CN117886799A - Protein degradation targeting chimeric compound for targeting degradation of GSK-3 beta and application thereof - Google Patents

Protein degradation targeting chimeric compound for targeting degradation of GSK-3 beta and application thereof Download PDF

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CN117886799A
CN117886799A CN202410042092.3A CN202410042092A CN117886799A CN 117886799 A CN117886799 A CN 117886799A CN 202410042092 A CN202410042092 A CN 202410042092A CN 117886799 A CN117886799 A CN 117886799A
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gsk
beta
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叶青
完颜俊超
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses a protein degradation targeting chimeric compound for targeting degradation of GSK-3 beta and application thereof, wherein the compound has a structural general formula shown in a formula P: wherein: r is selected from one of the following: hydrogen, halogen, alkyl having 1 to 5 carbon atoms, and alkoxy having 1 to 5 carbon atoms; n=1-7. The compound provided by the invention has good inhibitory activity on GSK-3 beta, and can be used for treating GSK-3 beta targeted related diseases. According to the invention, GSK-3 beta inhibition activity tests are carried out on 9 synthesized target compounds P1-P9, and the results show that the target compounds show good inhibition activity on GSK-3 beta, and the IC 50 value is 1.41+/-0.29-5.46+/-0.25 mu M.

Description

Protein degradation targeting chimeric compound for targeting degradation of GSK-3 beta and application thereof
Technical Field
The invention mainly relates to a protein degradation targeting chimeric compound for targeting and degrading GSK-3 beta and application thereof.
Background
Glycogen synthase kinase 3 (GSK-3) belongs to a multifunctional serine protein kinase in the phosphotransferase family. Mammalian GSK-3 has two subtypes, namely GSK-3α and GSK-3β, which have a high degree of homology in their catalytic domains, but differ significantly in the C-terminal and N-terminal domains. GSK-3 alpha and GSK-3 beta have only 36% sequence identity at their carboxy terminus and GSK-3 alpha has a glycine-rich extension at its amino terminus. GSK-3β is highly contained in the brain, mainly concentrated in neurons and astrocytes, and its expression level increases with age. GSK-3β is a therapeutic target for many diseases, and GSK3 β is involved in regulating glucose metabolism, cell signaling, cell proliferation, growth, migration, differentiation, cell cycle, embryonic development, apoptosis, insulin response, and various transcription factors to regulate organ growth and death. GSK3 beta plays a role in a plurality of diseases, such as diabetes, alzheimer's disease inflammation, cancer and the like, and inhibition of the activity of the GSK3 beta has important significance for the treatment of the diseases, and development of a protein degradation targeting chimeric compound for targeting degradation of GSK-3 beta can effectively reduce the expression of GSK-3 beta in cells, thereby effectively treating the related diseases targeted by GSK-3 beta.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to provide a protein degradation targeting chimeric compound for targeting and degrading GSK-3 beta and application thereof, and the compound is used for treating related diseases.
The technical scheme of the invention is as follows:
A protein degradation targeting chimeric compound for targeting and degrading GSK-3 beta, which has a structural general formula shown in a formula P:
wherein: r is selected from one of the following: hydrogen, halogen, alkyl having 1 to 5 carbon atoms, and alkoxy having 1 to 5 carbon atoms; n=1-7.
The invention also provides a synthetic route of the protein degradation targeting chimeric compound for targeting and degrading GSK-3 beta, which comprises the following steps:
(1) Firstly, using N-phenyl maleimide as a raw material, chloridizing with thionyl chloride to obtain a compound 2, and condensing with an indole Grignard reagent at room temperature under the action of ethyl magnesium bromide to obtain a compound 3;
(2) Copper oxide is used as a catalyst, and the compound 3 and methyl iodide undergo N-methylation reaction under the action of potassium carbonate to obtain a compound 4;
(3) Taking anhydrous benzene-THF with the volume ratio of 1-1.2:1 as a solvent, and condensing a compound 4 with an indole Grignard reagent with a substituent R under the reflux condition in the presence of ethyl magnesium bromide to obtain a compound 5;
(4) Under the action of cesium carbonate, the compound 5 and ethyl bromoacetate undergo N-alkylation reaction to obtain a compound 6;
(5) The compound 6 undergoes hydrolysis reaction under alkaline conditions to obtain a compound 7;
(6) The compound 7 and molten ammonium acetate are subjected to ammonolysis reaction under the protection of nitrogen to obtain a compound 8;
the substituents R on the benzene rings of compounds 5-8 and the indole Grignard reagent in step (3) are the same as in formula P.
