CN106913564B - Use of polyether compound - Google Patents
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Abstract
The invention discloses a polyether compound shown in a general formula I, and application of a chelating form, a hydration form or a pharmaceutically acceptable salt thereof in preparation of a medicament, and application of the medicament in preparation of a medicament for treating cancer and preventing cancer recurrence. The inventor finds that the polyether compound shown in the general formula I can inhibit the proliferation of malignant tumor cells and malignant tumor cell stem cells.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, in particular to polyether compounds, a preparation method thereof, a pharmaceutical composition containing the compounds and application of the compounds.
Background
Cancer has become one of the most major diseases that endanger human health. At present, the clinical treatment generally comprises means such as operation treatment, natural therapy, radiotherapy, chemotherapy, traditional Chinese medicine treatment and the like. The chemotherapy is to use chemotherapeutic drugs to kill or inhibit the growth of tumor cells, and the chemotherapeutic drugs can be classified into alkylating agents, antimetabolites, anticancer antibiotics, plants, hormones, miscellaneous drugs and the like, wherein the existing anticancer antibiotics can achieve a certain effect, but are easy to cause drug resistance of tumor cells after long-term use and often cause toxic and side effects. Therefore, there is a need to expand the diversity of such anti-cancer drugs. The invention discovers that the ether antibiotics have good effect of inhibiting the growth of tumors.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, it is an object of the present invention to propose a means capable of effectively treating or preventing cancer.
According to one aspect of the invention, the invention provides the use of polyether compounds of the general formula I, their chelated forms, hydrated forms or their pharmaceutically acceptable salts for the preparation of a medicament for the treatment of cancer and the prevention of cancer recurrence,
wherein, R is1The R is2The R is3The R is4The R is5The R is6The R is7And said R8Each independently of the others is hydrogen, -OH, -NH2Halogen, optionally substituted C1~10Linear or branched, saturated or unsaturated hydrocarbon radical, optionally substituted C1~10Straight or branched hydrocarbyloxy, optionally substituted C1~10Acyl, optionally substituted C6~20Aryl, optionally substituted heteroaryl,Or
Wherein R is9、R10Each independently of the others is hydrogen, -OH, -NH2Halogen, C1-5A linear or branched, saturated or unsaturated hydrocarbon group, a carboxyl group, an azido group, an oxime group, an amine group, a thiol group, an amide group, a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and optionally substituted by one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2Phenyl, benzyl, heteroaryl and-NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl, said heteroaryl being a 3-to 6-membered monocyclic or bicyclic heteroaryl, optionally containing 1-3 heteroatoms selected from N, O or S;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
The medicament can inhibit the growth of tumor cells and tumor stem cells, so that cancer cells are thoroughly eliminated, and the recurrence of cancer is prevented, particularly the recurrence of breast cancer is prevented.
According to an embodiment of the present invention, in formula I:
the R is1The R is2The R is3The R is4The R is5The R is6The R is7And said R8Each independently of the others is hydrogen, -OH, -NH2Halogen, optionally substituted C1~5Linear or branched, saturated or unsaturated hydrocarbon radical, optionally substituted C1~5Straight or branched hydrocarbyloxy, optionally substituted C1~5Acyl, optionally substituted phenyl, Or
Wherein, R is9、R10Each independently of the others is hydrogen, -OH, -NH2Halogen, C1~5A linear or branched, saturated or unsaturated hydrocarbon group, a carboxyl group, an azido group, an oxime group, an amine group, a thiol group, an amide group, a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and optionally substituted by one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2Phenyl, benzyl, heteroaryl, -NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl, said heteroaryl being a 5-to 6-membered monocyclic heteroaryl, and optionally containing 1-3 heteroatoms selected from N, O or S;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the present invention, in formula I:
