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Indeno pyrazole micromolecular tubulin inhibitor and preparation method and application thereof

A technology of tubulin inhibition and indenopyrazoles, which is applied in the chemical field, can solve the problems of drug resistance, high toxicity and side effects, and difficult synthesis, and achieve novel structure, reduce toxicity and side effects, and enhance specificity Effect

Active Publication Date: 2015-05-13
济南美高生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned drugs have many problems such as high toxicity and side effects, easy drug resistance, complex structure, and difficult synthesis. Finding new, efficient, and low-toxic microtubule inhibitors has become a hot spot in the research of anti-tumor drugs today.

Method used

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  • Indeno pyrazole micromolecular tubulin inhibitor and preparation method and application thereof
  • Indeno pyrazole micromolecular tubulin inhibitor and preparation method and application thereof
  • Indeno pyrazole micromolecular tubulin inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: the preparation of structural formula 1 compound

[0035] (1) Dissolve 5-ethoxy-6-hydroxy-1-indanone (Formula 1) (3.20g) in N,N-dimethylformamide (25mL), add imidazole (1.70g), and stir After 5 min, tert-butyldimethylsilyl chloride (3.76 g) was added and stirred for 1 h. Add a citric acid aqueous solution (100mL) with a mass fraction of 10%, let it cool in a refrigerator, filter with suction, and dry in vacuo to obtain 5-ethoxy-6-tert-butyldimethylsiloxy-1-indanone ( Formula 2) 4.65g, the yield is 91.4%. Melting point: 142–143°C. ESI-MS m / z 307.5[MH] + .

[0036](2) Dissolve 5-ethoxy-6-tert-butyldimethylsiloxy-1-indanone (Formula 2) (4.65g) in anhydrous tetrahydrofuran (60mL), cool to -78°C, Add 1M tetrahydrofuran solution (18.2mL) of lithium bis(trimethylsilyl)amide dropwise, stir for 2h, then raise the temperature to -45°C within 45min, add 3-ethoxylate dissolved in anhydrous tetrahydrofuran (15mL) phenyl phenyl isothiocyanate (3.17g), room tempera...

Embodiment 2

[0041] Embodiment 2: the preparation of structural formula 2 compound

[0042] (1) Dissolve 5-ethoxy-6-hydroxy-1-indanone (Formula 1) (3.20g) in N,N-dimethylformamide (25mL), add imidazole (1.70g), and stir After 5 min, tert-butyldimethylsilyl chloride (3.76 g) was added and stirred for 1 h. Add a citric acid aqueous solution (100mL) with a mass fraction of 10%, let it cool in a refrigerator, filter with suction, and dry in vacuo to obtain 5-ethoxy-6-tert-butyldimethylsiloxy-1-indanone ( Formula 2) 4.65g, the yield is 91.4%. Melting point: 142–143°C. ESI-MS m / z 307.5[MH] + .

[0043] (2) Dissolve 5-ethoxy-6-tert-butyldimethylsiloxy-1-indanone (Formula 2) (4.65g) in anhydrous tetrahydrofuran (60mL), cool to -78°C, Add 1M tetrahydrofuran solution (18.2mL) of lithium bis(trimethylsilyl)amide dropwise, stir for 2h, then raise the temperature to -45°C within 45min, add 3-ethoxylate dissolved in anhydrous tetrahydrofuran (15mL) phenyl phenyl isothiocyanate (3.17g), room temper...

Embodiment 3

[0048] Example 3: Anti-proliferation test

[0049] 1. Test method:

[0050] Human liver cancer HepG2 cells, human prostate cancer PC3 cells, human cervical cancer HeLa cells, human breast cancer MCF-7 cells and human leukemia K562 cells were given different concentrations of the compound of formula 1 (prepared in Example 1) and the compound of formula 2 ( Embodiment 2 preparation), put 37 ℃, 5%CO 2 The incubator was incubated for 72 hours, and the inhibitory rate of the compound on tumor cells was determined by the tetramethylazolate (MTT) colorimetric method, and the results are shown in Table 1.

[0051] 2. Test results:

[0052] Table 1 The compound of the present invention is to the inhibitory rate of different tumor cells

[0053]

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Abstract

The invention discloses an indeno pyrazole micromolecular tubulin inhibitor which is characterized by comprising a structure which is shown in a general formula I, wherein R represents NH2 or NHOH. The invention further discloses a preparation method of an indeno pyrazole compound or officinal salt of the indeno pyrazole compound. The compound disclosed by the invention is the indeno pyrazole micromolecular tubulin inhibitor which is novel in structure, and has strong proliferation inhibition activity to a human liver cancer HepG2 cell, a human prostatic cancer PC3 cell, a human cervical carcinoma HeLa cell, a human breast cancer MCF-7 cell and a human leukemia K562 cell. The mechanism of action of the compound is similar to that of colchicine. Tubulin polymerization can be inhbited, and the tubulin inhibitor has important meaning for enhancing the specificity and effectiveness of the medicine, reducing the toxic and side effects, preventing drug resistance and the like.

Description

technical field [0001] The invention relates to an indenopyrazole small-molecule tubulin inhibitor, a preparation method and application thereof, and belongs to the field of chemical technology. Background technique [0002] Microtubules are the main components of the cytoskeleton. They are composed of α-tubulin and β-tubulin heterodimers. They have the dynamic characteristics of polymerization and depolymerization. Plays an important role in the process of transportation and so on. [0003] Antimicrotubule drugs have become a major class of chemotherapy drugs and are widely used in clinical treatment of various tumors. Tubulin inhibitors affect and interfere with the kinetics of tubulin polymerization and depolymerization by binding to specific sites on tubulin, thereby blocking the formation of the M-phase spindle and arresting tumor cell growth at G2 / M Expect. At present, clinically used microtubule inhibitors mainly include drugs that inhibit tubulin depolymerization ...

Claims

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Application Information

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IPC IPC(8): C07D231/54A61K31/416A61P35/00A61P35/02
CPCY02P20/55C07D231/54
Inventor 刘兆鹏刘晏娜史艳秋张成梅
Owner 济南美高生物医药科技有限公司
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