CN109535068B - Pyridine substituted chalcone compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents
Pyridine substituted chalcone compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a pyridine substituted chalcone compound with a structure shown in a general formula I or a pharmaceutically acceptable salt thereof, and also discloses a preparation method and application of the compound or the pharmaceutically acceptable salt thereof. The compound or the medicinal salt thereof has small toxic and side effect, strong water solubility and difficult generation of drug resistance, can effectively inhibit the aggregation of tubulin, has stronger in-vitro and in-vivo anti-tumor activity, is more stable in metabolism and has good pharmacy prospect. The invention also comprises the combined application of the pyridine substituted chalcone compound or the pharmaceutically acceptable salt thereof and the TACC3 inhibitor to effectively inhibit the activity of the tumor cells with drug resistance to the tubulin.
Wherein the content of the first and second substances,
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a pyridine substituted chalcone compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Microtubules are the major components of the cytoskeleton and play an important role in maintaining cell morphology, cell division, signal transduction, etc., and therefore, tubulin is a promising target for novel chemotherapeutic drugs. Tubulin inhibitors can prevent the hyperproliferation of tumor cells and are an important class of anti-tumor therapeutic drugs. Currently, clinically used microtubule inhibitors mainly include drugs for inhibiting tubulin depolymerization, represented by paclitaxel, and drugs for inhibiting tubulin aggregation, represented by vinblastine. The drugs have the defects of large toxic and side effects, large synthesis difficulty, poor water solubility, easy generation of drug resistance and the like.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a pyridine substituted chalcone compound or pharmaceutically acceptable salt thereof, which has small toxic and side effects and strong water solubility and is not easy to generate drug resistance.
Another object of the present invention is to provide a process for the preparation of the above compound or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a pharmaceutical composition.
The last object of the present invention is to provide the use of the above compound or its pharmaceutically acceptable salt in the preparation of a medicament for treating diseases including, but not limited to, liver cancer, stomach cancer, colon cancer, breast cancer or hematological cancer.
The technical scheme is as follows: the invention provides a pyridine substituted chalcone compound with a structure shown in a general formula I or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
R 1 selected from hydrogen, lower alkanes, hydroxy, methoxy, halogen, cyano, ester, amide, carboxyl,Secondary amino, tertiary amino, hydroxymethyl or aldehyde group, wherein the lower alkane is alkane with 1-6 carbon atoms;
R 2 selected from hydrogen, lower alkanes, hydroxyl, methoxy, halogen, cyano, ester groups, amide groups, carboxyl groups, secondary amino groups, tertiary amino groups, hydroxymethyl groups or aldehyde groups;
R 3 selected from hydrogen, lower alkanes or halogen;
R 4 selected from hydroxy, amino, halogen, methoxy, methylthio, boronic acid, amino acid, hydroxymethyl or hydroxyethyl;
R 5 Selected from hydroxy, amino, halogen, methoxy, methylthio, boronic acid or phosphate groups;
R 6 selected from hydrogen, lower alkane, methoxy, hydroxymethyl, aromatic acyl or fatty acyl;
R 7 selected from hydrogen, lower alkanes, methoxy or halogen;
x is selected from C or N;
the position substituted by the alkenyl is 3-position, 4-position, 5-position, 6-position or 7-position of the indole.
Further, R 1 Selected from hydrogen, lower alkanes, hydroxy, methoxy, halogen, secondary or tertiary amino;
R 2 selected from hydrogen, lower alkanes, hydroxy, methoxy, halogen, secondary or tertiary amino;
R 3 selected from hydrogen or methyl;
R 4 selected from methoxy;
R 5 selected from hydroxyl;
R 6 selected from hydrogen, acetyl, benzoyl or hydroxymethyl;
R 7 selected from hydrogen;
x is selected from N;
the position substituted by the alkenyl is 3-position, 4-position or 5-position of the indole.
Further, the pyridine substituted chalcone compound with the general formula I or a pharmaceutically acceptable salt thereof is any one of the following compounds:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (4-methoxyphenyl) -2-methylpropan-2-en-1-one, having the following structural formula:
(E) -3- (3, 4-dimethoxyphenyl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one of the following structural formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -2-methyl-3- (3, 4, 5-trimethoxyphenyl) -propan-2-en-1-one having the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-4-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-5-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-6-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (5-methoxy-1H-indol-3-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (6-methoxy-1H-indol-3-yl) -2-methylpropan-2-en-1-one of the following structural formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -2-methyl-3- (1-methyl-1H-indol-5-yl) propan-2-en-1-one of the formula:
(E) -1- (2-chloro-6-methoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dichloropyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one, having the following structural formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (4-methoxyphenyl) propan-2-en-1-one having the following structural formula:
(E) -3- (3, 4-dimethoxyphenyl) -1- (2, 6-dimethoxypyridin-4-yl) propan-2-en-1-one having the following structural formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one having the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (4-methylthiophenyl) propan-2-en-1-one having the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) propan-2-en-1-one having the following structural formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-fluoro-4-methoxyphenyl) propan-2-en-1-one having the following structural formula:
(E) -3- (1-benzoyl-1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one, of the formula:
(E) -3- (1-acetyl-1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1- (furan-2-formyl) -1H-indol-3-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1-hydroxymethyl-1H-indol-3-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1-ethyl-1H-indol-3-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (5-fluoro-1H-indol-3-yl) -2-methylpropan-2-en-1-one of the following structural formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (6-fluoro-1H-indol-3-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -3- (5-chloro-1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one of the formula:
(E) -3- (6-chloro-1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one, of the formula:
(E)-4-(
-1- (3, 5-dimethoxyphenyl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one, of the formula:
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one hydrochloride having the following structural formula:
A pharmaceutical composition, which comprises a therapeutically effective amount of one or more pyridine-substituted chalcone compounds with a structure shown in the general formula I according to any one of claims 1 to 3 or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
The preparation method of the pyridine substituted chalcone compound or the pharmaceutically acceptable salt thereof comprises the following steps:
(1)
(2)
wherein the content of the first and second substances,
(1) reacting 2, 6-dichloroisonicotinic acid with ethyl magnesium bromide to obtain an intermediate 2, 6-dichloro-4-propionyl pyridine, protecting ketocarbonyl of the 2, 6-dichloro-4-propionyl pyridine under the condition of 2-bromoethanol to obtain an intermediate I, reacting the intermediate I with sodium methoxide at 80-120 ℃ to obtain an intermediate III, and reacting with sodium methoxide at 60-80 ℃ to obtain an intermediate II;
(2) and respectively removing protection from the intermediate I, the intermediate II and the intermediate III under the condition of concentrated hydrochloric acid to obtain an intermediate IV, an intermediate V and an intermediate VI, and respectively carrying out condensation reaction on the intermediate IV, the intermediate V and the intermediate VI and aldehyde to obtain a final product pyridine chalcone.