the R is1The R is2The R is3The R is4The R is5The R is6The R is7The R is8And said R9Each independently of the others is hydrogen, -OH, -NH2Halogen, optionally substituted C1~3Linear or branched, saturated or unsaturated hydrocarbon radical, optionally substituted C1~3Straight or branched hydrocarbyloxy, optionally substituted C1~3Acyl, optionally substituted phenyl,Or
Wherein, R is9、R10Each independently of the others is hydrogen, -OH, -NH2Halogen, C1~3A linear or branched, saturated or unsaturated hydrocarbon group, a carboxyl group, an azido group, an oxime group, an amine group, a thiol group, an amide group, a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and optionally substituted by one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2Phenyl, benzyl, heteroaryl, -NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl, said heteroaryl being a 5-to 6-membered monocyclic heteroaryl, and optionally containing 1 heteroatom selected from N, O or S;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the present invention, in formula I:
the R is1The R is2The R is3The R is4The R is5The R is6The R is7The R is8Each independently of the others is hydrogen, -OH, -NH2Halogen, -OCH3、-OCF3、C2-10A saturated aliphatic chain hydrocarbon, a propenyl group, a propynyl group, a 2- (trifluoromethyl) ethyl group, a 2-bromoethyl group, a 2-azidoethyl group, an acetyl group, a 2-halo (chloro, bromo) acetyl group, a 2-azidoacetyl group, a benzoyl group, a phenylacetyl group, an optionally substituted phenyl group, a substituted,Or
Wherein, R is9、R10Each independently of the others is hydrogen, -OH, -NH2Halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azido, oximino, amino, mercapto, amido, sulfate, rhamnosyl, phenyl or benzyl,and said phenyl and benzyl are optionally substituted by one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2、-NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the invention, said R1Is composed ofThe R is2The R is3The R is4Are all hydrogen, said R5Is methyl, said R7And said R8Are all-OH, the structural formula of the compound is as follows:
wherein R is6Is hydrogen, -OH, -NH2Halogen, -OCH3、-OCF3Methyl, ethyl, isopropyl, ethenyl, propenyl, propynyl, 2- (trifluoromethyl) ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo (chloro, bromo) acetyl, 2-azidoacetyl, benzoyl, phenylacetyl or
Wherein, R is10Is hydrogen, -OH, -NH2Halogen, methyl, ethyl, isopropyl, ethenyl, propenyl, carboxyl, azido, oximino, amino, mercapto, amido, sulfate, rhamnosyl, phenyl or benzyl, and said phenyl and benzyl are optionally substituted with one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2、-NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently saturated aliphaticC1-4Alkyl, phenyl or benzyl;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the invention, said R1Is composed ofR2、R3、R4Are all hydrogen, said R5Is methyl, said R6is-OH, the structural formula of the compound is as follows:
wherein R is7And R8Each independently of the others is hydrogen, -OH, -NH2Halogen, -OCH3、-OCF3Methyl, ethyl, isopropyl, vinyl, propenyl, propynyl, 2- (trifluoromethyl) ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo (chloro, bromo) acetyl, 2-azidoacetyl, benzoyl, phenylacetyl or,
Wherein, R is9Is hydrogen, -OH, -NH2Halogen, methyl, ethyl, isopropyl, ethenyl, propenyl, carboxyl, azido, oximino, amino, mercapto, amido, sulfate, rhamnosyl, phenyl or benzyl, and said phenyl and benzyl are optionally substituted with one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2、-NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the invention, said R2Is composed ofR1、R7And R8Are all-OH, R3And R5Are each hydrogen, R4Is methyl, the structural formula of the compound is as follows:
wherein R is6Is hydrogen, -OH, -NH2Halogen, -OCH3、-OCF3Methyl, ethyl, isopropyl, ethenyl, propenyl, propynyl, 2- (trifluoromethyl) ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo (chloro, bromo) acetyl, 2-azidoacetyl, benzoyl, phenylacetyl or
Wherein, R is10Is hydrogen, -OH, -NH2Halogen, methyl, ethyl, isopropyl, ethenyl, propenyl, carboxyl, azido, oximino, amino, mercapto, amido, sulfate, rhamnosyl, phenyl or benzyl, and said phenyl and benzyl are optionally substituted with one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2、-NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the invention, said R2Is composed ofR6is-OH, R3、R5Are each hydrogen, R4Is methyl, the structural formula of the compound is as follows:
wherein R is1,R7,R8Each independently of the others is hydrogen, -OH, -NH2Halogen, -OCH3、-OCF3Methyl, ethyl, isopropyl, vinyl, propenyl, propynyl, 2- (trifluoromethyl) ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo (chloro, bromo) acetyl, 2-azidoacetyl, benzoyl, phenylacetyl or,
