CN103284988A - Use of propargyl cysteine and analogue thereof in preparation of drug for treating immunity-related inflammation diseases - Google Patents
Use of propargyl cysteine and analogue thereof in preparation of drug for treating immunity-related inflammation diseases Download PDFInfo
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- CN103284988A CN103284988A CN2012100446973A CN201210044697A CN103284988A CN 103284988 A CN103284988 A CN 103284988A CN 2012100446973 A CN2012100446973 A CN 2012100446973A CN 201210044697 A CN201210044697 A CN 201210044697A CN 103284988 A CN103284988 A CN 103284988A
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Abstract
The invention belongs to the pharmaceutical field and relates to a use of propargyl cysteine and an analogue thereof in preparation of a drug for treating immunity-related inflammation diseases. The propargyl cysteine and the analogue thereof can be used for treating the related diseases caused by inflammation by activating the expression of peroxide roliferator-activated receptor-gamma. According to the in-vitro cell experiment result, the propargyl cysteine can be used for treating the immunity-related inflammation diseases by activating the peroxide roliferator-activated receptor-gamma, relieving the inflammatory response of macrophage and macrophage system RAW 264.7 cell, increasing the expression of cystathionine-gamma-lyase in the cell, promoting the generation of anti-inflammatory factor interleukin-10 and restraining the effects of tumor necrosis factor-alpha, macrophage inflammatory protein-1alhpa and macrophage inflammatory protein-1beta.
Description
Technical field
The invention belongs to pharmaceutical field, relate to propargyl cysteine and analog thereof the new purposes in pharmacy, be specifically related to propargyl cysteine and analog thereof the purposes in the immune related inflammation disease medicament of preparation treatment.
Background technology
At present, discover that peroxisome proliferation-activated receptors-γ (PPAR-γ) activates nuclear receptor as a part and regulates lipid and carbohydrate metabolism, but PPAR-γ negativity is regulated inflammatory reaction; Its negativity is regulated the inflammatory reaction effect and is suppressed and the effect of antagonism transcription factor NF-KB and AP-1 by transcribing.
There is report to point out, diallyl disulfide (DADS), a kind of liposoluble constituent in the Bulbus Allii can increase the preceding adipose cell of 3T3-L1 and express PPAR-γ; And pass through to discharge H as the analog SPRC of main active SAC in the Bulbus Allii
2S is, and cardiovascular produces protective effect.Described propargyl cysteine (SPRC) and analog thereof comprise that ethyl cystein (SEC), propylcysteine (SPC), allyl sulfydryl cysteine (SAMC), butyl cysteine (SBC) and amyl group cysteine (SPEC) etc. are the donor of hydrogen sulfide.
But up to now, the relevant PPAR-of activation of Shang Weijian γ regulates the immune inflammation reaction and treats the diseases related report that inflammatory reaction causes.
Summary of the invention
This purpose provides propargyl cysteine and the new purposes of analog in pharmacy thereof, is specifically related to propargyl cysteine and analog thereof the purposes in preparation treatment immune inflammation adjusting relevant disease medicine; Relate in particular to allyl cysteine and analog thereof and treat purposes in the diseases related medicine that inflammatory reaction causes by peroxide activator enzyme body proliferator activated receptor-γ (PPAR-γ) expression in preparation.
Among the present invention, described propargyl cysteine (SPRC) and analog thereof comprise that propargyl cysteine (SPRC), ethyl cystein (SEC), propylcysteine (SPC), allyl sulfydryl cysteine (SAMC), butyl cysteine (SBC) and amyl group cysteine (SPEC) have following molecular formula and structure:
Among the present invention, described propargyl cysteine (SPRC) and analog thereof have carried out zoopery, and the result shows that the result shows that described SPRC and analog thereof can be by discharging hydrogen sulfide (H
2S) activate the PPAR-gamma activity, can be further used for treating immune related inflammation disease.
Preferably, in one embodiment of the present of invention, described propargyl cysteine (SPRC) molecular formula is C
6H
9O
2NS, structural formula is:
It is synthetic by following route:
The L-cysteine hydrochloride is dissolved in the NH of pre-cooling
4OH (2M, 240ml) in the solution, (12g 0.124mol) fully stirs to add the 3-propargyl bromide; Mixed solution stirs the 2h after-filtration down at 0 ℃, and filtrate decompression distillation (＜40 ℃) evaporated in vacuo obtains white needle-like crystals behind the water/ethyl alcohol recrystallization of 2: 3 volume ratios, determine through magnetic resonance detection hydrogen spectrum.
Support Turnover of Mouse Peritoneal Macrophages and RAW264.7 mouse macrophage inflammatory model by former being commissioned to train, observe SPRC to the inflammation regulating action of the macrophage of this model, and detected the release of the TNF-α in the culture supernatant, IL-1 β, MIP-1 α, MIP-1 β and IL-10, IL-6; And the transcriptional activity of the expression of CSE and PPAR-γ and STAT3, AP-1, NF-κ B in the detection cell, also detect the activation situation of mitogen activated protein kinase (MAPK) simultaneously; The result shows that described SPRC can increase IL-10, the IL-6 level in the culture supernatant, suppresses the release of TNF-α, IL-1 β, MIP-1 α, MIP-1 β, the expression of inducing CSE and PPAR-γ simultaneously, and SPRC also can activate ERK1/2, STAT3; The result shows that SPRC can be used as medicine and regulates immune related inflammation reaction.