Further, the aldehyde is 3-hydroxy-4-methoxybenzaldehyde, 4-methoxybenzaldehyde or indole-3-formaldehyde.
The pyridine substituted chalcone compound or the medicinal salt thereof can be used for preparing antitumor medicaments.
Further, the tumor is liver cancer, gastric cancer, colon cancer, breast cancer or blood cancer.
Has the advantages that: the compound or the medicinal salt thereof has small toxic and side effect, strong water solubility and difficult drug resistance generation, can effectively inhibit the aggregation of tubulin, has stronger in-vitro and in-vivo anti-tumor activity, and has more stable metabolism and good medicament prospect compared with Combretastatin A-4.
Detailed Description
Example 1
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (4-methoxyphenyl) -2-methylpropan-2-en-1-one
(a) Dissolving 2, 6-dichloroisonicotinic acid (10g, 52mmol) in anhydrous THF, adding 2M ethyl magnesium bromide (80mL, 160mmol) dropwise under ice bath condition, reacting at room temperature for 2h, adding water for dilution, extracting with dichloromethane (50mL × 3), mixing organic phases, washing with saturated salt solution, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (PE/EA 4: 1) to obtain 9g of 1- (2, 6-dichloropyridin-4-yl) propane-1-one with a yield of 85%;
(b) 1- (2, 6-dimethylpyridin-4-yl) propan-1-one (6g, 29.4mmol) was dissolved in toluene, DBU (12.43ml, 88.2mmol), 2-bromoethanol (10.42ml, 147mmol) were added, and the reaction was allowed to proceed overnight at 80 ℃. Spin-drying toluene, diluting with water, extracting with dichloromethane (20mL × 3), mixing organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (PE/EA 40: 1) to obtain 6g of 2, 6-dichloro-4- (2-ethyl-1, 3-dioxane-2 yl) pyridine with a yield of 83%;
(c) 2, 6-dichloro-4- (2-ethyl-1, 3-dioxan-2-yl) pyridine (5g, 20.2mmol) was dissolved in methanol, sodium methoxide (10.89g, 202mmol) was added, and the reaction was allowed to proceed overnight at 100 ℃ with a sealed tube. Diluting rotary-dried methanol with water, extracting with dichloromethane (20mL multiplied by 3), combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, adding concentrated hydrochloric acid, reacting at room temperature for 2 hours, adding 2M sodium hydroxide solution to adjust the pH to be neutral, extracting with dichloromethane (20mL multiplied by 3), combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (PE/EA 4: 1) to obtain 3.2g of 1- (2, 6-dimethoxypyridin-4-yl) propan-1-one with the yield of 81%;
(d) dissolving 1- (2, 6-dimethoxypyridin-4-yl) propan-1-one (100mg, 0.51mmol) and 3-hydroxy-4-methoxybenzaldehyde (78mg, 0.51mmol) in absolute ethanol, adding sodium hydroxide particles (102mg, 2.55mmol), reacting at room temperature for 2h, diluting with water, extracting with dichloromethane (20mL × 3), mixing the organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (PE/EA 4: 1) to obtain 127mg of a yellow solid with a yield of 80%;
1 H NMR(300MHz，CDCl 3 )δ7.40(d，J＝8.4Hz，2H)，7.23(s，1H)，6.93(d，J＝8.4Hz，2H)，6.45(s，2H)，3.95(s，6H)，3.85(s，3H)，2.23(s，3H)； 13 CNMR(75MHz，CDCl 3 )δ1196.29，165.34，159.68，148.80，139.45，136.06，131.09，131.03，113.60，101.89，55.30，53.83，16.51；ESI-MS m/z：313.1 calcd for C 18 H 20 NO 4 [M+H] + 314.1。
example 2
(E) -3- (3, 4-dimethoxyphenyl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 100mg of a yellow solid was obtained in a yield of 72%;
1 H NMR(300MHz，CDCl 3 )δ7.21(s，1H)，7.14-7.03(m，3H)，6.45(s，2H)，3.93(s，6H)，3.88(s，6H)，2.11(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ196.33，165.45，150.34，149.26，149.11，138.82，136.39，129.75，124.08，112.72，111.80，101.84，55.98，55.89，53.80，16.41；ESI-MS m/z：343.1 calcd for C 19 H 22 NO 5 [M+H] + 344.1。
example 3
(E) -1- (2, 6-dimethoxypyridin-4-yl) -2-methyl-3- (3, 4, 5-trimethoxyphenyl) -propan-2-en-1-one
By following the procedure of example 1(d), 82mg of a yellow solid was obtained in a yield of 70%;