Wherein, R is9Is hydrogen, -OH, -NH2Halogen, methyl, ethyl, isopropyl, ethenyl, propenyl, carboxyl, azido, oximino, amino, mercapto, amido, sulfate, rhamnosyl, phenyl or benzyl, and said phenyl and benzyl are optionally substituted with one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2、-NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the invention, said R3Is composed ofR1、R7And R8Are all-OH, R2、R5Are each hydrogen, R4Is methyl, the structural formula of the compound is as follows:
wherein R is6Is hydrogen, -OH,-NH2Halogen, -OCH3、-OCF3Methyl, ethyl, isopropyl, ethenyl, propenyl, propynyl, 2- (trifluoromethyl) ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo (chloro, bromo) acetyl, 2-azidoacetyl, benzoyl, phenylacetyl or
Wherein, R is10Is hydrogen, -OH, -NH2Halogen, methyl, ethyl, isopropyl, ethenyl, propenyl, carboxyl, azido, oximino, amino, mercapto, amido, sulfate, rhamnosyl, phenyl or benzyl, and said phenyl and benzyl are optionally substituted with one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2、-NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the invention, said R3Is composed ofR1、R7And R6Are all-OH, R2、R5Are each hydrogen, R4Is methyl, the structural formula of the compound is as follows:
wherein R1, R7 and R8Each independently of the others is hydrogen, -OH, -NH2Halogen, -OCH3、-OCF3Methyl, ethyl, isopropyl, vinyl, propenyl, propynyl, 2- (trifluoromethyl) ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo (chloro, bromo) acetyl, 2-azidoacetyl, benzoyl, phenethylAcyl or
Wherein, R is9Is hydrogen, -OH, -NH2Halogen, methyl, ethyl, isopropyl, ethenyl, propenyl, carboxyl, azido, oximino, amino, mercapto, amido, sulfate, rhamnosyl, phenyl or benzyl, and said phenyl and benzyl are optionally substituted with one or more groups selected from halogen, -OCH3、-OH、-OCF3、-NH2、-NHRXand-NRX 2Wherein R is substituted by the group ofXEach independently of the other, is a saturated aliphatic C1-4Alkyl, phenyl or benzyl;
n is an integer of 2 to 7;
the halogen is-F, -Cl, -Br and-I.
According to an embodiment of the present invention, the polyether compound is one of the following compounds: r1 isor-OH, R2, R3 are each independentlyOr hydrogen, R4, R5 are each independently methyl or hydrogen, R6, R7, R8 are all-OH.
According to an embodiment of the present invention, the polyether compound is one of the following compounds:
according to an embodiment of the present invention, the cancer is brain cancer, skin cancer, kidney cancer, bone cancer, sarcoma, prostate cancer, uterine cancer, melanoma cancer, colon cancer, lymphoma, leukemia, pancreatic cancer, epithelial cell cancer, breast cancer, liver cancer, lung cancer, stomach cancer, ovarian cancer, and corresponding tumor cell stem cells.
According to an embodiment of the present invention, the medicament prevents cancer recurrence by inhibiting tumor cell stem cell proliferation.
At present, the compound taking polyether as a parent nucleus is mainly used as an antibiotic, and the inventor accidentally finds that the compound has good antitumor activity through a large number of experiments. The three compounds can have antitumor activity of different degrees by mixed culture with malignant tumor cells. Therefore, the compound taking polyether as a mother nucleus can be used for treating malignant tumor cells in a pharmaceutically acceptable administration form (free form, sodium salt or potassium salt form, chelated form and hydrated form), and the diversity of medicaments for treating the diseases is enriched. The inventor finds that the polyether compound shown in the general formula I can inhibit the proliferation of malignant tumor cells, and researches three compounds, namely a compound 1, a compound 2 and a compound 3, and finds that the polyether compound has an inhibiting effect on various cancer cells. Specifically, the inventors have demonstrated their opinion through the following experimental procedures:
(1) the inventor separately mixed-cultures a plurality of cancer cells and three compounds of compound 1, compound 2 and compound 3, especially sodium salts thereof in vitro. The inhibition rate and IC of the three compounds of compound 1, compound 2 and compound 3 on the proliferation of tumor cells are calculated by measuring the OD value by using an MTT staining method50(median inhibition rate). The inventor finds that the three compounds of the compound 1, the compound 2 and the compound 3 have different degrees of inhibition effects on various tumor cells.
