solution, wrapping the solution by using aluminum foil paper, and using the solution within 1 day;
4) adding Liperfluor solution into cells to make the final concentration of the Liperfluor solution be 10 mu mol, and culturing the cells in a 5% CO2 incubator at 37 ℃ for 30 min;
5) cells were observed under a fluorescent confocal microscope.
(6) Results of the experiment
The experimental results are shown in fig. 1, and the graph (1A) shows the morphology of the gastric cancer cell treated by W1131 under an electron microscope, which is represented by that mitochondria become small, mitochondrial cristae is decrease and even disappear, and mitochondrial membrane density is increased; FIG. 1B shows that W1131 can increase Fe2+ production in gastric cancer cells; FIG. 1C shows that W1131 can increase the production of gastric cancer cell lipid ROS; FIG. 1D shows that W1131 can increase the production of gastric cancer cell lipid peroxide MDA.
Example 3 Effect of W1131 on iron death-related proteins
(1) Fluorescent quantitative PCR
1) Total RNA extraction from cells
Firstly, treating cells for 48 hours by using W1131 with different concentrations, absorbing a culture medium, washing the cells twice by using PBS (phosphate buffer solution), adding Trizol into a fume hood, blowing the cells within 5min until the cells completely fall off, and transferring cell lysate into a 1.5mL centrifuge tube without RNase;
adding chloroform, shaking up and down for 15s, standing at room temperature for 10min, centrifuging at 4 ℃ and 12000rpm for 15min, carefully absorbing the upper layer transparent liquid into a new 1.5mL centrifuge tube, adding isopropanol, gently blowing and uniformly mixing by using a liquid transfer gun, and standing at room temperature for 10 min;
③ centrifuging at 4 ℃ and 12000rpm for 15min, carefully discarding the supernatant, adding 75 percent of freshly prepared precooled ethanol solution, slightly reversing the mixture up and down and mixing the mixture evenly, and centrifuging at 4 ℃ and 12000rpm for 15 min;
fourthly, discarding the supernatant, airing to obtain RNA precipitate, adding a proper amount of DEPC water to dissolve the RNA, using Nanodrop to determine the RNA concentration, and storing the labeled concentration at 80 ℃ below zero for later use.
2) The template DNA is obtained by reverse transcription.
3) According to the RNA concentration, a 10 mu L sample system is prepared from the DNA template (2ug), the primers and the 2XSYBR, fluorescence quantitative PCR is carried out, and then the result is subjected to statistical analysis.
The fluorescent quantitative PCR primers are shown in Table 1 below.
TABLE 1 fluorescent quantitative PCR primers
(2) Western blotting (Western Blot)
After the cells are treated by W1131 with different concentrations for 48 hours, the culture medium is sucked off, the cells are washed twice by PBS, cell lysate RIPA containing protease inhibitor and phosphatase inhibitor is added for cell lysis, the lysate is centrifuged for 15min at 15000rpm and 4 ℃, the supernatant is taken out for quantification, 5 × loading buffer is added, and boiling denaturation is carried out. Then separating protein samples by using polyacrylamide gel SDS-PAGE electrophoresis, transferring the protein samples to a nitrocellulose membrane (PVDF membrane), after blocking for 1h by 5% BSA, respectively incubating overnight at 4 ℃ by using primary antibodies of GPX4, SLC7A11, FTH1 and beta-Actin, respectively, then incubating for 1h at room temperature by using a rabbit secondary antibody and a mouse secondary antibody which are provided with fluorescent markers, and finally detecting the expression level of the protein by using a Tanon developing instrument.
(3) Results of the experiment
The experimental results are shown in fig. 2, and fig. (2A) shows that W1131 can dose-dependently inhibit mRNA expression of iron death-related genes GPX4, SLC7a11, and FTH 1; figure (2B) shows that W1131 is able to inhibit protein expression of GPX4, SLC7a11 and FTH 1.