(7) The compound 9 and the compound 10 are subjected to condensation reaction under the action of DIPEA to obtain a compound 11;
(8) The compound 11 and H 2 are subjected to hydrogenation reduction reaction under the catalysis of palladium carbon to obtain a compound 12;
n in the compounds 10-12 is the same as in formula P.
(9) The compound 8 and the compound 12 undergo condensation reaction in the presence of TEA and HATU to obtain the target product.
The invention also provides application of the protein degradation targeting chimeric compound for targeting and degrading GSK-3 beta in preparing medicines for regulating and controlling GSK-3 beta signal paths.
By adopting the technology, compared with the prior art, the invention has the following beneficial effects:
the protein degradation targeting chimeric compound which is designed and synthesized by the invention and is used for degrading GSK-3 beta is a novel compound and can be used for treating GSK-3 beta targeting related diseases.
Detailed Description
The invention will be further illustrated with reference to specific examples, but the scope of the invention is not limited thereto.
1. Preparation of intermediates and target compounds:
example 1: n-phenyl-dichloro-maleimide (2)
22.5G (0.13 mol) of N-phenylmaleimide and 160mL of thionyl chloride were put into a three-necked flask, and after stirring and dissolution, the flask was cooled to 0℃and 25mL of anhydrous pyridine was slowly added dropwise thereto, followed by refluxing for 2 hours. At the end of the reaction, excess thionyl chloride was removed by concentration under reduced pressure, 200mL of ice water was poured into the residue, dichloromethane was extracted (100 mL. Times.3), the organic phases were combined, and the organic phase was washed with saturated brine (300 mL. Times.3) and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, recrystallization from 100mL of methylene chloride, filtration and drying gave 20.0g of Compound 2 as a yellow solid in 60.0% yield.
Example 2: 3-chloro-4- (1H-indol-3-yl) -1-phenyl-1H-pyrrole-2, 5-dione (3)
3.0G (25.74 mmol) of indole, 5mL of anhydrous benzene and 12.5mL (25.00 mmol) of ethyl magnesium bromide solution (2 mol/L in THF) are added dropwise under the protection of nitrogen, and the reaction is carried out for 30min at room temperature after the dropwise addition, so as to obtain the indole Grignard reagent. 4.0g (16.50 mmol) of Compound 2 was charged in the reaction flask, and 10mL of THF was injected under nitrogen, and the indole Grignard reagent was slowly dropped at low temperature and reacted at room temperature for 4 hours after the dropping was completed. After completion of the reaction, the mixture was poured into 100mL of ice water, quenched, made weakly acidic with aqueous hydrochloric acid, extracted with dichloromethane (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (150 mL. Times.3) and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, recrystallization from ethyl acetate, filtration and drying gave 2.9g of compound 3 as a red solid in 54.4% yield.
Example 3: 3-chloro-4- (1-methyl-1H-indol-3-yl) -1-phenyl-1H-pyrrole-2, 5-dione (4)
In a reaction flask was charged 500mg (1.55 mmol) of Compound 3, 10mM LDMF,214mg (1.55 mmol) of potassium carbonate, 99mg (1.24 mmol) of copper oxide, 8.8g (62.00 mmol) of methyl iodide, and reacted at room temperature for 4 hours. After completion of the reaction, the mixture was quenched by pouring into 100mL of water, extracted with methylene chloride (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (150 mL. Times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, recrystallization from ethyl acetate, filtration, and drying gave 250mg of compound 4 as a red solid in 47.9% yield.
Example 4:3- (1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -1-phenyl-1H-pyrrole-2, 5-dione (5 a)
1.1G (9.28 mmol) of indole, 5mL of anhydrous benzene and nitrogen were added to a three-necked flask, and 4.46mL (8.92 mmol) of ethyl magnesium bromide solution (2 mol/L in THF) was slowly dropped at a low temperature to complete the reaction at room temperature for 30min to obtain an indole Grignard reagent (for use). 2.0g (5.95 mmol) of Compound 4 was charged into the reaction flask, and 10mL of THF was injected under nitrogen, and the indole Grignard reagent was slowly dropped at low temperature, and the reflux reaction was completed for 4 hours. After the completion of the reaction, the mixture was quenched by pouring into ice water, diluted with 2N hydrochloric acid solution, extracted with dichloromethane (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (150 mL. Times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography (DCM: pe=10:1, v/v) gave 1.5g of red solid 5a in 60.5% yield.