(2) The inventor finds that the three compounds have obviously stronger inhibition effects on the proliferation of various cancer cells than the inhibition effects of the taxol and the salinomycin (salinomycin) which is found to have anticancer effects in the same class, and the inhibition effects of the three compounds are partially stronger than the inhibition effects of the salinomycin.
Drawings
Figure 1 shows a schematic representation of a spectrum of compound 1 according to one embodiment of the present invention;
figure 2 shows a schematic map of compound 2 according to one embodiment of the present invention;
figure 3 shows a schematic map of compound 3 according to one embodiment of the present invention;
FIG. 4 shows a schematic diagram of a stem cell flow assay according to one embodiment of the present invention.
Detailed Description
The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
Example 1
The compound 1, the compound 2 and the compound 3 are obtained by fermenting Streptomyces hygroscopicus subtype Streptomyces and Streptomyces endous subtype Streptomyces, and the specific method is as follows:
two Streptomyces hygroscopicus subtypes and Streptomyces endous subtypes are respectively inoculated on an SFM plate and cultured for about three days to four days. When colonies are formed in the SFM culture medium, selecting single colonies to a seed culture medium for culture for about three days to four days, inoculating the single colonies to a fermentation culture medium according to the amount of 1 percent (the components of the fermentation culture medium are 30g/L of soluble starch, 10g/L of soybean cake powder, 2.5g/L of yeast extract, CaCO33g/L, pH 7.2). The culture conditions are as follows: 30 ℃ and 220 rpm, and culturing for 7 to 8 days.
And when the culture is carried out for 7 th or 8 th day, collecting fermentation liquor, separating the supernatant from the mycelium by high-speed centrifugation, adding the same amount of acetone into the mycelium to break the bacteria, carrying out ultrasonic treatment for 20min, carrying out rotary evaporation on the acetone, extracting the supernatant and the mycelium by using the same amount of ethyl acetate, and repeating the steps once. Concentrating by rotary evaporation to dryness, then carrying out crude separation by using a silica gel column to obtain a crude product detected by using HPLC, and considering that the HPLC result shows that the yield of the three strains is higher, carrying out TLC (thin layer chromatography) plate on a concentrated sample, carrying out color development in an iodine cylinder, removing a very obvious point, dissolving the point by using methanol, carrying out high-speed centrifugation, taking a supernatant as a mass spectrum to determine the position of a target point, wherein the detection result of the compound is shown in figures 1-3, wherein figure 1 shows that the compound is a compound 1, figure 2 shows that the compound is a compound 2, and figure 3 shows that the compound is a compound 3.
Example 2
MTT experiment is utilized to detect the inhibition effect of the sodium salt of the compound 1 and the paclitaxel on MCF-7 tumor cells, and the specific method is as follows:
respectively taking logarithmic growth phaseMCF-7 (Breast cancer cells, basic medical college culture Collection of Wuhan university), when the cells overgrow 80% of the bottle wall, the cells were suspended by digestion with 0.25% -EDTA trypsin (3min-5 min). The cell suspension was seeded into a 96-well cell culture plate (about 5000 cells per well) at 200. mu.L per well; the control group was a group to which 200. mu.L of cells without drug was added per well; blank group is a group to which 200. mu.L of medium without cells was added per well. The 96-well cell culture plate inoculated with the cells was placed in a cell culture plate containing 5% CO2Incubate in the incubator at 37 ℃ overnight to allow the cells to adhere. Sample compound 1 sodium salt, salinomycin (salinomycin) and the existing anticancer drug paclitaxel are respectively dissolved in DMSO to prepare 100mg/mL stock solutions, and then diluted into sample solutions with different concentrations (the final concentration of DMSO is less than 0.1%) by using corresponding culture media before use. 200 μ L of sample solutions (Compound 1 sodium salt, salinomycin) or paclitaxel