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Application of a naphthalene-1,4-diketone compound as an hcbs enzyme inhibitor

A technology of compounds and diketones, applied in the application field of hCBS enzyme inhibitors, can solve the problems of unclear amino acid residues and the like

Inactive Publication Date: 2017-10-17
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The 3D crystal structure of hCBS pure enzyme has been reported, which provides a certain structural basis for the design of its targeted inhibitors, but the amino acid residues related to substrate-binding are still unclear

Method used

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  • Application of a naphthalene-1,4-diketone compound as an hcbs enzyme inhibitor
  • Application of a naphthalene-1,4-diketone compound as an hcbs enzyme inhibitor
  • Application of a naphthalene-1,4-diketone compound as an hcbs enzyme inhibitor

Examples

Experimental program
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Effect test

Embodiment 1

[0064] Embodiment 1, source truncated hCBS △ Expression and purification of 414-551 (hCBS-413) expression and purification method

[0065] According to Frank, N., in Arch Biochem Biophys470,64-72 (2008), Oliveriusova, J., J Biol Chem277, 48386-94 (2002). Or Janosik, M. et al. in Acta Crystallogr D BiolCrystallogr57, 289- 91 (2001), the method described in, first hCBS △ 414-551hCBS-413) gene was cloned into glutathione S-transferase (GST) fusion expression vector pGEX-KG, then overexpressed and then affinity-purified using GST-agarose column.

[0066] Sequence Listing SEQ ID No: 1 is the amino acid sequence of hCBS enzyme;

[0067] Use of compound Compd.4 as hCBS enzyme inhibitor:

Embodiment 2

[0068] Example 2. Determination of the inhibition rate of different concentrations of compound Compd.4 on hCBS enzyme activity:

[0069] Step 1. Preparation of buffer solution: add Tris-HCl concentration of 50mM, PLP concentration of 100μM, hCBS-413 concentration of 100nM, L-Cys concentration of 4mM, D, L-HCys concentration of 4mM to the enzymatic reaction vessel Ionic water solution, pH=8.6;

[0070] Step 2. Prepare the enzymatic reaction mixture: add compound Compd.4 to the buffer solution prepared in step 1, and prepare compound Compd.4 at concentrations of 400 μM, 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.2 μM, 3.125μM, 1.56μM, 0.78μM enzymatic reaction mixture to form an enzymatic reaction system;

[0071] Step three, preparation of H 2 S gas detection system:

[0072] in H 2 Add 50 μL of DTNB solution into the S gas detection container, and the DTNB solution is a deionized aqueous solution with a concentration of DTNB of 300 μM, a concentration of Tris-HCl of 262 mM, ...

Embodiment 3

[0079] Example 3. Determination of the inhibition rate of different concentrations of compound Compd.10 on hCBS enzyme activity;

[0080] Step 1. Preparation of buffer solution: add Tris-HCl concentration of 50mM, PLP concentration of 100μM, hCBS-413 concentration of 100nM, L-Cys concentration of 4mM, D, L-HCys concentration of 4mM to the enzymatic reaction vessel Ionic water solution, pH=8.6;

[0081] Step 2. Prepare the enzymatic reaction mixture: add compound Compd.10 to the buffer solution prepared in step 1, and prepare compound Compd.10 at concentrations of 400 μM, 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.2 μM, 3.125μM, 1.56μM, 0.78μM enzymatic reaction mixture to form an enzymatic reaction system;

[0082] Step three, preparation of H 2 S gas detection system:

[0083] in H 2 Add 50 μL of DTNB solution into the S gas detection container, and the DTNB solution is a deionized aqueous solution with a concentration of DTNB of 300 μM, a concentration of Tris-HCl of 262 m...

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Abstract

The invention discloses the application of a naphthalene-1,4-diketone compound as an hCBS enzyme inhibitor, in particular to the compound 2-chloro-3-(4-methylpiperidin-1-yl)naphthalene-1,4 - Use of diketones as hCBS enzyme inhibitors. The IC50 of the small molecular compound on the hCBS enzymatic reaction in vitro is 20 μM. The small molecular compound can be used as a tool drug for studying the H2S signaling pathway, and a lead compound for developing drugs for treating circulatory shock, stroke, Down syndrome and tumors and other diseases related to H2S.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the application of an hCBS enzyme inhibitor. Background technique [0002] human endogenous H 2 S gas molecules participate in and regulate many physiological and pathological processes, and are important regulators of signal transduction pathways. Endogenous H 2 Abnormal changes were found in S content. Therefore, endogenous H is currently required 2 Specific inhibitors or activators of S signaling serve as molecular probe tools to further elucidate H 2 Physiological functions of S, and treatment with H 2 Small molecule drug leads for S-related diseases. [0003] CBS (cystathionineβ-synthase, cystathionine-β-synthase) is a PLP-dependent (pyridoxal-5'-phosphate-dependent) enzyme, vitamin B 6 dependent enzyme. In the human body, CBS catalyzes the substrates L-cysteine ​​(Cysteine) and L-homocysteine ​​(L-Homocysteine) to produce endogenous H 2 S gas. Excess H has been found in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/451A61P9/00A61P9/10A61P25/00A61P35/00C12Q1/527C12Q1/02
CPCA61K31/451C12Q1/02C12Q1/527A61P9/00A61P9/10A61P25/00A61P35/00G01N21/253G01N21/75G01N2021/3185C12Q1/25G01N21/31
Inventor 钮琦吴方周越洋于晶
Owner SHANGHAI JIAO TONG UNIV
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