Example 5:3- (4-bromo-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -1-phenyl-1H-pyrrole-2, 5-dione (5 b)
The synthesis procedure of compound 5b was the same as that of compound 5a except that indole was replaced with an equivalent molar amount of 4-bromoindole, and the reaction gave a red solid 5b in 11.9% yield.
Example 6:3- (5-bromo-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -1-phenyl-1H-pyrrole-2, 5-dione (5 c)
The synthesis procedure of compound 5c was the same as that of compound 5a except that indole was replaced with 5-bromoindole in the same molar amount, and the reaction gave a red solid, 5c, in 20.3% yield.
Example 7:3- (6-bromo-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -1-phenyl-1H-pyrrole-2, 5-dione (5 d)
The synthesis procedure for compound 5d was the same as that for compound 5a except that the indole was replaced with an equivalent molar amount of 6-bromoindole, which was reacted to give a red solid 5d in 67.7% yield.
Example 8:3- (5-methoxy-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -1-phenyl-1H-pyrrole-2, 5-dione (5 e)
The synthesis procedure of compound 5e was the same as that of compound 5a except that indole was replaced with 5-methoxyindole in the same molar amount, and the reaction gave a red solid 5e in 56.3% yield.
Example 9:2- (3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-1-phenyl-2, 5-hydrogen-1H-pyrrol-3-yl) -1H-indol-1-yl) acetic acid ethyl ester (6 a)
Into the reaction flask, 100mg (0.24 mmol) of the compound 5a,5 mM, 234mg (0.72 mmol) of cesium carbonate was added, and the mixture was reacted at room temperature for 15 minutes, and further 80mg (0.48 mmol) of ethyl bromoacetate was added and the reaction was carried out at room temperature for 1 hour. After completion of the reaction, the mixture was quenched with 25mL of water, extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL. Times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography (DCM: PE: ea=1:2:1, v/v/v) gave 110mg of red solid 6a in 88.4% yield.
Example 10:2- (4-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-1-phenyl-2, 5-dihydro-1H-pyrrol-3-yl) ethyl) -1H-indol-1-yl) acetic acid ester (6 b)
The synthesis procedure of compound 6b was the same as that of compound 6a except that compound 5a was replaced with an equivalent molar amount of compound 5b, and the reaction gave a red solid 6b in a yield of 78.1%.
Example 11:2- (5-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-1-phenyl-2, 5-dihydro-1H-pyrrol-3-yl) ethyl) -1H-indol-1-yl) acetic acid ester (6 c)
The synthesis procedure of compound 6c was the same as that of compound 6a except that compound 5a was replaced with an equivalent molar amount of compound 5c, and the reaction gave a red solid 6c in 87.6% yield.
Example 12:2- (6-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-1-phenyl-2, 5-dihydro-1H-pyrrol-3-yl) ethyl) -1H-indol-1-yl) acetic acid ester (6 d)
The synthesis procedure of compound 6d was the same as that of compound 6a except that compound 5a was replaced with an equivalent molar amount of compound 5d, and the reaction gave a red solid 6d in 82.0% yield.
Example 13:2- (5-methoxy-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-1-phenyl-2, 5-dihydro-1H-pyrrol-3-yl) ethyl) -1H-indol-1-yl) acetic acid ester (6 e)
The synthesis procedure of compound 6e was the same as that of compound 6a except that compound 5a was replaced with an equivalent molar amount of compound 5e, and the reaction gave a red solid 6e in 73.5% yield.
Example 14:2- (3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydrofuran-3-yl) -1H-indol-1-yl) acetic acid (7 a)
110Mg (0.21 mmol) of compound 6a,2.5mL of THF, 25.2mg (1.05 mmol) of lithium hydroxide in 2.5mL of water were added to the reaction flask, and then 0.5mL of methanol was added to the flask, and the reaction was carried out at room temperature for 1 hour. At the end of the reaction, quench it in a suitable amount of water, adjust it to acidity with aqueous hydrochloric acid, extract it with ethyl acetate (20 mL. Times.3), combine the organic phases, wash the organic phases with saturated brine (50 mL. Times.3) and dry over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave 100mg of red solid 7a which was used directly in the next step.
