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Anti-apoptosis Mcl-1 protein inhibitor, and applications thereof

A protein inhibitor, mcl-1 technology, applied in the field of medicine, can solve the problems of toxicity, short metabolic half-life, and low inhibitory activity, and achieve the effect of increasing inhibitory activity, good safety, and reversing multidrug resistance of tumors

Inactive Publication Date: 2016-02-10
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But they all have shortcomings, for example, GX15-070 has cytotoxicity independent of Bax / Bak, so it is facing elimination
In addition, there are many defects such as low inhibitory activity in the body, short metabolic half-life, and continuous use can easily cause liver and kidney toxicity.

Method used

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  • Anti-apoptosis Mcl-1 protein inhibitor, and applications thereof
  • Anti-apoptosis Mcl-1 protein inhibitor, and applications thereof
  • Anti-apoptosis Mcl-1 protein inhibitor, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Preparation of 6,7-dihydroxy-4-methylcoumarin (C-2)

[0023]

[0024] Weigh 1.5g of 1,2,4-triacetoxybenzene into a three-neck flask, add 1ml of ethyl acetoacetate, 5ml of perchloric acid, stir at room temperature for 20 minutes, heat to 80°C, react for 3h, and detect the reaction by TLC At the end, the reaction solution was slowly poured into 30ml of ice water, stirred for 30min, filtered, and the filter cake was collected, which was the crude product. The crude product was dissolved in 20ml of methanol, heated to reflux, cooled to room temperature after 1h, filtered, and the filter cake was collected and vacuum-dried to obtain 1.1g of compound C-2 as a milky white solid.

[0025] The NMR test results are as follows:

[0026] 1 HNMR(400MHz,d-DMSO)δ:2.31(s,3H,CH 3 ),6.09(s,1H,C=CH),6.73(s,1H,ArH),7.00(s,1H,ArH),9.34(s,br,1H,ArOH),10.19(s,br,1H, ArOH);

[0027] 13 CNMR (100MHz, d-DMSO) δ: 18.68, 103.13, 109.89, 110.86, 111.96, 143.24, 148.17, 150.58, 153.68, 161....

Embodiment 2

[0029] Preparation of 6,7-dihydroxy-4-trifluoromethylcoumarin (C-3)

[0030]

[0031] Weigh 1.5g of 1,2,4-triacetoxybenzene into a three-necked flask, add 1.4ml of ethyl trifluoroacetoacetate, 5ml of perchloric acid, stir at room temperature for 20 minutes, heat to 80°C, and react for 3h. The reaction was detected by TLC, and the reaction solution was slowly poured into 30 ml of ice water, stirred for 30 min, filtered, and the filter cake was collected, which was the crude product. The crude product was dissolved in 20ml of methanol, heated to reflux, cooled to room temperature after 1h, filtered, the filter cake was collected, and dried in vacuo to obtain 1.3g of compound C-3 as a light yellow solid. The NMR test results are as follows:

[0032] 1 HNMR (400MHz, d-DMSO) δ: 6.71(s, 1H, C=CH), 6.86(s, 1H, ArH), 7.03(s, 1H, ArH), 9.78(s, br, 1H, ArOH), 10.61(s,br,1H,ArOH);

[0033] 13 CNMR (100MHz, d-DMSO) δ: 104.01, 105.05, 108.89, 112.12, 120.94, 123.68, 144.03, 149.59,...

Embodiment 3

[0035] Preparation of 6,7-dihydroxy-4-chloromethylcoumarin (C-4)

[0036]

[0037]Weigh 1.5g of 1,2,4-triacetoxybenzene into a three-neck flask, add 1.3ml of ethyl 4-chloroacetoacetate, 5ml of perchloric acid, stir at room temperature for 20 minutes, heat to 80°C, and react for 3h , TLC detection of the end of the reaction, the reaction solution was slowly poured into 30ml of ice water, stirred for 30min, filtered, and the filter cake was collected, which was the crude product. The crude product was dissolved in 20ml of methanol, heated to reflux, cooled to room temperature after 1h, filtered, and the filter cake was collected and dried in vacuo to obtain 1.2g of compound C-3 as a milky white solid.

[0038] The NMR test results are as follows:

[0039] 1 HNMR(400MHz,d-DMSO)δ:4.90(s,2H,CH 2 Cl),6.40(s,1H,C=CH),6.78(s,1H,ArH),7.12(s,1H,ArH),9.48(s,br,1H,ArOH),10.39(s,br,1H ,ArOH).

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Abstract

The invention discloses an anti-apoptosis Mcl-1 protein inhibitor, and applications thereof, and belongs to the field of medical technology. The anti-apoptosis Mcl-1 protein inhibitor is a 6,7-dihydroxycoumarin derivative, and the general structure is represented by formula (I), wherein R1 and R2 are used for representing H or (C1-C6) alkyl groups, R3 is used for representing H or CH2NR5R6, NR5R6 is one randomly selected from dimethylamine, diethylamine, dipropyl amine, diisopropylamine, pyrrolidine, piperidine, morpholine, piperazine, or structure derivatives thereof, R4 is used for representing one randomly selected from H, (C1-C6) alkyl groups, CF3, OH-(C1-C6) alkyl groups, and halogenated-(C1-C6) alkyl groups. The anti-apoptosis Mcl-1 protein inhibitor is used for inducing cell apoptosis via competitive binding and antagonism with Mcl-1 protein, killing tumor cells, and can be taken as an anticancer medicine. The anti-apoptosis Mcl-1 protein inhibitor is low in molecular weight, excellent in membrane permeable performance, and high in safety, and possessing a promising prospect in development of medicines.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an anti-apoptosis Mcl-1 protein inhibitor and application thereof. Background technique [0002] The essence and basic process of cancer occurrence and development are being gradually revealed, and molecularly targeted new anti-tumor drugs for its occurrence and development mechanism have become the leading direction of anti-tumor drug research. In recent years, some key proteins related to tumor cell differentiation and apoptosis have been used as drug screening targets, and new anticancer drugs that selectively act on the target sites with high efficiency, low toxicity and strong specificity have become the current anticancer drug research. Another new direction of development. [0003] Bcl-2 family proteins play a very important role in the regulation of apoptosis. This family of proteins contains two types of proteins with opposite functions: one is anti-apopto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/37A61K31/4025A61K31/453A61P35/00
Inventor 杨凌王平葛广波宁静于洋
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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