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Thiazole couplet pyrazolone series compound and application of the same as Bcl-2 family protein antagonist

A technology of thiazole bipyrazolone and compound is applied to thiazole bipyrazolone compound and its application field as Bcl-2 family protein antagonist, and can solve the problem of decreasing fluorescence polarization value and the like

Inactive Publication Date: 2009-01-14
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When this method is used to detect small molecules that inhibit the binding of Bcl-2 family proteins to natural substrate polypeptides, the compound to be tested is added to the system where fluorescently labeled polypeptides and proteins coexist. If the compound can also specifically bind to the protein, it will Competes with fluorescently labeled peptides to inhibit their binding to proteins, resulting in a decrease in fluorescence polarization

Method used

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  • Thiazole couplet pyrazolone series compound and application of the same as Bcl-2 family protein antagonist
  • Thiazole couplet pyrazolone series compound and application of the same as Bcl-2 family protein antagonist
  • Thiazole couplet pyrazolone series compound and application of the same as Bcl-2 family protein antagonist

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1: Preparation of (E)-4-(2-(4-chlorophenyl)hydrazono)-3-methyl-1-(4-phenylthiazol-2-yl)-1H-pyrazole- 5(4H)-keto

[0092] 1. Synthesis of (Z)-2-(2-(4-chlorophenyl)hydrazono)-3-oxobutanoic acid ethyl ester (formula II-05)

[0093]

[0094]

[0095] Suspend 1.276g (10mmol) of 4-chloroaniline (Formula I-05) in 8mL of water, slowly inject 5mL of concentrated HCl at about room temperature, and slowly inject 0.690g (10mmol) of A 5mL aqueous solution of sodium nitrate was directly filtered into a 25mL ethanol solution containing 1.28mL (10mmol) ethyl acetoacetate and 8g (97.5mmol) sodium acetate, a yellow solid was precipitated, suction filtered, washed with water, and recrystallized from absolute ethanol to obtain 1.914 g of yellow needle-like crystals (71% yield).

[0096] After testing, the structure is correct, and the test results are as follows: mp 80-84°C; IR (KBr): v 2994, 1704, 1617, 1587, 1528, 1495, 1474, 1456, 1419, 1396, 1372, 1330, 1276, 1205, 116...

Embodiment 2

[0107] Embodiment 2: formula X-04, X-05, X-06, X-07, X-09, X-10, X-13, X-19, X-20, X-24, X-26, X Synthesis of -27, X-31, X-32, X-33, X-34, X-35, X-37, X-39, X-40, X-41 compounds

[0108] One, the synthesis of formula II-01-04 and formula II-06-17

[0109]

[0110]

[0111]

[0112] Under conditions similar to those of the compound of formula II-05 in Example 1, compounds of formula II-01-04 and formula II-06-17 were obtained from the corresponding formula I-01-04 and formula I-06-17: ( Z)-2-(2-phenylhydrazono)-3-oxobutanoic acid ethyl ester (formula II-01); (Z)-2-(2-(4-fluorophenyl)hydrazono) -3-oxobutanoic acid ethyl ester (formula II-02); ); (Z)-2-(2-(3-chlorophenyl)hydrazono)-3-oxobutanoic acid ethyl ester (formula II-04); (Z)-2-(2-(3, 4-dichlorophenyl) hydrazono)-3-oxobutanoic acid ethyl ester (formula II-06); (Z)-2-(2-(2-methylphenyl) hydrazono)-3 -Ethyl oxobutyrate (formula II-07); (Z)-2-(2-(3-methylphenyl)hydrazono)-3-oxobutanoic acid ethyl ester (formula I...

Embodiment 3

[0122] Embodiment 3: Thiazole bipyrazolone compounds to Bcl-x L Fluorescence polarization detection of inhibition

[0123] Glutathione-S-transferase (GST) fused Bcl-x L (GST-Bcl-x L) protein was expressed in Escherichia coli BL21, and was separated and purified by glutathione sepharose column affinity chromatography; the fluorescently labeled polypeptide was Bid BH3 polypeptide labeled with 5-FAM at the N-terminal (sequence: 5-FAM -QEDIIRNIARHLAQVGDSMDR); compounds X-04, X-05, X-06, X-07, X-09, X-10, X-13, X-19, X-20, X-21, X-24, X -26, X-27, X-31, X-32, X-33, X-34, X-35, X-37, X-39, X-40, X-41 were prepared by the above method, and the rest of the compounds were purchased from From SPECS Corporation.

[0124] One, compound formula X-04, the inhibition constant determination of X-07 and X-10

[0125] In test buffer (1× phosphate buffered saline, containing 0.02% (w / v) NaN 3 ) by adding GST-Bcl-x L 1×PBS solution of different concentrations of the compound and DMSO solut...

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Abstract

The invention discloses a thiazole bipyrazolone compound as well as applications thereof in preparing a small molecular inhibitor of Bcl-2 family proteins and antitumor drugs, the thiazole bipyrazolone compound has the above structural formula, and the thiazole bipyrazolone compound has the activity for inhibiting the combination of Bcl-xL and natural substrate polypeptide (Bid BH3 polypeptide) in the micromole range, and can serve as the small molecular inhibitor of the Bcl-2 family proteins for inhibiting the anti-apoptosis activity thereof; and the compound shows a certain inhibitory activity to human breast cancer MDA-MB-231 cells and MCF-7 cells, and is expected to be developed into the antitumor drugs of targeted Bcl-2 family proteins.

Description

technical field [0001] The present invention relates to a kind of thiazole bipyrazolone compound and the application of small molecule inhibitor thereof as Bcl-2 family protein antagonist, especially (E)-4-(2-(arylhydrazono)- 3-Methyl-1-(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-one compounds and their application as Bcl-2 family protein antagonists. These compounds can inhibit Bcl -2 family protein member Bcl-x L The combination with the natural substrate polypeptide (Bid BH3 polypeptide) can be used as a Bcl-2 family protein to inhibit its anti-apoptotic activity, and is expected to be developed into a new type of anti-tumor drug. Background technique [0002] Apoptosis (also known as programmed cell death in some cases) is a normal death mechanism to remove senescent cells or abnormal cells, and the disorder of this mechanism is directly related to the occurrence of various diseases. Since the 1990s, people have gradually discovered that the occurrence of tumors is caused by...

Claims

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Application Information

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IPC IPC(8): C07D417/04A61K31/427A61P35/00
Inventor 王任小马大为李勋孙威周炳城石志敏张兴龙朱翠侠李雯雯
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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