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Application of phenyl thiophene derivatives in preparing antitumor drugs

An anti-tumor drug, the technology of phenylpropylthiophene, which is applied in the chemical industry, can solve the problems of anti-tumor drug adverse reactions and other problems, and achieve the effect of less drug resistance, obvious effect and inhibition of proliferation

Inactive Publication Date: 2010-12-22
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 phenyl thiophene derivatives in preparing antitumor drugs

Examples

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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, FD1 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. According to the binding data of BIAcore, 2-({6-[(3-carbonyl-4,5,6,7-tetrahydro-1-phenylpropylthiophen-2-yl)amino]-6-oxoacetyl }Amine)-4,5,6,7-tetrahydro-1-phenylpropylthiophene-3-carboxylic acid combined with CypJ equilibrium-di...

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. The principle is that the oligopeptide substrate containing proline, such as N-succinyl-Ala-Ala-Pro-Phe p-nitroanilide (N-Succinyl-Ala-Ala-Pro-Phep-nitroanilide) in the solution The formula 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- The chymotrypsin is cleaved to release the pigment group p-nitroaniline, and the PPIase activity of CyP can be obtained by continuously measuring the change of the absorbance value at 390nm.

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

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Abstract

The invention belongs to the field of genetic engineering and chemistry, relating to the application of FD1 in preparing antitumor drugs. The invention provides the application of a micro molecular compound, i.e. 2-({6-[(3-carbonyl-4,5,6,7-tetrahydro-1-phenyl thiophene-2-group) amino]-6-oxo-acetyl}amine)-4,5,6,7-tetrahydro-1-phenyl thiophene-3-formic acid (FD1) in preparing the antitumor drugs. The compound can significantly inhibit tumor cell proliferation. FD1 is a drug designed aiming at cell targets CYPJ, and is not easy to form drug resistance, and in addition, the effect is particularly obvious on tumor cells of high expression CYPJ protein. Therefore, the micro molecular compound of the invention is developed as a new antitumor drug, and has obvious antitumor effect and good specificity.

Description

technical field [0001] The invention belongs to the fields of chemical industry and medicine, and relates to 2-({6-[(3-carbonyl-4,5,6,7-tetrahydro-1-phenylpropylthiophene-2-yl)amino]-6-oxo Application of acetyl}amino)-4,5,6,7-tetrahydro-1-phenylpropylthiophene-3-carboxylic acid 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 more attention to its impact on th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/381A61P35/00A61P1/16A61P11/00
Inventor 余龙张明君陈帅
Owner FUDAN UNIV
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