1 H NMR(300MHz，CDCl 3 )δ7.20(s，1H)，6.64(s，2H)，6.47(s，2H)，3.97(s，6H)，3.89(s，3H)，3.88(s，6H)，2.25(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ196.33，165.44，153.30，149.27，139.51，138.49，136.07，130.20，107.70，101.85，60.83，56.20，53.79，16.33；ESI-MS m/z：373.1 calcd for C 20 H 24 NO 6 [M+H] + 374.1。
example 4
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-4-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 102mg of a yellow solid was obtained in 83% yield;
1 H NMR(300MHz，CDCl 3 )δ9.60(s，1H)，7.85(d，J＝8.2Hz，1H)，7.43(d，J＝8.2，1H)，7.23(s，1H)，7.18-6.92(m，3H)，6.73(s，2H)，3.93(s，6H)，2.18(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ196.36，165.45，149.31，139.39，134.55，133.08，130.32，129.25，126.47，122.69，120.62，111.48，101.89，99.76，53.83，16.54.；ESI-MSm/z：322.1 calcd for C 19 H 19 N 2 O 3 [M+H] + 323.1。
example 5
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-5-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 77mg of a yellow solid was obtained in a yield of 87%;
1 H NMR(300MHz，CDCl 3 )δ9.72(s，1H)，7.93(d，J＝8.2Hz，1H)，7.44(dd，J＝8.4，2.2Hz，1H)，7.36(d，J＝8.4Hz，1H)，7.29(d，J＝8.2Hz，1H)，7.23(s，1H)，7.14(d，J＝2.2Hz，1H)，6.71(s，2H)，3.93(s，6H)，2.14(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ196.29，165.45，148.81，138.99，136.50，136.33，129.47，127.05，125.72，123.24，120.64，111.71，101.89，101.49，53.83，16.41；ESI-MS m/z：322.1 calcd for C 19 H 19 N 2 O 3 [M+H] + 323.1。
example 6
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-6-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 63mg of a yellow solid was obtained in a yield of 57%;
1 H NMR(300MHz，CDCl 3 )δ8.72(s，1H)，7.64(d，J＝8.4Hz，1H)，7.52(d，J＝2.2Hz，1H)，7.45(s，1H)，7.30(d，J＝8.4Hz，1H)，7.20(dd，J＝8.4，2.2Hz，1H)，6.56(d，J＝8.4Hz，1H)，6.49(s，2H)，3.95(s，6H)，2.31(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ196.29，165.45，148.81，139.16，136.04，136.00，131.39，129.72，125.67，121.00，120.51，110.61，102.62，101.89，53.83，16.41；ESI-MS m/z：322.1 calcd for C 19 H 19 N 2 O 3 [M+H] + 323.1。
example 7
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 92mg of a yellow solid was obtained in 89% yield;
1 H NMR(300MHz，CDCl 3 )δ8.82(s，1H)，7.71(s，1H)，7.62(m，1H)，7.56(d，J＝8.1Hz，1H)，7.42(d，J＝8.1Hz，1H)，7.18(s，1H)，6.86(s，2H)，6.56(m，1H)，3.83(s，6H)，2.30(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ198.78，160.43，141.55，135.76，131.55，127.60，126.43，123.28，120.95，118.52，113.24，111.52，107.06，103.53，55.57，15.01；ESI-MS m/z：322.1 calcd for C 19 H 19 N 2 O 3 [M+H] + 323.1。
example 8
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (5-methoxy-1H-indol-3-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 97mg of a yellow solid was obtained in a yield of 86%;
1 H NMR(300MHz，CDCl 3 )δ8.65(s，1H)，7.65(s，1H)，7.62(s，1H)，7.52(s，1H)，7.32(s，1H)，6.95(s，1H)，6.52(s，2H)，3.97(s，6H)，3.84(s，3H)，2.26(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ195.77，165.44，153.64，148.87，132.46，131.14，130.09，128.52，126.21，113.30，112.63，111.78，103.56，101.84，55.65，53.80，16.65；ESI-MS m/z：352.1 calcd for C 20 H 21 N 2 O 4 [M+H] + 353.1。
Example 9
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (6-methoxy-1H-indol-3-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 53mg of a yellow solid was obtained in a yield of 77%;
1 H NMR(300MHz，CDCl 3 )δ8.65(s，1H)，7.85(s，1H)，7.63(s，1H)，7.52(s，1H)，7.12(s，1H)，6.85(s，1H)，6.52(s，2H)，3.97(s，6H)，3.84(s，3H)，2.26(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ195.77，165.44，153.64，148.87，132.46，131.14，130.09，128.52，126.21，113.30，112.63，111.78，103.56，101.84，55.65，53.80，16.65；ESI-MS m/z：352.1 calcd for C 20 H 21 N 2 O 4 [M+H] + 353.1。
example 10
(E) -1- (2, 6-dimethoxypyridin-4-yl) -2-methyl-3- (1-methyl-1H-indol-5-yl) propan-2-en-1-one
Following the procedure of example 7, (E) -3- (1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one was obtained. Dissolving (E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one (90mg, 0.29mmol) in anhydrous DMF, adding sodium hydride (10mg, 0.43mmol) and iodomethane (22. mu.l, 0.37mmol) to react at room temperature for 1H, adding water to dilute, and filtering to obtain a yellow solid 70mg, yield 82%;
