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Application of 5,6,7,4'-tetrahydroxyflavone and its derivatives in the preparation of jak tyrosine protein kinase inhibitors

A technology of tyrosine protein and kinase inhibitors, which is applied in the application field of 5,6,7,4'-tetrahydroxyflavone and its derivatives in the preparation of JAK tyrosine protein kinase inhibitors, and can solve the problem of scutellarin Undiscovered problems, to achieve significant application value, strong affinity effect

Active Publication Date: 2015-07-29
KPC PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, more efficient and precise targets and mechanisms of scutellarin have not been discovered

Method used

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  • Application of 5,6,7,4'-tetrahydroxyflavone and its derivatives in the preparation of jak tyrosine protein kinase inhibitors
  • Application of 5,6,7,4'-tetrahydroxyflavone and its derivatives in the preparation of jak tyrosine protein kinase inhibitors
  • Application of 5,6,7,4'-tetrahydroxyflavone and its derivatives in the preparation of jak tyrosine protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 : Inhibitory effect of 5,6,7,4'-tetrahydroxyflavone and its derivatives on JAK enzyme

[0050] Enzyme selection model

[0051]Determination principle: The enzyme selection method is established according to the classic method reported by Abukhalaf et al. in 1993 (see Abukhalaf IK, et al (1993): Protein phosphatase assay using a modification of the P81paper protein kinase assay procedure. J Biochem Biophys Methods. 26:95-104). The principle of the experimental determination is: when there is ATP in the reaction system, JAK can transfer the γ phosphorus on the ATP to the specific tyrosine on the polypeptide substrate. Since part of the γ-phosphorus of ATP used in the reaction is labeled isotope 33, it can release β-rays. The intensity of γ-phosphorus incorporated into the polypeptide can be accurately measured by a liquid scintillation instrument, thereby determining the degree of phosphorylation of the substrate polypeptide molecule and the activity of tyro...

Embodiment 2

[0075] Example 2 : 5,6,7,4'-Tetrahydroxyflavone and its derivatives have half inhibitory doses of JAK3 and JAK2 (IC 50 ) determination

[0076] In order to accurately determine the inhibitory strength of 5,6,7,4'-tetrahydroxyflavone and its derivatives against JAK3 and JAK2 tyrosine protein kinases, half inhibitory dose (IC 50 ) enzymatic assay, see figure 2 and image 3 , and the ordinate is the percentage of inhibition of tyrosine kinase. The results showed that the 50% inhibitory doses of scutellarin and 5,6,7,4'-tetrahydroxyflavone and its derivatives against JAK3 tyrosine protein kinase were 6.9 micromoles and 3.0 micromoles respectively, while the reference substance The PFE 50% inhibitory dose was 19 micromolar. The 50% inhibitory doses of scutellarin and 5,6,7,4'-tetrahydroxyflavone and its derivatives against JAK2 tyrosine protein kinase are 57 micromoles and 4.2 micromoles respectively. Since scutellarin and 5,6,7,4'-tetrahydroxyflavone and its derivatives ha...

Embodiment 3

[0077] Example 3 : 5,6,7,4'-tetrahydroxyflavone and its derivatives cell assay process and results Cell model

[0078]Assay principle: Freshly prepared human peripheral blood lymphocytes were used as research objects in the experiment. Since peripheral blood lymphocytes are densely distributed with interleukin-2 receptors (IL2R), the activation of IL2R is mainly transmitted through the activation of JAK3. When IL2R is bound by interleukin-2 (IL-2), it immediately activates the associated JAK3, and JAK3 further activates STAT5 / STAT6. The activated further activated STAT5 / STAT6 is then transferred to the nucleus to initiate the expression of multiple target genes controlled by it. Interferon gamma (IFN gamma) is one of the controlled expression proteins, which is immediately secreted outside the lymphocytes once it is synthesized. By measuring the concentration of interferon gamma in the lymphocyte culture medium, the effect of drug molecules on cellular immune function can ...

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Abstract

The invention relates to the field of medicines, discloses application of 5,6,7,4'-tetrahydroxyflavone and derivatives thereof as a JAK tyrosine protein kinase inhibitor, and especially relates to application of 5,6,7,4'-tetrahydroxyflavone and derivatives thereof as a JAK tyrosine protein kinase inhibitor in preparing medicines for treating diseases related to JAK / STAT signal transduction pathway abnormity. The 5,6,7,4'-tetrahydroxyflavone and derivatives thereof provided in the invention have a strong inhibition effect on JAK tyrosine protein kinase and an enzymological binding characteristic of competitive inhibition; the 5,6,7,4'-tetrahydroxyflavone and derivatives thereof further can penetrate cell membranes and effectively intercept activation of a JAK / STAT signal transduction pathway, thereby inhibiting lymphocytes from secreting cytokines such as interferon to peripheral tissue. According to pharmacological research, the 5,6,7,4'-tetrahydroxyflavone and derivatives thereof have an obvious effect in relaxing vessels; therefore, it is indicated that the 5,6,7,4'-tetrahydroxyflavone and derivatives thereof have a critical clinical application value.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to the application of 5,6,7,4'-tetrahydroxyflavone and derivatives thereof as JAK tyrosine protein kinase inhibitors, in particular to 5,6,7,4'-tetrahydroxyflavone The application of the invention and its derivatives as JAK tyrosine protein kinase inhibitors in the preparation of medicines for preventing and treating diseases related to JAK / STAT signal transduction path abnormalities. Background technique [0002] 5,6,7,4'-Tetrahydroxyflavone, commonly known as scutellarin aglycone, or scutellarin aglycone, is the main component of scutellarin widely used in cardiovascular and cerebrovascular diseases—— The sugar-free portion of scutellarin. 5,6,7,4'-Tetrahydroxyflavone is one of the flavonoid active ingredients of the medicinal plant Erigeron scutellaria. [0003] Erigeron breviscapus (Vant.) Hand-Mazz is a plant of the family Asteraceae. It has the functions of promoting blood ci...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/7048A61K31/352A61P9/10A61P9/00A61P35/00A61P35/02A61P37/00A61P19/02A61P29/00A61P37/06A61P37/08
Inventor 杨兆祥张伟普俊学白奕阳周荣光刘一丹
Owner KPC PHARM INC
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