Example 15:2- (4-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydrofuran-3-yl) -1H-indol-1-yl) acetic acid (7 b)
The synthesis procedure of compound 7b was the same as that of compound 7a except that compound 6a was replaced with an equivalent molar amount of compound 6b, and the reaction was carried out to give red solid 7b, which was directly put into the next step.
Example 16:2- (5-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydrofuran-3-yl) -1H-indol-1-yl) acetic acid (7 c)
The synthesis procedure of compound 7c was the same as that of compound 7a except that compound 6a was replaced with an equivalent molar amount of compound 6c, and the reaction was carried out to give red solid 7c, which was directly put into the next step.
Example 17:2- (6-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydrofuran-3-yl) -1H-indol-1-yl) acetic acid (7 d)
The synthesis procedure for compound 7d was identical to that for compound 7a, except that compound 6a was replaced with an equivalent molar amount of compound 6d, and reacted to give red solid 7d, which was directly fed to the next step.
Example 18:2- (5-methoxy-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydrofuran-3-yl) -1H-indol-1-yl) acetic acid (7 e)
The synthesis procedure of compound 7e is the same as that of compound 7a, except that compound 6a is replaced by an equivalent molar amount of compound 6e, and the reaction gives a red solid 7e which is directly put into the next step.
Example 19:2- (3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetic acid (8 a)
Into the reaction flask was charged 0.25mmol of compound 7a,2.0g (25 mmol) of ammonium acetate, and the mixture was reacted at 140℃for 5 hours under nitrogen atmosphere. After completion of the reaction, the mixture was quenched with 50mL of water, extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL. Times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, purification of the residue by silica gel column chromatography (PE: EA: acoh=50:50:1, v/v/v) gave 50mg of red solid 8a in 50.1% two-step yield.
Example 20:2- (4-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetic acid (8 b)
The synthesis procedure of compound 8b was the same as that of compound 8a except that compound 7a was replaced with an equivalent molar amount of compound 7b, and the reaction gave a red solid 8b in a two-step yield of 22.1%.
Example 21:2- (5-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetic acid (8 c)
The synthesis procedure of compound 8c was the same as that of compound 8a except that compound 7a was replaced with an equivalent molar amount of compound 7c, and the reaction gave a red solid 8c in a two-step yield of 31.3%.
Example 22:2- (6-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetic acid (8 d)
The synthesis procedure of compound 8d was the same as that of compound 8a except that compound 7a was replaced with an equivalent molar amount of compound 7d, and the reaction gave a red solid 8d in 21.9% yield in two steps.
Example 23:2- (5-methoxy-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetic acid (8 e)
The synthesis procedure of compound 8e was the same as that of compound 8a except that compound 7a was replaced with an equivalent molar amount of compound 7e, and the reaction gave 8e as a red solid in a two-step yield of 23.4%.
Example 24:4- ((2- (2- (2- (2-azidoethoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (11 a)
In a reaction flask were placed 293mg (1.06 mmol) of compound 9, 300mg (1.38 mmol) of compound 10a,10ml of LDMF, 317 mg (2.76 mmol) of N, N-diisopropylethylamine and the temperature was raised to 80℃for reaction for 4h. After completion of the reaction, the mixture was poured into 100mL of ice water, quenched, extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (150 mL. Times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography (PE: ea=1:4, v/v) gave 120mg of green oily liquid 11a in 23.8% yield.
In the molecular structure of compound 10a, n=3.
Example 25:4- ((14-azido-3, 6,9, 12-tetraoxatetradecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (11 b)
The synthesis procedure of compound 11b was the same as that of compound 11a except that compound 10a was changed to an equivalent molar amount of compound 10b, and the reaction gave 11b as a green oily liquid in a yield of 32.6%.
In the molecular structure of compound 10b, n=4.
Example 26:4- ((17-azido-3, 6,9,12, 15-pentaoxaheptadecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (11 c)
The synthesis procedure of compound 11c was the same as that of compound 11a except that compound 10a was replaced with an equivalent molar amount of compound 10c, and the reaction gave 11c as a green oily liquid in a yield of 38.8%.
In the molecular structure of compound 10c, n=5.