1 H NMR(300MHz，CDCl 3 )δ7.88(d，J＝8.4Hz，1H)，7.58(d，J＝8.4Hz，1H)，7.36(dd，J＝8.4，2.2Hz，1H)，7.25(d，J＝2.2Hz，1H)，7.13(s，1H)，6.72(s，2H)，6.69(d，J＝8.4Hz，1H)，3.93(s，6H)，3.66(s，3H)，2.14(s，3H)。 13 C NMR(75MHz，CDCl 3 )δ196.33，165.45，148.81，138.99，137.17，136.52，131.30，128.90，128.66，125.60，120.54，108.94，101.83，100.53，53.80，32.16，16.41；ESI-MS m/z：336.1 calcd for C 20 H 21 N 2 O 3 [M+H] + 337.1。
example 11
(E) -1- (2-chloro-6-methoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one
Following the procedures of example 1(a), (b), 2, 6-dichloro-4- (2-ethyl-1, 3-dioxan-2-yl) pyridine was obtained;
dissolving 2, 6-dichloro-4- (2-ethyl-1, 3-dioxane-2 yl) pyridine (5g, 20.2mmol) in methanol, adding sodium methoxide (10.89g, 202mmol), reacting at 60 ℃ overnight, diluting with water in spin-dried methanol, extracting with dichloromethane (20mL × 3), combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating, adding concentrated hydrochloric acid, reacting at room temperature for 2h, adding 2M sodium hydroxide solution to adjust pH to neutrality, extracting with dichloromethane (20mL × 3), combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (PE/EA 4: 1) to obtain 3.2g of 1- (2-chloro-6-methoxypyridin-4-yl) propan-1-one with a yield of 80%; by following the procedure of example 1(d), 50mg of a yellow solid was obtained in 83% yield;
1 H NMR(300MHz，CDCl 3 )δ7.35(s，1H)，7.25(s，1H)，7.13(d，J＝8.4Hz，1H)，7.11(s，1H)，7.05(d，J＝2.2Hz，1H)，6.95(dd，J＝8.4，2.2Hz，1H)，3.92(s，3H)，3.92(s，3H)，2.12(s，3H). 13 C NMR(75MHz，CDCl 3 )δ196.14，165.18，150.53，148.82，147.56，147.00，138.51，136.33，130.61，122.20，117.82，115.36，112.46，106.91，56.21，53.75，16.41；ESI-MS m/z：333.1 calcd for C 17 H 17 ClNO 4 [M+H] + 334.1。
Example 12
(E) -1- (2, 6-dichloropyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one
By following the procedures of examples 1(a), (d), 60mg of a yellow solid was obtained in 65% yield;
1 H NMR(300MHz，CDCl 3 )δ7.78(s，2H)，7.13(d，J＝8.4Hz，1H)，7.11(s，1H)，7.05(d，J＝2.2Hz，1H)，6.95(dd，J＝8.4，2.2Hz，1H)，3.92(s，3H)，2.12(s，3H)。 13 C NMR(75MHz，CDCl 3 )δ195.86，150.80，148.77，146.98，144.85，138.17，136.33，130.60，122.54，122.20，115.38，112.46，56.20，16.41；ESI-MS m/z：337.1 calcd for C 17 H 14 Cl 2 NO 3 [M+H] + 338.1。
example 13
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 30mg of a yellow solid was obtained in 85% yield;
1 H NMR(300MHz，CDCl 3 )δ7.18(d，J＝2.2Hz，1H)，7.08(d，J＝8.4Hz，1H)，6.94(dd，J＝8.4，2.2Hz，1H)，6.88(s，1H)，6.45(s，2H)，3.96(s，6H)，3.94(s，3H)，2.23(s，3H). 13 C NMR(75MHz，CDCl 3 )δ196.29，165.45，149.26，148.45，146.96，138.84，136.33，130.61，122.16，115.36，112.39，101.89，56.22，53.80，16.41；ESI-MS m/z：329.1 calcd for C 18 H 20 NO 5 [M+H] + 330.1。
example 14
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (4-methoxyphenyl) propan-2-en-1-one
By following the procedure of example 1(d), 31mg of a yellow solid was obtained in 83% yield;
1 H NMR(300MHz，CDCl 3 )δ7.76(d，J＝15.7Hz，1H)，7.59(d，J＝8.6Hz，2H)，7.21(d，J＝15.7Hz，1H)，6.94(d，J＝8.6Hz，2H)，6.77(s，2H)，3.97(s，6H)，3.87(s，3H). 13 C NMR(75MHz，CDCl 3 )δ190.04，165.60，161.81，145.78，144.78，130.80，127.91，122.28，114.34，100.75，55.30，53.83；ESI-MS m/z∶299.1 calcd for C 17 H 18 NO 4 [M+H] + 300.1。
example 15
(E) -3- (3, 4-dimethoxyphenyl) -1- (2, 6-dimethoxypyridin-4-yl) propan-2-en-1-one
Following the procedure of example 1(d), 51mg of a yellow solid was obtained in 73% yield;
1 H NMR(300MHz，CDCl 3 )δ7.75(d，J＝15.7Hz，1H)，7.27(d，J＝2.2Hz，1H)，7.22(d，J＝15.7Hz，1H)，7.18(dd，J＝8.2，2.2Hz，1H)，6.90(d，J＝8.2Hz，1H)，6.78(s，2H)，3.98(s，6H)，3.96(s，3H)，3.94(s，3H). 13 C NMR(75MHz，CDCl 3 )δ190.00，165.71，151.18，151.17，146.74，143.64，129.10，123.50，122.21，112.06，110.51，100.75，56.04，56.00，53.80；ESI-MS m/z：329.1 calcd for C 18 H 20 NO 5 [M+H] + 330.1。
example 16
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one
By following the procedure of example 1(d), 63mg of a yellow solid was obtained in 83% yield;