solutions (100 μ g/mL, 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL) at different concentrations (100 μ g/mL, 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL) were added to each of the different experimental groups; the control group was a group in which 200. mu.L of the culture medium was added to adherent cells; the blank group was cell-free and 200. mu.L of medium was added. Then, after the 96-well cell culture plate added with the drug solution of different concentrations (100, 10, 1, 0.1, 0.01. mu.g/L of the sample solution or salinomycin or paclitaxel solution) was cultured in a cell culture chamber (37 ℃) for 48 hours, 20. mu.L of 0.5mg/mL of thiazole blue (MTT) was added to each well of the above 96-well cell culture plate, and then the plate was further placed in the cell culture chamber (37 ℃) for culture. After 2-4 hours, 96 well cell culture plates incubated with MTT were centrifuged in a high speed centrifuge at 2000rpm for 10 minutes. Following centrifugation, the supernatant in the 96-well cell culture plates was removed, and the formazan blue crystals generated at the bottom of the 96-well plates were then solubilized by adding 100 μ L of dimethyl sulfoxide (DMSO) to each well. After the 96-well cell culture plate added with DMSO is shaken for 10 minutes on a plate oscillator, an enzyme linked immunosorbent detector is used for detecting an OD value (reference wavelength is 490nm) under the wavelength of 570nm, and the inhibition rate and IC are calculated50(median inhibition rate).
Inhibition ratio%0)/(A-A1)×100%
In the formula: a represents the OD value of the control group; a. the0OD values representative of the sample set; a. the1Represents the OD value of the blank group.
Test article | IC for MCF-750(μmol/L) |
|
1.63±0.04 |
Paclitaxel | 8.49±1.43 |
Salinomyicn | 3.86±0.08 |
As can be seen from the results shown in the table above, compound 1 sodium salt has more significant inhibitory effect on MCF-7 cell proliferation in vitro than paclitaxel, and has IC (integrated Circuit) effect on MCF-7 cell strain50The value is reduced by 5.21 times compared with paclitaxel and 2.34 times compared with salinomycin. The sodium salt of the compound 1 has stronger inhibition effect on MCF-7 tumor cell proliferation, and the inhibition effect is obviously stronger than that of taxol.
Example 3:
MTT experiment is utilized to detect the inhibition effect of the compound 3 and the taxol on MCF-7 tumor cells, and the experimental method and the detection method are the same as those of the example 2, except that the compound 2 is adopted. Sodium salt of Compound 3 and IC of paclitaxel on MCF-7 cells50The values are shown in the following table.
Compound 2 sodium salt and paclitaxelIC on MCF-7 cells50Value of
Test article | IC for MCF-750(μmol/L) |
Compound 2 sodium salt | 2.25±0.19 |
Paclitaxel | 8.49±1.43 |
Salinomyicn | 3.86±0.08 |
The results shown in the table show that the sodium salt of the compound 2 has more remarkable inhibition effect on MCF-7 cell proliferation in vitro than salinomycin and paclitaxel, and the sodium salt has IC (integrated Circuit) of MCF-7 cell strains50The value is reduced by 3.77 times compared with taxol and is equivalent to salinomycin. The sodium salt of the compound 2 has stronger inhibition effect on MCF-7 tumor cell proliferation, and the inhibition effect is obviously stronger than that of taxol.
Example 4:
MTT experiment is utilized to detect the inhibition effect of the compound 3 and the taxol on MCF-7 tumor cells, and the experimental method and the detection method are the same as those of the example 2, except that the compound 3 is adopted. Sodium salt of Compound 3 and IC of paclitaxel on MCF-7 cells50The values are shown in the following table.
Test article | IC for MCF-750(μmol/L) |
Compound 3 sodium salt | 5.19±1.4 |
Paclitaxel | 8.49±1.43 |
Salinomyicn | 3.86±0.08 |
As shown in the results, the sodium salt of compound 3 has more significant inhibition effect on MCF-7 cell proliferation in vitro than paclitaxel, and has IC (integrated Circuit) effect on MCF-7 cell strain50The value is reduced by 1.61 times compared with that of taxol. The sodium salt of the compound 4 has stronger inhibition effect on MCF-7 tumor cell proliferation, the inhibition effect is stronger than that of taxol, but the anticancer activity is inferior to that of salinomycin.
