Application of derivative of pyridine carboxamide in preparation of anti-tumor medicaments

An anti-tumor drug, a technology of picolinamide, which is applied to the application of picolinamide derivatives in the preparation of anti-tumor drugs, and the application field in the preparation of anti-tumor drugs, can solve problems such as adverse reactions of anti-tumor drugs, and achieve non-resistant Medicinal properties, anti-proliferation, obvious effect

Inactive Publication Date: 2012-05-23
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] Malignant tumors have become one of the most important causes of human death, but currently available anti-tumor drugs have various adverse reactions. Therefore, finding new anti-tumor drugs with low side effects has become a hot spot in the field of biomedicine

Method used

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  • Application of derivative of pyridine carboxamide in preparation of anti-tumor medicaments

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Experimental program
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Embodiment 1

[0027] Example 1 Virtual Screening of CypJ Small Molecule Inhibitors

[0028]In the PDB protein structure database, the X-ray diffraction crystal structure of the human CYPA protein was retrieved (PDB code: 1CWA). This structure is the crystal structure of CYPA in complex with its natural inhibitor cyclosporin A (CsA). From this structure, the active site of CYPA was determined, and several key amino acid sites in the active site that could be inhibited by CsA were determined. According to the highly homologous sequence between CYPJ and CYPA, we cooperated with the Shanghai Institute of Materia Medica, Chinese Academy of Sciences to establish a 3D structure model, which was also confirmed in subsequent protein crystallization and structural analysis (CYPJ PDB code: 1XYH). Several small molecule databases were screened against the CypJ active site. The small molecule databases used for screening mainly include SPECS and CNPD. Finally, FD7 of the present invention was screene...

Embodiment 2

[0029] Example 2 Utilizes BIAcore Molecular Interaction Instrument to Verify Virtual Screening Results

[0030] The BIAcore molecular interaction instrument is based on surface plasmon resonance technology to track the interaction between biomolecules without any markers, thus ensuring the authenticity of the experimental results to the greatest extent. During the experiment, the target biomolecules (CypJ protein) were immobilized on the surface of the sensor chip, and then the small molecule compounds were dissolved in a solvent and flowed over the surface of the chip. The monitor can track the changes in the whole process of binding and dissociation between molecules in the detection solution and target biomolecules on the chip surface in real time. Through the binding data of BIAcore, the N of the present invention 2 , N 5 -Bis [2-(3,4-dimethoxyphenyl) ethyl]-2,5-pyridine carboxamide combined with CypJ equilibrium-dissociation constant KD (M): 4.64×10 -5 .

Embodiment 3

[0031] Example 3 Use of Enzyme Activity Experiments to Prove the Ability of Small Molecular Compounds to CypJ Enzyme Activity Inhibition

[0032] There are many methods for measuring CyP activity, but α-chymotrypsin-coupled enzymic assay is the most commonly used. Its principle is that the oligopeptide substrate containing proline, such as N-succinyl-Ala-Ala-Pro-Phe p-nitroanilide (N-Succinyl-Ala-Ala-Pro-Phe p-nitroanilide) in solution The cis and trans structures are in balance, and CyP can catalyze the cis-trans isomerization of the substrate, that is, catalyze the change of proline from cis to trans; when it is in the trans structure, the C-terminal p-nitroanilide is α -Cymotrypsin is cleaved to release the pigment group p-nitroaniline, and the PPIase activity of CyP can be obtained by continuously measuring the change of absorbance at 390nm.

[0033] In the present invention, the reaction without adding small molecule inhibitors is used as a control reaction, and the inhi...

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Abstract

The invention belongs to the field of genetic engineering and chemistry, and relates to the application of a derivative of pyridine carboxamide in the preparation of anti-tumor medicaments. The invention provides the application of a small-molecular compound N2,N5-di[2-(3,4-dimethoxyphenyl)ethyl]-2,5-pyridine carboxamide in the preparation of the anti-tumor medicaments. The compound can remarkably suppress the multiplication of tumor cells. The medicaments prepared from the compound for a cellular target CYPJ are difficult for patients to form medicament resistance, and have evident effect onthe tumor cells of high-expression CYPJ proteins. Therefore, the small-molecular compound of the invention is developed as a novel anti-tumor medicament, has evident tumor suppression effect and highspecificity, and provides a novel way and means for the treatment and cure of tumors.

Description

technical field [0001] The invention relates to the fields of chemical engineering and medicine, and relates to the application of a pyridinecarboxamide derivative in the preparation of antitumor drugs. Specifically related to N 2 , N 5 -Application of bis[2-(3,4-dimethoxyphenyl)ethyl]-2,5-pyridinecarboxamide in the preparation of antitumor drugs. Background technique [0002] Cycliphilins (CyPs) are ubiquitously distributed intracellular proteins that are highly conserved in plants, bacteria, and mammals. They were originally discovered as cellular receptors for cyclosporin A. Cyclosporin A (Cyclosporin A, CsA) is a cyclic polypeptide containing 11 amino acids isolated from fungal metabolites. It is an immunosuppressant for organ transplantation and autoimmune diseases, and has been widely used clinically. , with annual sales of more than 5 billion US dollars. Since CsA has shown various toxic and side effects since it was used in clinical practice, people pay more and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/44A61P35/00
Inventor 余龙张明君陈帅
Owner FUDAN UNIV
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