1 H NMR(300MHz，CDCl 3 )δ7.55(d，J＝15.6Hz，1H)，7.48(d，J＝15.7Hz，1H)，6.97(s，2H)，6.95(s，2H)，3.93(s，6H)，3.88(s，6H)，3.80(s，3H) 13 C NMR(75MHz，CDCl 3 )δ189.84，165.71，153.41，146.84，145.73，141.12，130.52，122.23，106.08，100.69，60.83，56.23，53.81；ESI-MS m/z：359.1 calcd for C 19 H 22 NO 6 [M+H] + 360.1。
example 17
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (4-methylthiophenyl) propan-2-en-1-one
By following the procedure of example 1(d), 59mg of a yellow solid was obtained in a yield of 72%;
1 HNMR(300MHz，CDCl 3 )δ7.74(d，J＝15.7Hz，1H)，7.53(d，J＝8.2Hz，2H)，7.30(d，J＝15.7Hz，1H)7.24(d，J＝8.2Hz，2H)，6.77(s，2H)，3.97(s，6H)，2.52(s，3H). 13 C NMR(75MHz，CDCl 3 )δ189.98，165.60，146.43，144.23，138.11，132.51，128.67，127.33，122.06，100.75，53.83，15.41；ESI-MS m/z：315.1 calcd for C 17 H 18 NO 3 S[M+H] + 316.1。
example 18
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) propan-2-en-1-one
By following the procedure of example 1(d), 83mg of a yellow solid was obtained in a yield of 72%;
1 HNMR(300MHz，CDCl 3 )δ7.65(d，J＝15.7Hz，1H)，7.46(d，J＝2.2Hz，1H)，7.40(d，J＝15.7Hz，1H)7.12(d，J＝8.2Hz，1H)，7.06(dd，J＝8.2，2.2Hz，1H)，6.97(s，2H)，3.93(s，6H)，3.82(s，3H). 13 C NMR(75MHz，CDCl 3 )δ190.00，165.60，148.28，148.20，146.68，143.69，129.56，123.13，122.50，114.83，113.52，100.75，56.22，53.83；ESI-MS m/z：315.1 calcd for C 17 H 18 NO 5 [M+H] + 316.1。
example 19
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-fluoro-4-methoxyphenyl) propan-2-en-1-one
By following the procedure of example 1(d), 77mg of a yellow solid was obtained in 66% yield;
1 HNMR(300MHz，CDCl 3 )δ7.65(d，J＝15.7Hz，1H)，7.46(d，J＝2.2Hz，1H)，7.40(d，J＝15.7Hz，1H)7.12(d，J＝8.2Hz，1H)，7.06(dd，J＝8.2，2.2Hz，1H)，6.97(s，2H)，3.93(s，6H)，3.82(s，3H). 13 C NMR(75MHz，CDCl 3 )δ190.00，165.60，153.33，151.31，148.39，146.55，144.03，129.44，125.21，122.24，115.60，115.21，100.75，56.49，53.83.；ESI-MS m/z：317.1 calcd for C 17 H 16 FNO 4 [M+H] + 318.1.
example 20
(E) -3- (1-benzoyl-1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one
Following the procedure of example 7, (E) -3- (1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one was obtained. Dissolving (E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one (100mg, 0.32mmol) in anhydrous DCM, adding solid sodium hydroxide (31mg, 0.80mmol), dropwise adding benzoyl chloride (54. mu.l, 0.48mmol) to react at room temperature for 1H, adding water for dilution, extracting with dichloromethane (50 mL. times.3), combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (PE/EA 10: 1) to obtain a white solid 100mg, the yield is 73%;
1 HNMR(300MHz，CDCl 3 )δ8.34(d，J＝8.2Hz，1H)，7.84-7.75(m，2H)，7.62(dq，J＝14.9，7.4Hz，4H)，7.54-7.30(m，4H)，6.50(s，2H)，3.98(s，6H)，2.16(s，3H). 13 C NMR(75MHz，CDCl 3 )δ196.76，168.49，163.33，151.73，135.75，133.94，133.86，132.62，129.98，129.32，128.86，128.17，125.95，124.43，118.80，117.24，116.39，100.63，53.85，14.54.；ESI-MSm/z：426.1calcd for C 26 H 23 N 2 O 4 [M+H] + 427.1。
example 21
(E) -3- (1-acetyl-1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 20, 30mg of a pale yellow solid was obtained in 52% yield;
1 HNMR(300MHz，CDCl 3 )δ8.43(d，J＝8.2Hz，1H)，7.73(s，1H)，7.53-7.30(m，4H)，6.52(s，2H)，3.98(s，6H)，2.74(s，3H)，2.30(s，3H). 13 C NMR(75MHz，CDCl 3 )δ196.80，168.48，163.34，151.68，135.82，135.27，133.87，129.72，126.22，125.72，124.21，118.72，117.84，116.61，100.64，53.86，24.14，14.74；ESI-MSm/z：364.1calcd for C 21 H 21 N 2 O 4 [M+H] + 365.1。
Example 22
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1- (furan-2-formyl) -1H-indol-3-yl) -2-methylpropan-2-en-1-one
Following the procedure of example 20, 65mg of a pale yellow solid was obtained in 71% yield;
1 HNMR(300MHz，CDCl 3 )δ8.48(d，J＝8.2Hz，1H)，8.39(s，1H)，7.77(d，J＝1.7Hz，1H)，7.52(d，J＝4.7Hz，2H)，7.50-7.30(m，3H)，6.74(s，1H)，6.53(s，2H)，3.99(s，6H)，2.38(s，3H). 13 C NMR(75MHz，CDCl 3 )δ163.35，146.80，134.16，127.22，126.01，124.55，121.46，118.67，117.98，116.69，112.75，100.65，99.43，53.92，53.86，32.47，14.63，7.87.；ESI-MS m/z：416.1 calcd for C 24 H 21 N 2 O 5 [M+H] + 417.1。
example 23
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1-hydroxymethyl-1H-indol-3-yl) -2-methylpropan-2-en-1-one