Example 4W 1131 inhibition of gastric cancer cell proliferation and metastasis
(1) Cell counting assay for cell growth
1) Taking each cell in logarithmic growth phase, digesting the cell, counting, and measuring by (5-10) × 104A hole is inoculated in a 6-hole plate with the density of 2mL per hole, and the plate is placed in a constant temperature incubator to be cultured until cells adhere to the wall;
2) after adherence, adding corresponding DMSO into a control group, and adding W1131 or (and) Fer-1 into an administration group;
3) after 72 hours of drug treatment, the cell state was observed under a microscope and cell counting was performed.
(2) Plate cloning experiment
1) Taking cells in logarithmic phase, digesting, counting, and uniformly inoculating 800 cells per well into a six-well plate;
2) after the cells adhere to the wall, adding a culture medium containing a medicinal solvent into a control group, adding W1131 with different concentrations into an administration group, and arranging 3 compound holes in each group;
3) replacing the culture medium every three days, and adding W1131 with corresponding concentration;
4) culturing for 8-12 days until a macroscopic white cell clone group grows out in the control group;
5) discarding the culture medium, washing once with normal-temperature PBS, adding 4% paraformaldehyde, fixing the cells at room temperature for 15min, sucking the fixing solution, washing 1 time with PBS, adding crystal violet dye in the dark, dyeing for 30min in the dark, finally slowly washing off the redundant dyeing solution with running water, drying at room temperature, scanning the plate, and calculating the cell clone formation number in each hole.
(3) Transwell cell invasion assay
1) Appropriate amounts of Transwell were removed and nested into new 24-well plates, the porous membrane was fully immersed by addition of blank medium and pre-activated for 1h or overnight at 37 ℃.
2) Taking cells in logarithmic growth phase, counting after digestion, and uniformly inoculating 2 × 104 cells per well into an upper chamber of a Transwell chamber, wherein the upper chamber and the lower chamber are both cultured overnight in a culture medium containing 10% FBS at 37 ℃ in a 5% CO2 culture box;
3) after the cells were attached to the wall, the cell plates were removed, the upper and lower chamber media were aspirated, and washed once with PBS. Culture medium containing corresponding concentration of drug solvent (0.1% DMSO) is added into the upper chamber of the control group, and small molecule compounds with different concentrations are respectively administered into the upper chamber of the administration group, and cultured in 5% CO2 incubator at 37 deg.C for 12-24 h. Wherein, the culture medium containing 2% FBS is used in the upper chamber, and the culture medium containing 20% FBS is added in the lower chamber as an induction factor.
4) Discarding the culture medium, washing with PBS once, and fixing with 4% paraformaldehyde for 15 min;
5) gently scrape the upper cells (uninfected cells) with a cotton swab;
6) washing with PBS twice, and dyeing with crystal violet in dark for 30 min;
7) and washing twice with PBS, washing off unstained crystal violet, drying at room temperature, observing under a microscope, photographing, and counting.
(4) Results of the experiment
The results of the experiment are shown in FIG. 3. FIG. 3A shows that W1131 is capable of significantly inhibiting the growth of gastric cancer cells, and that this growth inhibition can be partially reversed by the iron death inhibitor, Fer-1; fig. 3B shows that W1131 can significantly inhibit the clonogenic formation of gastric cancer cells; FIG. 3C is a colony formation statistic chart; FIG. 3D shows that W1131 can inhibit the invasive ability of gastric cancer cells concentration-dependently; FIG. 3E is a corresponding statistical chart.
Example 5 combination of W1131 and 5-FU in inhibition of tumor growth in gastric cancer 5-FU-resistant strains
(1) The CCK8 method for determining cell viability is the same as above
(2) Plate cloning experiments are as above
(3) Results of the experiment
The experimental result is shown in FIG. 4, and the graph (4A) shows that MGC803 and MGC803/5-FU cells have different sensitivity to 5-FU, IC50 of MGC803 is 5.045 μ M, IC50 of MGC803/5-FU is 55.62 μ M, and the drug resistance index is about 11, which indicates that the 5-FU gastric cancer drug-resistant strain is successfully constructed; FIG. 4B shows that W1131 in combination with 5-FU can more significantly inhibit the growth of MGC803/5-FU cells; FIG. 4C shows that W1131 in combination with 5-FU can more significantly inhibit the clonogenic activity of MGC803/5-FU cells.