Example 27:4- ((20-azido-3,6,9,12,15,18-hexaoxaeicosyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (11 d)
The synthesis procedure of compound 11d was the same as that of compound 11a except that compound 10a was changed to an equivalent molar amount of compound 10d, and the reaction gave 11d as a green oily liquid in 36.7% yield.
In the molecular structure of compound 10d, n=6.
Example 28:4- ((23-azido-3, 6,9,12,15,18, 21-heptaoxatricosyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (11 e)
The synthesis procedure of compound 11e was the same as that of compound 11a except that compound 10a was replaced with an equivalent molar amount of compound 10e, and the reaction gave 11e as a green oily liquid in 22.5% yield.
In the molecular structure of compound 10e, n=7.
Example 29:4- ((2- (2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (12 a)
To the reaction flask, 90mg (0.19 mmol) of compound 11a,18mg of palladium on carbon, 5mL of ethanol were charged and reacted at room temperature for 1 hour. At the end of the reaction, palladium on carbon was removed by suction filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (DCM: meOH: tea=100:10:1, v/v/v) to give 50mg of green oily liquid 12a in 85.1% yield.
Example 30:4- ((14-amino-3, 6,9, 12-tetraoxatetradecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (12 b)
The synthesis procedure of compound 12b was the same as that of compound 12a except that compound 11a was changed to an equivalent molar amount of compound 11b, and the reaction gave 12b as a green oily liquid in a yield of 70.0%.
Example 31:4- ((17-amino-3, 6,9,12, 15-pentaoxaheptadecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (12 c)
The synthesis procedure of compound 12c was the same as that of compound 12a except that compound 11a was changed to an equivalent molar amount of compound 11c, and the reaction gave 12c as a green oily liquid in a yield of 52.6%.
Example 32:4- ((20-amino-3,6,9,12,15,18-hexaoxaeicosyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (12 d)
The synthesis procedure of compound 12d was the same as that of compound 12a except that compound 11a was changed to an equivalent molar amount of compound 11d, and the reaction gave 12d as a green oily liquid in a yield of 65.5%.
Example 33:4- ((23-amino-3, 6,9,12,15,18, 21-heptaoxatricosyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (12 e)
The synthesis procedure of compound 12e was the same as that of compound 12a except that compound 11a was replaced with an equivalent molar amount of compound 11e, and the reaction gave 12e as a green oily liquid in a yield of 60.9%.
Example 34: n- (2- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) -2- (3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetamide (P1)
22Mg (0.055 mmol) of compound 8a,20mg (0.05 mmol) of compound 12a,16mg (0.15 mmol) of triethylamine, 5mL of DMF,23mg (0.06 mmol) of HATU were added to the reaction flask and reacted at room temperature for 2h. At the end of the reaction, quench it in a suitable amount of water, extract it with ethyl acetate (20 mL. Times.3), combine the organic phases, wash the organic phases with saturated brine (50 mL. Times.3) and dry over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, purification of the residue by silica gel column chromatography (EA: meoh=15:1, v/v), reaction to give P1 as a red solid, yield 34.0％.1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.94(s,1H),8.41–8.27(m,1H),7.81(s,2H),7.67–7.51(m,1H),7.42(d,J＝8.2Hz,1H),7.33(d,J＝8.2Hz,1H),7.13(d,J＝8.7,2.3Hz,1H),7.10–6.96(m,3H),6.79(t,J＝8.8Hz,2H),6.71–6.57(m,3H),5.06(dd,J＝12.9,5.3Hz,1H),4.92(s,2H),3.85(s,3H),3.67–3.59(m,2H),3.59–3.40(m,12H),3.30–3.22(m,2H),2.95–2.82(m,1H),2.66–2.52(m,2H),2.06–2.00(m,1H).ESI-MS:m/z[M+H]+830.
Example 35: n- (14- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3,6,9, 12-tetraoxatetradecyl) -2- (3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetamide (P2)
The synthesis procedure of compound P2 is the same as that of P1, except that compound 12a is replaced by compound 12b with the same molar quantity, and the red solid P2 is obtained by reaction, and the yield is 22.8％.1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),10.93(s,1H),8.30(t,J＝5.6Hz,1H),7.81(d,J＝1.2Hz,2H),7.57(t,J＝8.6,7.1Hz,1H),7.41(d,J＝8.2Hz,1H),7.33(d,J＝8.3Hz,1H),7.13(d,J＝8.6Hz,1H),7.09–6.97(m,3H),6.85–6.72(m,2H),6.72–6.54(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),4.91(s,2H),3.85(s,3H),3.61(t,J＝5.4Hz,2H),3.57–3.41(m,16H),3.27(q,J＝5.7Hz,2H),2.94–2.81(m,1H),2.67–2.52(m,2H),2.09–2.01(m,1H).ESI-MS:m/z[M+H]+874.