Following the procedure of example 7, (E) -3- (1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one was obtained. Dissolving (E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one (100mg, 0.32mmol) in water, adding 1mL of 37% formaldehyde aqueous solution, reacting at 80 ℃ for 2H with a catalytic amount of TBAF (8mg, 10% mol), extracting with dichloromethane (50 mL. times.3), combining the organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (PE/EA 4: 1) to obtain 60mg of bright yellow solid with 53% yield;
1 HNMR(300MHz，CDCl 3 )δ7.90(m，1H)，7.69(m，1H)，7.46(m，1H)，7.30(m，1H)，7.25(m，1H)，7.23(s，1H)，6.72(s，2H)，5.76(s，2H)，3.93(s，6H)，2.21(s，3H). 13 C NMR(75MHz，CDCl 3 )δ195.43，165.44，148.87，137.89，133.11，132.01，128.92，125.56，123.87，121.43，121.36，115.80，110.08，101.84，70.04，53.80，16.29.；ESI-MS m/z：352.1 calcd for C 20 H 21 N 2 O 4 [M+H] + 353.1。
example 24
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (1-ethyl-1H-indol-3-yl) -2-methylpropan-2-en-1-one
Following the procedure of example 10, 60mg of a yellow solid was obtained in 73% yield;
1 HNMR(300MHz，CDCl 3 )δ7.70(s，1H)，7.59(m，2H)，7.40(m，1H)7.31(s，1H)，7.19(m，1H)6.97(s，2H)，4.26(q，J＝7.0Hz，2H)，3.93(s，6H)，2.27(s，3H)，1.59(t，J＝7.0Hz，3H). 13 CNMR(75MHz，CDCl 3 )δ196.85，163.19，153.17，137.19，135.63，130.03，129.67，128.47，123.04，120.93，118.80，112.02，109.81，100.55，53.82，41.77，15.34，14.26.；ESI-MS m/z：350.1 calcd for C 21 H 23 N 2 O 3 [M+H] + 351.1。
example 25
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (5-fluoro-1H-indol-3-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 77mg of a yellow solid was obtained in 66% yield;
1 H NMR(300MHz，CDCl 3 )δ8.76(s，1H)，7.68(s，1H)，7.56(s，1H)，7.35(m，1H)，7.17(m，1H)，7.04(m，1H)，6.49(s，2H)，3.99(s，6H)，2.26(s，3H)； 13 C NMR(75MHz，DMSO)δ196.03，163.11，153.58，137.14，132.90，131.22，129.64，113.88，113.75，111.94，111.39，111.03，103.63，103.31，100.58，60.19，53.97；ESI-MS m/z：340.1 calcd for C 19 H 18 FN 2 O 3 [M+H] + 341.1。
example 26
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (6-fluoro-1H-indol-3-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 50mg of a yellow solid was obtained in 71% yield;
1 H NMR(300MHz，CDCl 3 )δ8.74(s，1H)，7.62(s，2H)，7.50-7.39(m，1H)，7.03(m，1H)，6.50(s，2H)，3.98(s，6H)，2.26(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ196.03，163.11，153.58，137.14，132.90，131.22，129.64，113.88，113.75，111.94，111.39，111.03，103.63，103.31，100.58，60.19，53.97；ESI-MS m/z：340.1 calcd for C 19 H 18 FN 2 O 3 [M+H] + 341.1。
example 27
(E) -3- (5-chloro-1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one
Following the procedure of example 1(d), 63mg of a yellow solid was obtained in 76% yield;
1 H NMR(300MHz，CDCl 3 )δ8.69(s，1H)，7.55(m，2H)，7.35(s，1H)，7.09(m，1H)，6.50(s，2H)，3.98(s，6H)，2.26(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ196.11，163.10，153.50，136.78，134.79，130.95，130.13，128.83，125.63，123.06，117.75，114.21，111.51，100.64，54.00，14.48.ESI-MS m/z：356.1 calcd for C 19 H 18 ClN 2 O 3 [M+H] + 357.1。
example 28
(E) -3- (6-chloro-1H-indol-3-yl) -1- (2, 6-dimethoxypyridin-4-yl) -2-methylpropan-2-en-1-one
Following the procedure of example 1(d), 82mg of a yellow solid was obtained in 83% yield
1 H NMR(300MHz，CDCl 3 )δ8.69(s，1H)，7.55(m，2H)，7.35(s，1H)，7.09(m，1H)，6.50(s，2H)，3.98(s，6H)，2.26(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ196.11，163.10，153.50，136.78，134.79，130.95，130.13，128.83，125.63，123.06，117.75，114.21，111.51，100.64，54.00，14.48.ESI-MS m/z：356.1 calcd for C 19 H 18 ClN 2 O 3 [M+H] + 357.1。
Example 29
(E) -1- (3, 5-dimethoxyphenyl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one
By following the procedure of example 1(d), 55mg of a yellow solid was obtained in 67% yield. 1 H NMR (300MHz，CDCl 3 )δ8.82(s，1H)，7.71(s，1H)，7.62(m，1H)，7.56(m，1H)，7.42(m，1H)，7.27(m，1H)，7.20(m，1H)，6.86(m，2H)，6.64(m，1H)，3.83(s，6H)，2.30(s，3H)； 13 C NMR(75MHz，CDCl 3 )δ197.89，160.43，141.55，135.76，135.56，131.55，127.60，126.43，123.28，120.95，118.52，113.24，111.52，107.06，103.53，55.57，15.01.ESI-MS m/z：321.1 calcd for C 20 H 20 NO 3 [M+H] + 322.1。
Example 30
(E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one hydrochloride
