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Aurora A protein inhibitor, preparation method thereof and medicament use

A technology of protein kinase inhibitor and application, applied in the field of AuroraA protein inhibitor and its preparation

Active Publication Date: 2019-07-05
SHENZHEN INST OF ADVANCED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The specificity problem is a major factor restricting the application of AuroraA protein kinase inhibitors, and the resistance of malignant tumors to small molecule drugs is also a major problem

Method used

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  • Aurora A protein inhibitor, preparation method thereof and medicament use
  • Aurora A protein inhibitor, preparation method thereof and medicament use
  • Aurora A protein inhibitor, preparation method thereof and medicament use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: synthetic Py-Im-Ht (synthetic route sees figure 1 )

[0052] 1. Synthesis of Precursor 1

[0053] Add hydrazine resin (0.61mmol / g, 400mg, 0.244mmol) and dichloromethane (3ml) into a 50mL solid phase reactor, and swell the resin for 20min. Extract dichloromethane, add 20% piperidine / DMF solution (3ml) to the resin, blow air for 5min, remove solvent, then add 20% piperidine / DMF solution (3ml), blow air for 5min, remove solvent, The resin was washed with DMF (4x 3 mL). Boc-Py-OH (234mg, 0.976mmol, 4eq.) and triphosgene (BTC, 95mg, 0.322mmol, 0.33eq) were dissolved in 2mL of anhydrous THF, and collidine (collidine, 284μL, 2.928mmol, 12eq.), the reaction immediately produces a large amount of white precipitate, after adding the reaction for 3min, then add 2mL DIEA / DMF solution (5%, v / v), the white precipitate completely disappears, transfer the reaction solution to the In the phenylhydrazine resin of the protective group, N2 was bubbled and mixed, and the ...

Embodiment 2

[0069] Embodiment 2: Py-Im-Ht inhibits Aurora A protein expression experiment in tumor cells (HeLa and A549)

[0070]Take Hela cells and A549 cells in the logarithmic growth phase, inoculate 1 mL per well (50,000 cells) in a 12-well plate, and culture them in a 37-degree, 5% carbon dioxide incubator for 24 hours; The original culture medium was added to DMEM high-glucose medium containing different concentrations of Compound 2, so that the drug concentration in each well was 0 μM, 10 μM, 20 μM, and 30 μM; the cells were put back into the incubator and incubated for 72 hours; Digest with 0.25% trypsin at room temperature for 1 min, resuspend the cells in fresh DMEM medium, centrifuge at 3000 rpm for 3 minutes, collect the cells, and wash twice with ice-cold PBS. Remove PBS, centrifuge at 5000rpm for 3 minutes, add RIPA lysate, incubate on ice for 2 hours, centrifuge at 13000rpm at 4 degrees for 15min, collect the supernatant, measure the protein concentration by BCA method, add...

Embodiment 3

[0071] Example 3: Experiment of Py-Im-Ht inhibiting tumor cell proliferation and cell cycle

[0072] Take tumor cells (HeLa, A549 or MDA-MB-231) in the logarithmic growth phase, inoculate 1 mL per well (containing 100,000 cells) in a 6-well plate or 0.1 mL per well (containing 5,000 cells) In a 96-well plate, cultured in a 37°C, 5% carbon dioxide cell incubator for 24 hours; aspirated the original medium, and added it to DMEM high-glucose medium containing different concentrations of Py-Im-Ht; put the cells back into Incubate in an incubator for 48 hours to 72 hours, use a microscope to count the final cell number and the number of cells in each division period or use the CCK-8 kit to measure cell viability, the results are as follows Figure 4 shown. It can be seen that with the prolongation of drug action time, the number of Hela cells and A549 cells decreased significantly ( Figure 4 A&B), indicating that the drug can effectively inhibit the proliferation of tumor cells....

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Abstract

The invention relates to an Aurora A protein inhibitor, a preparation method thereof and medicament use, in particular to a compound shown as a formula I and pharmaceutically acceptable salt thereofand the compound of the formula I orsalt which can be used as medicines or use of a composition comprising the compound of the formula I or the pharmaceutically acceptable salt thereof in an Aurora A protein kinase inhibitorand in the manufacture of a medicament for the treatment or prevention of a cell hyperproliferative disease.

Description

technical field [0001] The invention relates to the field of medicines, in particular to an Aurora A protein inhibitor, a preparation method and a medicine use thereof. Background technique [0002] Aurora A is a member of the Aurora protein kinase family. It is a serine / threonine kinase that plays an important role in cell proliferation and participates in many processes of cell mitosis, including cell G2 / M transition, mitotic spindle assembly, and chromatid separation. It plays an important role in regulating the process of cell mitosis. Studies have found that the human Aurora A gene is located in the q13 region of chromosome 20, which is frequently amplified in breast cancer and highly expressed in many types of tumors. Aurora A is present at the centrosome from the beginning of neutral duplication to the end of mitosis. Aberrant expression of Aurora A leads to centrosome amplification, genomic aneuploidy and chromosomal instability. Because Aurora A is abnormally exp...

Claims

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Application Information

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IPC IPC(8): C07D403/14A61K31/496A61P35/00
CPCA61P35/00C07D403/14Y02P20/55
Inventor 李红昌粟武房丽晶卢丹逸张建超刘科
Owner SHENZHEN INST OF ADVANCED TECH
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