Example 6 combination of W1131 with 5-FU inhibits tumor growth in an in vivo model
(1) Mouse subcutaneous gastric cancer cell transplantation tumor model
1) Taking stomach cancer drug-resistant cells in logarithmic growth phase, counting after digestion, mixing precooled PBS and Matrigel according to a ratio of 1:1, and re-suspending cells to obtain 2 × 106Cells were suspended in 100. mu.L of ice. Injecting 100 mu L of cell suspension into subcutaneous parts on two sides of the abdomen and the back of a 4-5-week-old immunodeficient nude mouse respectively;
2) the volume of the subcutaneous tumor to be treated is about 50mm3And then, randomly divided into 4 groups. The groups and dosing settings were as follows: control group, daily placebo (i.e. solvent for dissolution: 15% castor oil + 85% sterile PBS); 5-FU group, administered every other day, and injected intraperitoneally at a dose of 20 mg/kg; the medicine is administered daily and is injected into abdominal cavity in the W1131 group, and the dosage is 5 mg/kg; a W1131+5-FU combined administration group;
3) continuously administering the medicine for four weeks, measuring the weight and the tumor size of the mouse every three days, and drawing a weight growth curve of the mouse;
4) four weeks after dosing, mice were sacrificed for dissection, subcutaneous tumors were dissected off, and weighed.
(2) Results of the experiment
As shown in FIG. 5, in FIG. 5A, the change in tumor volume during the administration in the mouse subcutaneous gastric cancer cell transplantation tumor model is shown, and both of W1131 and 5-FU alone can inhibit the growth of tumor in nude mice; compared with a single group, the W1131 and 5-FU combined drug group can more obviously inhibit the growth of tumors of nude mice, and the W1131 and 5-FU have better combined effect in vivo; FIG. 5B is an appearance of exfoliated drug-resistant gastric carcinoma subcutaneous tumors 25 days after administration; FIG. 5C shows that the combined use of W1131 and 5-FU can significantly reduce the weight of gastric cancer tumor, wherein the tumor inhibition rate of 5-FU group is about 23.31%, the tumor inhibition rate of W1131 group is about 51.7%, and the tumor inhibition rate of the two combined groups is about 76.08%.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. The application of the nitrofuran small molecular compound in preparing the medicine for inducing iron death and/or relieving gastric cancer chemotherapy resistance is characterized in that the nitrofuran small molecular compound has a structure shown as a formula (I):
2. the use according to claim 1, wherein the nitrofuran small molecule compound is used for preparing a medicine for inhibiting gastric cancer cell cloning.
3. The use according to claim 1, wherein the nitrofuran small molecule compound is used for preparing a medicament for inhibiting gastric cancer cell metastasis infiltration.
4. The use according to claim 1, wherein the nitrofuran small molecule compound is used for preparing a medicament for inhibiting the growth of gastric cancer cells.
5. The use according to claim 1, wherein the nitrofurans small molecule compound is used for preparing a medicament for reducing the expression of mRNA and/or protein of the critical proteins of iron death GPX4, SLC7A11 and/or FTH 1.
6. The use according to claim 1, wherein the nitrofurans small molecule compound is used for preparing a medicament for inducing gastric cancer iron death.
7. The use of claim 1, wherein the drug for reducing the resistance to gastric cancer chemotherapy is a 5-FU drug.
8. The use according to any one of claims 1 to 7, wherein the medicament comprises a nitrofuran small molecule compound or a pharmaceutically acceptable salt or solvate thereof, and further comprises 5-FU.
9. The use of claims 1 to 8, wherein the medicament comprises a nitrofuran small molecule compound or a pharmaceutically acceptable salt or solvate thereof, and further comprises one or more pharmaceutically acceptable carriers, diluents or excipients.
10. The use of claim 1, wherein the medicament is in the form of injection, capsule, tablet, pill or granule.
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