Example 5:
the preparation method of the sodium salt derivative compound of the compound with the general formula is as follows:
Example 6:
the preparation method of the sodium salt derivative compound of the compound with the general formula is as follows:
Example 7
The inhibition effect of the compounds 1, 2 and 3 on various tumor cells is detected, and the specific method is as follows:
(1) cell recovery: before the experiment, the surface of the ultra-clean workbench is irradiated by ultraviolet rays for 30 min. Preheating the water bath to 37 deg.C, and preheating the freshly prepared culture medium in the water bath. Taking out the frozen cells, quickly putting the frozen tube into a preheated water bath kettle for quick thawing, and continuously shaking to quickly thaw the liquid in the tube. After about 1-2min, the liquid in the freezing tube is completely dissolved, and the freezing tube is taken out and wiped on the outer wall of the freezing tube by a cotton ball containing 70% alcohol. The cells in the cryopreserved tubes were aspirated and transferred to 15ml centrifuge tubes, while 5ml of pre-warmed complete medium was added. Centrifuging at low speed of 500g for 3-5min, and removing supernatant. 10ml of culture solution is added into a centrifugal tube, and the mixture is gently blown and beaten into cell suspension. After counting and viability determination by trypan blue staining, the cell suspension was added to a 10cm dish and incubated overnight in an incubator containing 37 ℃/5% CO 2.
(2) Cell culture: the culture medium and the passage ratio required by the cell culture are referred to ATCC, and the culture medium of the cell is changed into phenol red-free culture medium + 10% FBS in the first passage culture process before the cell experiment.
(3) Cell inhibition experiments: all compound samples were diluted in DMSO at 8-concentration 5-fold gradient and tested in complete media without phenol red to prepare solutions at the experimental concentration (5-fold final concentration).
The cell viability detection method comprises the following steps:
a) inoculating cells: log phase cells were collected, cell suspension concentration was adjusted, 40 μ l of cell suspension was seeded in 384-well plates, and marginal wells were filled with sterile PBS.
b) The cell plates were incubated overnight at 37 ℃/5% CO2 incubator and 10 μ L of a 5-fold test concentration sample of the compound was added the next day.
c) Cells were incubated at 37 ℃/5% CO2Incubations were performed in an incubator and observed with an inverted microscope for 72 hours.
d) Reading a plate: after 72 hours incubation at room temperature for 10min, 30. mu.L of CellTiter-Glo reaction mixture per well was added, the plate was shaken for 2-3 min and incubated at room temperature for 10 min. RLU values were read at Phetastar (BMG labtech) and the data saved.
Cell Growth inhibition% × 100% × [1-RLU sample/RLU negative ], where RLU samples are RLU values for wells with sample or positive control wells and RLU negative is RLU values with DMSO only. Data analysis is carried out by using GraphPad Prism 6.0 software, and the results are shown in the following table, which shows that the compound has obvious inhibition effect on various tumors.
IC of Compound 1, Compound 2 and Compound 3 on various tumor cells50Value of
Example 8:
the inhibition effect of the compound 1, the compound 2 and the compound 3 on the proliferation of the tumor stem cells is detected by the following specific method:
(1) content determination of enriched stem cells in suspension culture:
cell culture object: human breast cancer cell line MDA-MB-231 cells.
The culture mode is as follows: culturing by adopting a suspension cell culture mode and culturing in a 37-degree incubator.
Suspension cell culture medium (200 ml): b274 ml; 80 μ l of insulin; DMEM-F12194 ml; 40 μ l of hEGF; double resistance: 2ml of
Culture bottles: t25(15 ml); t75(75 ml);
inoculation density: 1000/ml;
the detection kit comprises: aldefluorTM kit;
Culturing time: about 10 to 15 days (shake more than 2 times per day).
