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Thymine derivatives and quinazoline-dione derivatives for the inhibition of hsp27

A technology of thymine and derivatives, which is applied in the direction of sugar derivatives, medical preparations containing active ingredients, and compounds of Group 5/15 elements of the periodic table, etc., which can solve the problem of no antibacterial concentration value and no compound active substance concentration Numerical issues

Inactive Publication Date: 2017-08-18
DRESDEN UNIVERSITY OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

European patent WO 2009 / 156182 A2 does not show the verification method of the hypothetical experiment on these compounds, so this public document has neither the value of the inhibitory concentration nor the value of the active substance concentration of each compound for reference.

Method used

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  • Thymine derivatives and quinazoline-dione derivatives for the inhibition of hsp27
  • Thymine derivatives and quinazoline-dione derivatives for the inhibition of hsp27
  • Thymine derivatives and quinazoline-dione derivatives for the inhibition of hsp27

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0170] Example 1 - "SpeedScreen Assay" Test of Purine Derivatives

[0171] A computerized method is used to predict and determine low-molecular compounds with potential as HSP27 inhibitors, and the gel filtration method is used to conduct experiments on these low-molecular compounds.

[0172] This method for detecting molecular bonds and using gel filtration, known in 2004 as the "SpeedScreen Assay" [cf: Muckenschnabel et al., 2004], is used with adaptations to the needs of the present invention, the separation In the method, larger molecules such as proteins can pass through the matrix of Sephadex G-25, while low-molecular compounds (small molecules) penetrate into the matrix and cannot pass through. Among them, PD SpinTrap G-25 of GE Healthcare was used for the separation method. Under centrifugation at 800 g for 2 min (according to the instructions), these columns pass molecular weights greater than / equal to 5000 g / mol, while smaller molecules are retained in the matrix. ...

example 2

[0180] Example 2 - "SpeedScreen Assay" Test of Thymine Derivatives

[0181] A computerized method is used to predict and determine low-molecular compounds with potential as HSP27 inhibitors, and the gel filtration method is used to conduct experiments on these low-molecular compounds.

[0182] This method for detecting molecular bonds and using gel filtration, known in 2004 as the "SpeedScreen Assay" [cf: Muckenschnabel et al., 2004], is used with adaptations to the needs of the present invention, the separation In the method, larger molecules such as proteins can pass through the matrix of Sephadex G-25, while low-molecular compounds (small molecules) penetrate into the matrix and cannot pass through. Among them, PD SpinTrap G-25 of GE Healthcare was used for the separation method. Under centrifugation at 800 g for 2 min (according to the instructions), these columns pass molecular weights greater than / equal to 5000 g / mol, while smaller molecules are retained in the matrix. ...

example 3

[0190] Example 3 - Binding detected using biofilm interferometry

[0191] Bio-thin film interferometry is used to detect interactions between biomolecules. It is an optical interferometry technique that measures white light reflected by two surfaces, one surface consisting of a layer of immobilized target protein in front of the biosensor and an internal reference. surfaces together. Binding of the ligand to the target protein changes the interference pattern and can be detected in real time.

[0192] For detection, the tool ForteBio Octet Red 384 was used, and the target protein HSP27 was biotinylated and bound to the corresponding sensor (SSA). The main advantage of this method of analysis is that neither immobilization nor labeling of the analyte is required. The purine derivatives according to the general formula (I) or (II) are pre-determined by a computerized method in a concentration range (K D ) 333 micromol / L and 10 nmol / L for these assays.

[0193] Utilize biofil...

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PUM

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Abstract

The present invention relates to novel HSP27 inhibitors, in particular thymine derivatives according to general formula (VI), (VII) or (VII) and phenothiazine derivatives according to formula (V), and to their use as drugs for the selective inhibition of the heat shock protein HSP27 (HSPB1), in particular for use in the treatment of carcinomas or cystic fibrosis, said inhibitors having a particularly advantageous activity in the lower micromolar or sub-micromolar active ingredient concentration range with respect to HSP27.

Description

technical field [0001] The present invention relates to a novel thymine derivative and its application as medicine for selective inhibition of heat shock protein HSP27 (HSPB1). Background technique [0002] For some cancers, the treatment with cytostatics will not be effective from the beginning. Even if the patient suffers from an easily curable cancer type, the treatment with cytostatics may fail after a period of time. One possible reason is the development of resistance, whereby tumor cells become less sensitive to cytostatics, the biological processes behind which are known. [0003] It can be seen that the treatment of various tumor cell lines with cytostatics leads to an increase in the expression of cellular proteins, which has a great impact on the protection and stability of the correct folding of receptors, enzymes and cellular structural proteins. [0004] Heat shock protein is an evolutionarily highly conserved protein formed by cells under sublethal stress con...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D279/22C07D279/26C07D473/30C07D519/00C07D239/553C07D239/96C07F9/6561C07D403/12C07H19/073A61K31/513A61K31/5415A61K31/522A61K31/517A61K31/675A61K31/7072A61P35/00
CPCA61K31/522A61K31/5415A61K31/708C07D239/553C07D239/96C07D279/22C07D279/26C07D403/12C07D473/30C07D519/00C07F9/65616C07H19/073A61K2300/00A61K45/06A61P35/00A61K31/513
Inventor 迈克尔·施罗德张艺馨约克-克里斯坦·海因里希乔基姆·豪普特赛尼汀·多那康达偑特拉·乐尼各
Owner DRESDEN UNIVERSITY OF TECHNOLOGY
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