Following the procedure of example 13, (E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one was obtained. Dissolving (E) -1- (2, 6-dimethoxypyridin-4-yl) -3- (3-hydroxy-4-methoxyphenyl) -2-methylpropan-2-en-1-one (50mg, 0.15mmol) in ethyl acetate, slowly adding an ethyl acetate solution of hydrogen chloride dropwise, and performing suction filtration to obtain 49mg of a light yellow solid with the yield of 90%;
1 H NMR(300MHz，CDCl 3 )δ7.18(d，J＝2.2Hz，1H)，7.08(d，J＝8.4Hz，1H)，6.94(dd，J＝8.4，2.2Hz，1H)，6.88(s，1H)，6.45(s，2H)，3.96(s，6H)，3.94(s，3H)，2.23(s，3H). 13 C NMR(75MHz，CDCl 3 )δ196.29，165.45，149.26，148.45，146.96，138.84，136.33，130.61，122.16，115.36，112.39，101.89，56.22，53.80，16.41；ESI-MS m/z：365.1 calcd for C 18 H 20 NO 5 [M-Cl] + 330.1。
Example 31
Tablets were prepared by a conventional method using the formulation of Table 1.
TABLE 1 formulation composition
| Name (R) | Content (g/100 tablets) |
| Product of example 30 | 5g |
| Hydroxypropyl methylcellulose E5 | 1.5g |
| Microcrystalline cellulose MCC102 | 1.8g |
| 8% Povidone K30 | Proper amount of |
| Stearic acid magnesium salt | 0.2g |
Example 32: performance test
Pharmacological (antiproliferative) experiments of (a) part of the compounds:
1. experimental methods
(1) Digesting and counting cells to obtain a concentration of 5 × 10 4 Cell suspension at individual/MI, 100. mu.l of cell suspension was added to each well of a 96-well plate (5X 10 cells per well) 3 Individual cells);
(2) the 96-well plate was placed at 37 ℃ in 5% CO 2 Culturing in an incubator for 24 hours;
(3) examples 1-30 were diluted with complete medium to the desired concentration and then 100ul of the medium containing examples was added to each well;
(4) the 96-well plate was placed at 37 ℃ in 5% CO 2 Culturing for 72 hours in an incubator;
(5) MTT method:
a. MTT staining of 96-well plates, λ 490nm, and OD determination;
b. 20Ml MTT (5mg/Ml) was added to each well and the culture was continued in the incubator for 4 hours;
c. discarding the culture medium, adding 150Ml DMSO into each well for dissolving, and shaking for 10 min to mix gently; lambda is 490nm, and an enzyme-labeling instrument reads the OD value of each hole;
(6) calculating an inhibition rate:
2. results of the experiment
TABLE 2 IC of antiproliferative activity of the compounds of the invention against 5 human cancer cell lines 50 Value (μ M)
The 5 human cancer cell lines were derived from Kjeki Biotechnology development, Inc., cis-platinum and CA-4 as a control group.
And (4) conclusion: as can be seen from the table, example 13 shows superior antitumor activity for five cell lines, and the activity is superior to that of positive control CA-4 and cisplatin example.
(II) in vitro anti-tubulin aggregation assay of partial compounds:
1. experimental methods
And taking the compound mother liquor, diluting the compound mother liquor by times to a final concentration, and using the compound mother liquor for subsequent tests. Concentrations were set at 5, and each concentration was biologically repeated 3 times. The amount of tubulin (cytoskeleton) at 2mg/mL was resuspended in PEM buffer [80mM PIPES (pH6.9), 0.5mM EGTA, 2mM MgCl 2 And 15% glycerol]Then preincubated with compound or solvent DMSO for 5 minutes on ice. Before the tubulin polymerization was detected, GTP-containing PEG was added to a final concentration of 3 mg/mL. The absorbance was measured at 340nm after 30 minutes by means of a Berthold LB941 microplate-type multifunctional microplate reader. By setting blank control group, Graphpad calculates IC of different compounds 50 Results are in μ M.
2. Results of the experiment
Table 3 pharmacological test results of tubulin aggregation in vitro of a portion of the compounds of the invention:
And (4) conclusion: it can be seen from the table that the compounds tested all have a better effect in inhibiting tubulin polymerization, with the compounds of examples 7 and 13 being the most effective.