Example 36: n- (17- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3,6,9,12, 15-pentoxaheptadecyl) -2- (3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetamide (P3)
The synthesis procedure of compound P3 is the same as that of P1, except that compound 12a is replaced by compound 12c with the same molar quantity, and the red solid P3 is obtained by reaction, and the yield is 19.7％.1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),10.93(s,1H),8.30(t,J＝5.6Hz,1H),7.81(d,J＝1.4Hz,2H),7.62–7.54(m,1H),7.41(d,J＝8.2,1.0Hz,1H),7.33(d,J＝8.3Hz,1H),7.13(d,J＝8.6Hz,1H),7.10–6.97(m,3H),6.79(t,J＝9.2,8.2,1.0Hz,2H),6.70–6.56(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),4.92(s,2H),3.85(s,3H),3.62(d,J＝5.5Hz,2H),3.58–3.42(m,20H),3.27(q,J＝5.6Hz,2H),2.96–2.81(m,1H),2.63–2.53(m,2H),2.06–2.00(m,1H).ESI-MS:m/z[M-H]+916.
Example 37: n- (20- ((2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3,6,9,12,15,18-hexacosyl) -2- (3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetamide (P4)
The synthesis procedure of compound P4 is the same as that of P1, except that compound 12a is replaced by compound 12d with the same molar quantity, and the red solid P4 is obtained by reaction, and the yield is 16.9％.1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),10.94(s,1H),8.32(t,J＝5.6Hz,1H),7.81(d,J＝1.9Hz,2H),7.57(q,J＝8.6,7.1Hz,1H),7.41(d,J＝8.2Hz,1H),7.33(d,J＝8.3Hz,1H),7.13(d,J＝8.6Hz,1H),7.08–6.95(m,3H),6.84–6.73(m,2H),6.68–6.57(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),4.92(s,2H),3.85(s,3H),3.61(t,J＝5.4Hz,2H),3.58–3.41(m,24H),3.27(q,J＝5.6Hz,2H),2.98–2.80(m,1H),2.64–2.53(m,2H),2.08–2.01(m,1H).ESI-MS:m/z[M+H]+963.
Example 38: n- (23- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3,6,9,12,15,18, 21-heptaoxatricosyl) -2- (3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) acetamide (P5)
The synthesis procedure of compound P5 is the same as that of P1, except that compound 12a is replaced by compound 12e with the same molar quantity, and the red solid P5 is obtained by reaction, and the yield is 13.0％.1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),10.94(s,1H),8.34(t,J＝5.6Hz,1H),7.81(d,J＝1.7Hz,2H),7.58(q,J＝8.5,7.1Hz,1H),7.41(d,J＝8.3Hz,1H),7.33(d,J＝8.2Hz,1H),7.14(d,J＝8.6Hz,1H),7.09–6.96(m,3H),6.78(t,J＝8.7Hz,2H),6.70–6.56(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),4.92(s,2H),3.85(s,3H),3.61(t,J＝5.4Hz,2H),3.57–3.43(m,28H),3.27(q,J＝5.6Hz,2H),2.95–2.81(m,1H),2.62–2.54(m,2H),2.06–2.01(m,1H).
Example 39:2- (4-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) -N- (20- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -3,6,9,12,15,18-hexa-oxa-ne) acetamide (P6)
The synthesis of compound P6 is the same as that of P1 except that compound 12a is changed into compound 12d with the same molar quantity, compound 8a is changed into compound 8b, triethylamine is changed into N, N-diisopropylethylamine with the same molar quantity, and the red solid P6 is obtained through reaction, and the yield is high 30.7％.1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),10.99(s,1H),8.24(t,J＝5.6Hz,1H),7.98(s,1H),7.58(q,J＝8.6,7.1Hz,1H),7.47(d,J＝8.3,0.8Hz,1H),7.43–7.38(m,2H),7.25(d,J＝7.6,0.8Hz,1H),7.17–7.01(m,4H),6.82–6.77(m,1H),6.74–6.66(m,1H),6.61(t,J＝5.8Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.83(s,2H),3.82(s,3H),3.61(t,J＝5.4Hz,2H),3.58–3.38(m,24H),3.28–3.18(m,2H),2.95–2.82(m,1H),2.65–2.53(m,2H),2.07–2.01(m,1H).
