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Indolylcarboxylic acid compound and application thereof in preparation of antitumor drugs

A technology of indole carboxylic acid and compound, which is applied in the field of cyclin-dependent kinase 4 inhibitor, can solve the problems of large toxic and side effects, limited clinical application, high cytotoxicity and the like, and achieves the effect of low toxicity

Inactive Publication Date: 2016-07-20
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, fascaplysin is a compound with a planar structure that can be embedded in DNA molecules, and its effect is similar to that of DNA intercalating agents basalpine and ellipticine. limit its clinical application
[0003] The specific CDK4 inhibitor fascaplysin has good tumor suppressive effect, but its planar structure allows it to be embedded in DNA molecules and has high cytotoxicity

Method used

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  • Indolylcarboxylic acid compound and application thereof in preparation of antitumor drugs
  • Indolylcarboxylic acid compound and application thereof in preparation of antitumor drugs
  • Indolylcarboxylic acid compound and application thereof in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1 Preparation of indole carboxylic acid compounds as represented by formula (I)

[0026] 1. Instrument

[0027] (1) Melting point is measured with WRS-2 microcomputer melting point measuring instrument (Shanghai Shengyan Ultrasonic Instrument Co., Ltd.);

[0028] (2) The IR spectrum was measured with a NicoletImpact410 infrared spectrometer, and the KBr tablet was pressed;

[0029] (3) 1HNMR is measured with a JEOLFX90Q Fourier transform nuclear magnetic resonance instrument;

[0030] (4) MS was determined by Nicolet2000 Fourier transform mass spectrometer and MAT-212 mass spectrometer.

[0031] 2. Preparation method

[0032]

[0033] (1) 2-(3-indolyl)-N-phenylacetamide (Ⅰ-1)

[0034] Synthetic Route 1: Dissolve 5.00mmol of indole-3-acetic acid in 15.00mL of dry tetrahydrofuran, add SOCl dropwise in an ice-water bath 2 6.00mmol was added dropwise, 50 Flow for one hour, spin dry the solvent, and use it directly in the next step without purification. ...

Embodiment 2

[0052] Example 2 Toxicity assessment of indole carboxylic acid compounds represented by formula (I)

[0053]

[0054] In the present invention, the natural product Fascaplysin (planar pentacyclic structure parent nucleus) with specific and selective CDK4 small molecule inhibitory activity is used as the lead compound, and the ring-opening idea is used to retain its interaction site with CDK4, and the computer-aided drug design software is used to design A series of derivatives of non-planar specific fascaplysin were developed. Select planar maximum 2-(3-indolyl)-N-phenylacetamide (I-1) (n=1n 1 =0) and fascaplysin (formula (II)) were simulated by chem3D software for dihedral angle data, and then their planarity was compared.

[0055] Table 1 The dihedral angle data of fascaplysin and indole carboxylic acid compound I-1

[0056]

[0057] According to the data simulated by computer drug design software, the compound of the present invention has the largest 2-(3-indolyl)-N...

Embodiment 3

[0060] Example 3 Verification experiment of CDK4 inhibitory activity of indole carboxylic acid compounds represented by formula (I)

[0061] 1. Materials

[0062] Instrument TECAN Safire2 measuring instrument, black wall and black bottom 384-well plate (CORNING, USA), plate shaker (Jiangsu Guangming Experimental Instrument Factory), reagent CDK4 / clyclinD, pRb protein substrate, DMSO (Sigma)

[0063] 2. Experimental method:

[0064] (1) Take 133ul of 5× buffer and add it to 367ul of water to obtain 500ul of 1.33× kinase buffer;

[0065](2) Add 0.2ul of CDK4 / clyclinD and 0.8ul of substrate to 199ul of 1.33×kinase buffer to obtain 200ul of kinase / substrate mixture;

[0066] (3) Add 6ul10mMATP to 144ul1.33×kinase buffer to obtain 150ul4×ATP solution;

[0067] (4) Add 0.2ul of phosphorylated peptide to 49.8ul of 1.33×kinase buffer to obtain 50ul of phosphorylated peptide solution;

[0068] (5) Take 2ul10 -2 M mother solution was added to 498ul water to obtain 500ul4× test comp...

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Abstract

The invention relates to the field of pharmaceutical chemistry and discloses an indolylcarboxylic acid compound represented by a formula (I) shown in the description and an application thereof in the preparation of antitumor drugs. The indolylcarboxylic acid compound disclosed by the invention plays a role in inhibiting cyclin-dependent kinase 4 and can be used for preparing the antitumor drugs and providing more pharmaceutical choices for tumor treatment.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and relates to an indole carboxylic acid compound and its application in the preparation of antitumor drugs, especially the application as a cyclin-dependent kinase 4 inhibitor. Background technique [0002] Cyclin-dependent kinases (CDKs) are a class of serine (Ser) / threonine (Thr) kinases with a molecular weight of about 35-40kD, which were first discovered in Schizosaccharomyces saccharomyces and Saccharomyces pombe. More than 40% homogenic and named Cdc28 and Cdc2. In mammals, 10 members have been found, Cdc2 (CDK1), CDK2-10. CDKs play a central role in the cell cycle regulatory network. It is generally believed that CDK2, CDK4, and CDK6 in CDKs are closely related to tumorigenesis, and are often overexpressed in tumor cells, such as breast cancer, esophageal cancer, and primary liver cancer. The regulation of cell cycle G1 / S phase restriction point is very important. In the regulatory n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/18A61K31/405A61P35/00
Inventor 贺殿孙晓飞宋鹏飞杨竹青
Owner LANZHOU UNIVERSITY
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