And (III) in vivo antitumor experiments of part of compounds:
1. experimental methods
90 female Balb/c nude mice with the week age of 3 weeks and the weight of 12-16g are provided by Shanghai Slek laboratory animals, Inc. Collecting cultured hepatocarcinoma H22 cells, counting, and adjusting cell suspension concentration to 1.5 × 10 7 One per ml, 0.1ml was inoculated subcutaneously per axilla on the right side of nude mice. Measuring the diameter of the nude mouse transplanted tumor with a vernier caliper, and after 7 days of tumor cell inoculation, the tumor grows to 50-75mm 3 At this time, 10 mice were divided into 9 groups at random. Dissolving the compound in DMSO, dripping poloxamer mother liquor, and adding physiological saline to required dosage. The final concentration of DMSO was 1% and the final concentration of poloxamer was 2%. Each group of nude mice is administrated, the abdominal cavity of the model group is injected with equal amount of solvent for 1 time per day for 21 days; injecting 20mg/kg cis-platinum into tail vein of the positive control group, injecting 1 time per day for 21 days; experimental groups 20mg/kg of example 7, 13, 20, 23, 24, 30, CA-4 was injected intravenously. 1 injection per day for 21 days; the nude mice were sacrificed 21 days after the end of the administration, and the tumor mass was surgically removed and weighed. Tumor growth inhibition (%) was calculated, the results were analyzed by SPSS 17.0, and statistical analysis was performed between groups by t-test, which was calculated as follows:
2. Results of the experiment
TABLE 4 in vivo antitumor Activity of some of the Compounds of the invention
And (4) conclusion: it can be seen from the table that the compounds of examples 7, 13 and 30 showed better tumor growth inhibition activity, and the inhibition rates thereof were higher than those of the positive control cisplatin group and the CA-4 group, and the examples had better effect on the body weight of mice than the cisplatin group, which indicates that the compounds in the examples had less toxicity and better drug efficacy than cisplatin.
And (IV) the combination of part of compounds and TACC3 inhibitor inhibits drug-resistant tumor cell experiments:
as a member of the human acidic coillimated-coil-binding protein family, Transforming acidic coillimated-coil-binding protein 3(TACC3) is a key central body protein, which is up-regulated in many cancers. Although the specific mechanism of action of TACC3 is not clear, the combination of TACC3 inhibitor and paclitaxel tubulin inhibitor can effectively improve the sensitivity of paclitaxel-resistant tumor cells to the tubulin inhibitor, and is a potential strategy for solving the drug resistance of the tubulin inhibitor. After the partial compounds are combined with the TACC3 inhibitor KHS101, the sensitivity of drug-resistant tumor cells to the compounds can be greatly increased, the growth of the drug-resistant tumor cells can be effectively inhibited, and a new way for treating tumors by using the tubulin inhibitor is provided.
1. Experimental methods
(1) Tumor sensitive cells (HCT-8, A549) and tubulin-resistant tumor cells (HCT-8/Taxol, A549/Taxol) are digested, counted and prepared to a concentration of 5 × 10 4 Cell suspension at Per Ml, 100. mu.l of cell suspension per well in 96-well plates (5X 10 per well) 3 Individual cells);
(2) the 96-well plate was placed at 37 ℃ in 5% CO 2 Culturing in an incubator for 24 hours;
(3) the compounds representing examples 7 and 30 were diluted with complete medium to the desired concentration, and then 100ul of the medium containing examples was added to each well, while 5 μ M of the TACC3 inhibitor KHS101 was added to the tumor-resistant cell group;
(4) the 96-well plate was placed at 37 ℃ in 5% CO 2 Culturing for 72 hours in an incubator;
(5) MTT method:
a. MTT staining of 96-well plates, λ 490nm, and OD determination;
b. 20Ml MTT (5mg/Ml) was added to each well and the incubation was continued in the incubator for 4 hours;
c. discarding the culture medium, adding 150Ml DMSO into each well for dissolving, and shaking for 10 min to mix gently; lambda is 490nm, and an enzyme-labeling instrument reads the OD value of each hole;
(6) calculating an inhibition rate:
2. results of the experiment
Combination of the compound of Table 5 with the TACC3 inhibitor KHS101 for the inhibition of drug resistant tumor cells
And (4) conclusion: as can be seen from the table, the fold-resistance of examples 7 and 30 to drug-resistant tumor cells is smaller than that of paclitaxel, indicating that the compounds of the present invention are not easy to generate drug resistance. After the exemplified drugs 7 and 30 and the TACC3 inhibitor KHS101 are combined for use, the sensitivity of drug-resistant tumor cells to compounds can be greatly increased, the growth of the tumor drug-resistant cells can be inhibited, and a new way is provided for overcoming clinical tumor drug resistance at present.
Claims (4)
1. Pyridine substituted chalcones and pharmaceutically acceptable salts thereof, as shown in the following structure:
wherein:
R 1 selected from methoxy;
R 2 selected from methoxy;
R 4 selected from methoxy, methylthio;
R 5 selected from hydroxyl and methoxy;
R 6 selected from hydrogen, acetyl, benzoyl, hydroxymethyl;
R 7 selected from hydrogen and methoxy.
2. Pyridine substituted chalcones and pharmaceutically acceptable salts thereof, as shown in the following structure:
3. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to claim 1 and a pharmaceutically acceptable carrier.
4. Use of a compound of claim 1 or a salt thereof for the preparation of a medicament for the treatment of liver cancer diseases.
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