Example 40:2- (5-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) -N- (20- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -3,6,9,12,15,18-hexa-oxa-ne) acetamide (P7)
The synthesis of compound P7 is the same as that of P1 except that compound 12a is changed into compound 12d with the same molar quantity, compound 8a is changed into compound 8c, triethylamine is changed into N, N-diisopropylethylamine with the same molar quantity, and the red solid P7 is obtained through reaction, and the yield is high 34.5％.1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),10.99(s,1H),8.32(t,J＝5.6Hz,1H),7.83(d,J＝2.7Hz,2H),7.58(t,J＝8.6,7.1Hz,1H),7.46(d,J＝8.2Hz,1H),7.30(d,J＝8.7Hz,1H),7.17–7.10(m,2H),7.10–7.01(m,2H),6.87(d,J＝1.9Hz,1H),6.77–6.66(m,2H),6.61(t,J＝5.8Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.91(s,2H),3.88(s,3H),3.61(t,J＝5.4Hz,2H),3.57–3.41(m,24H),3.25(q,J＝5.7Hz,2H),2.95–2.83(m,1H),2.63–2.52(m,2H),2.07–2.01(m,1H).
Example 41:2- (6-bromo-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) -N- (20- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -3,6,9,12,15,18-hexa-oxa-ne) acetamide (P8)
The synthesis of the compound P8 is the same as that of P1 except that the compound 12a is changed into a compound 12d with the same molar quantity, the compound 8a is changed into a compound 8d, and the triethylamine is changed into N, N-diisopropylethylamine with the same molar quantity, and the red solid P8 is obtained by reaction, and the yield is high 37.0％.1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),10.99(s,1H),8.33(t,J＝5.6Hz,1H),7.88(s,1H),7.78(s,1H),7.64–7.54(m,2H),7.43(d,J＝8.2Hz,1H),7.14(d,J＝8.6Hz,1H),7.09–7.01(m,2H),6.81–6.56(m,5H),5.06(dd,J＝12.9,5.3Hz,1H),4.93(s,2H),3.87(s,3H),3.61(t,J＝5.4Hz,2H),3.57–3.43(m,24H),3.28(q,J＝5.6Hz,2H),2.95–2.81(m,1H),2.65–2.52(m,2H),2.07–2.00(m,1H).
Example 42:2- (5-methoxy-3- (4- (1-methyl-1H-indol-3-yl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indol-1-yl) -N- (20- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -3,6,9,12,15,18-hexa-oxa-ne) acetamide (P9)
The synthesis of compound P9 is the same as that of P1 except that compound 12a is changed into compound 12d with the same molar quantity, compound 8a is changed into compound 8e, triethylamine is changed into N, N-diisopropylethylamine with the same molar quantity, and the red solid P9 is obtained through reaction, and the yield is high 51.7％.1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),10.94(s,1H),8.34(t,J＝5.6Hz,1H),7.93(s,1H),7.72(s,1H),7.58(t,J＝8.5,7.1Hz,1H),7.43(d,J＝8.2Hz,1H),7.18(d,J＝8.9Hz,1H),7.13(d,J＝8.6Hz,1H),7.10–7.02(m,2H),6.92(d,J＝8.0Hz,1H),6.71(t,J＝7.5Hz,1H),6.61(t,J＝5.9Hz,1H),6.56(dd,J＝8.8,2.5Hz,1H),6.06(d,J＝2.4Hz,1H),5.06(dd,J＝13.0,5.3Hz,1H),4.90(s,2H),3.83(s,3H),3.61(t,J＝5.4Hz,2H),3.57–3.42(m,J＝5.8Hz,24H),3.27(q,J＝5.6Hz,2H),2.95(s,3H),2.92–2.81(m,1H),2.66–2.52(m,2H),2.07–2.00(m,1H).