The experimental process comprises the following steps:
(1) after the cells are cultured, the cells are subpackaged into 15ml centrifuge tubes, T25 bottles are cleaned once, and 250g of balancing centrifugation is carried out for 10 min;
(2) the supernatant was removed, 1ml (0.05%) of each pancreatin was added and washed once with PBS, transferred to a T25 flask and gently pipetted into individual cells for 5min to 10 min;
(3) transferring to a 15ml centrifuge tube, and carrying out balancing centrifugation for 250g for 10 min;
(4) adding 1ml PBS in two times, transferring to 1.5ml EP tube, beating uniformly, taking a small amount to count;
(5) counting 10-20 ten thousand cells and an EP tube, centrifuging to remove PBS, and adding 1ml of kit buffer solution for resuspension;
(6) adding 10 μ l of DEAB into another EP tube, adding 10 μ l of activated Aldfluor reagent into the cell EP tube, quickly mixing, sucking 0.5ml of activated DEAB into the EP tube, mixing well, and culturing in a 37-degree incubator for 45 min;
(7) after 45min, the supernatant was removed by centrifugation (250g, 10min), 0.5ml of reagent buffer was added for resuspension, and the cells were kept on ice in the dark.
The flow cytometry is adopted to detect the cells, and the experimental result is shown in figure 4, the content of the stem cells in the adherent cells is 2.36%, and the proportion of the stem cells obtained after the suspension cell culture is 25.95%, so that the improvement is nearly 11 times. There were significant differences between the data. Thus, we can see that the purpose of enriching the stem cells is achieved.
(2) Drug inhibition test:
medicine preparation: compound 1, compound 2 and compound 3
Cell types: step (1) enriched stem cells
Cell inoculation: cells were seeded in 96 wells at 12000 cells per well per 120. mu.L.
Diluted concentration of drug: dilution with PBS: setting the concentration: 100. mu.g/ML, 20. mu.g/ML, 4. mu.g/ML, 0.8. mu.g/ML, 0.16. mu.g/ML, 0.032. mu.g/ML, 0.0064. mu.g/ML, 0.00128. mu.g/ML, 0.000256. mu.g/ML.
Adding a compound: the cell plates were incubated overnight at 37 ℃/5% CO2 incubator and 10 μ L of a 5-fold test concentration sample of the compound was added the next day.
Detection time and detection mode: after 72h of administration, the assay was performed by MTT method, followed by dissolution in a triple solution (10% SDS, 5% isobutanol, 0.1% concentrated HCl) and OD detection at 570nm with a microplate reader.
Each compound was independently repeated once. The results are shown in the following table
Test drug | IC50(g/ml) |
|
1.176E-06±0.041 |
Compound 2 | 2.35E-06±0.152 |
Compound 3 | 4.251E-06±0.129 |
The results show that the compound 1, the compound 2 and the compound 3 have obvious inhibition effect on tumor stem cells, so that the relapse of tumors can be inhibited.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (2)
1. Use of a polyether compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer and prevention of cancer recurrence, said polyether compound being one of:
the cancer is selected from brain cancer cell T98G, brain cancer cell U-87MG, skin cancer cell MeWo, skin cancer cell SK-MEL-2, renal cancer cell A-498, renal cancer cell ACHN, liver cancer cell SK-HEP-1, liver cancer cell Hep 3B2.1-7, liver cancer cell Hep G2, bone cancer cell MG-63, bone cancer cell SJSA-1, synovial sarcoma cell SW 982, ovarian cancer cell SK-OV-3, ovarian cancer cell OVCAR-4, prostate cancer cell PC-3, prostate cancer cell DU 145, uterine sarcoma cell SK-UT-1, uterine sarcoma cell MES-SA/Dx5, rhabdomyosarcoma cell A-204, rhabdomyosarcoma cell A-673, melanoma cell G-361, melanoma cell A375, colon cancer cell HCT 116, melanoma cell, Colo 205 colon cancer cells, MKN-45 stomach cancer cells, NUGC-4 stomach cancer cells, A549 lung cancer cells, Calu-3 lung cancer cells, MD spleen macrophages, MV-4-11 blood cancer cells, K562 blood cancer cells, AHH-1 lymph cancer cells, Jurkat lymphoma cells, DOHH2 lymphoma cells, HPAC pancreatic cancer cells, MIA pancreatic cancer cells, PaCa-2 pancreatic cancer cells and MCF-7 breast cancer cells.
2. The use according to claim 1, wherein the medicament prevents cancer recurrence by inhibiting tumor cell stem cell proliferation.
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