2. Biological Activity test
Enzyme level GSK-3 beta inhibition activity test method: the C-terminal 6 XHis fusion GSK-3 beta protein of an escherichia coli expression system is purified by a Ni2+ affinity purification method, a Z-LYTE kinase kit of Invitrongen of a 10L reaction system is adopted for kinase activity detection, and each sample has 3 multiple holes. The test samples were dissolved in DMSO and stored at low temperature (DMSO concentration in the final system was controlled within a range that did not affect the activity of the test). The fluorescence intensity at 445nM and 520nM under 400nM excitation is detected by using an enzyme-labeled instrument Envision multi-labeled microwell plate detector (Perkinelmer company product), and the substrate phosphorylation rate of the sample hole is calculated by using a formula provided by the kit, so as to reflect the kinase activity. The IC 50 value was obtained by fitting GRAPHPAD PRISM software with an inhibition greater than 50% and the positive compound used in the experiment was Staurosporine. GSK-3 beta inhibition activity test was performed on 9 target compounds P1 to P9 synthesized, and the results are shown in the following table (Staurosporine is a control compound).
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The biological activity test result shows that 9 compounds have better inhibition activity on GSK-3 beta, and the IC 50 value is 1.41+/-0.29-5.46+/-0.25 mu M, wherein the inhibition activity of the compound P6 is the best (IC 50 =1.41+/-0.29 mu M).
What has been described in this specification is merely an enumeration of possible forms of implementation for the inventive concept and may not be considered limiting of the scope of the present invention to the specific forms set forth in the examples.

Claims (5)

1. A protein degradation targeting chimeric compound for targeting and degrading GSK-3 beta is characterized in that the compound has a structural general formula shown in a formula P:
wherein: r is selected from one of the following: hydrogen, halogen, alkyl having 1 to 5 carbon atoms, and alkoxy having 1 to 5 carbon atoms; n=1-7.
2. The protein degradation targeting chimeric compound of the targeting degradation GSK-3 beta according to claim 1, wherein the synthesis method of the compound is as follows: the compound 8 and the compound 12 undergo condensation reaction under the existence of TEA and HATU to obtain a target product P, and the reaction formula is as follows:
The substituent R in the structure of the compound 8 and n in the structure of the compound 12 are the same as those in the formula P.
3. A class of protein degradation targeting chimeric compounds for the targeted degradation of GSK-3β according to claim 2 wherein the synthetic route of compound 8 is:
(1) Firstly, using N-phenyl maleimide as a raw material, chloridizing with thionyl chloride to obtain a compound 2, and condensing with an indole Grignard reagent at room temperature under the action of ethyl magnesium bromide to obtain a compound 3;
(2) Copper oxide is used as a catalyst, and the compound 3 and methyl iodide undergo N-methylation reaction under the action of potassium carbonate to obtain a compound 4;
(3) Taking anhydrous benzene-THF with the volume ratio of 1-1.2:1 as a solvent, and condensing a compound 4 with an indole Grignard reagent with a substituent R under the reflux condition in the presence of ethyl magnesium bromide to obtain a compound 5;
(4) Under the action of cesium carbonate, the compound 5 and ethyl bromoacetate undergo N-alkylation reaction to obtain a compound 6;
(5) The compound 6 undergoes hydrolysis reaction under alkaline conditions to obtain a compound 7;
(6) The compound 7 and molten ammonium acetate are subjected to ammonolysis reaction under the protection of nitrogen to obtain a compound 8;
the substituents R on the benzene rings of compounds 5-8 and the indole Grignard reagent in step (3) are the same as in formula P.
4. A class of protein degradation targeting chimeric compounds for the targeted degradation of GSK-3β according to claim 2 wherein the synthetic route of compound 12 is:
(a) The compound 9 and the compound 10 are subjected to condensation reaction under the action of DIPEA to obtain a compound 11;
(b) The compound 11 and H 2 are subjected to hydrogenation reduction reaction under the catalysis of palladium carbon to obtain a compound 12;
n in the compounds 10-12 is the same as in formula P.
5. The use of a class of protein degradation targeting chimeric compounds targeted to degrade GSK-3β according to claim 1 for the preparation of a medicament for modulating GSK-3β signaling pathway.
CN202410042092.3A 2024-01-11 2024-01-11 Protein degradation targeting chimeric compound for targeting degradation of GSK-3 beta and application thereof Pending CN117886799A (en)

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