Test by cell in vitro, the result shows, the inflammatory reaction that described sulfur propargyl cysteine (SPRC) can alleviate Turnover of Mouse Peritoneal Macrophages and mouse macrophage RAW264.7 cell by peroxide activator enzyme body proliferator activated receptor-γ (PPAR-γ), increase cystathionie-γ-lyases (CSE) expression in the cell, and the generation of promotion anti-inflammatory factors interleukin 10 (IL-10), also can suppress the tumor necrosis factor-alpha (TNF-α) that macrophage discharges simultaneously, macrophage inflammatory protein-1 α (MIP-1 α), macrophage inflammatory protein-1 β short inflammatory mediators such as (MIP-1 β), its effect is relevant with transcriptional activator 3 (STAT3) with the activation signal transduction with rise extracellular signal-regulated kinase 1/2 (ERK1/2).
Description of drawings
Fig. 1 has shown the influence that the mice RAW264.7 of SPRC macrophage chemotactic factor discharges,
Wherein, A and C have shown the time-effect relationship that the macrophage inflammatory protein of SPRC (MIP)-1 α and MIP-1 β discharge, cell adopts the ELISA method to detect MIP-1 α and MIP-1 β concentration in the supernatant with containing SPRC (1,50,100,200 μ M) culture fluid cultivation 4,18,24h; B and D have shown the dose-effect relationship that the macrophage inflammatory protein of SPRC (MIP)-1 α and MIP-1 β discharge, and cell is cultivated 24h with containing SPRC (1,50,100,200 μ M) culture fluid, adopts the ELISA method to detect MIP-1 α and MIP-1 β concentration in the supernatant; Data are represented (n=3) with mean ± standard deviation,
*P＜0.05;
*P＜0.01 vs control.
Fig. 2 has shown that SPRC supports the influence that the peritoneal macrophage chemotactic factor discharges to former being commissioned to train,
Wherein, former being commissioned to train supported peritoneal macrophage with containing SPRC (100 μ M) culture fluid cultivation 24h, adopts the ELISA method to detect MIP-1 α (A) and MIP-1 β (B) concentration in the supernatant; Data are represented (n=3) with mean ± standard deviation,
*P＜0.05;
*P＜0.01 vs control.
But Fig. 3 has shown the release of the SPRC promotion mice RAW264.7 macrophage inducing cell factor,
Wherein, A has shown the time-effect relationship that SPRC induces IL-10 to discharge, and cell adopts the ELISA method to detect IL-10 concentration in the supernatant with containing SPRC (1,50,100,200 μ M) culture fluid cultivation 4,18,24h;
B has shown the dose-effect relationship that SPRC induces IL-10 to discharge, and cell is cultivated 24h with containing SPRC (1,50,100,200 μ M) culture fluid, adopts the ELISA method to detect IL-10 concentration in the supernatant;
C has shown that SPRC induces former being commissioned to train to support peritoneal macrophage IL-10 release, and cell is cultivated 24h with containing SPRC (100 μ M) culture fluid, adopts the ELISA method to detect IL-10 concentration in the supernatant;
Data are represented (n=3) with mean ± standard deviation,
*P＜0.05;
*P＜0.01 vs control.
Fig. 4 has shown the influence of the mice RAW264.7 of SPRC macrophage release of cytokines,
Wherein, the influence to IL-6 (A), TNF-α (B), IL-1 β (C) release of SPRC dose dependent, cell is cultivated 24h with the SPRC (1-200 μ M) that contains variable concentrations, and cytokine concentrations adopts the ELISA method to detect in the supernatant; Data are represented (n=3) with mean ± standard deviation,
*P＜0.05;
*P＜0.01 vs control.
Fig. 5 has shown the influence (24h) of the mice RAW264.7 of SPRC macrophage transcription factor (NF-κ B, AP-1, STAT-3) transcriptional activity,
Wherein, the transcriptional activity that influences NF-κ B (A), AP-1 (B), STAT-3 (C) of SPRC dose dependent; Cell adopts and contains SPRC (1-200 μ M) cultivation 24h, extracts nucleoprotein and adopts DNA to detect the transcriptional activity of NF-κ B (A), AP-1 (B), STAT-3 (C) in conjunction with experiment; Data are represented (n=3) with mean ± standard deviation,
*P＜0.05 vs control.
Fig. 6 has shown the influence that the mice RAW264.7 of SPRC macrophage PPAR-γ expresses,
Wherein, A has shown that the PPAR-γ that induces of SPRC dose dependent expresses, and xanthine-guanine phosphotransferase (HRPT) is represented its relative expression quantity as confidential reference items albumen with PPAR-γ/HRPT in proper order;
B has shown DNA in conjunction with experiment, and cell adopts and contains SPRC (100 μ M) cultivation 24h, extracts nucleoprotein and adopts DNA to detect PPAR-γ in conjunction with transcriptional activity in conjunction with experiment;
C has shown immunofluorescence research;
Data are represented (n=3) with mean ± standard deviation,
*P＜0.05 vs control.
Fig. 7 has shown the influence that the mice RAW264.7 of SPRC macrophage CSE expresses,
Wherein, cell adopts and contains SPRC (100 μ M) cultivation 24h, extracts albumen, and Western blot analyzes CSE and expresses, and HRPT is as confidential reference items albumen;
A:Western blot analyzes CSE, HRPT and expresses:
B: represent the CSE relative expression quantity with CSE/HRPT;
Data are represented (n=3) with mean ± standard deviation,
*P＜0.05 vs control.
Fig. 8 has shown the influence that the mice RAW264.7 of SPRC macrophage p-ERK1/2 expresses,
Wherein, cell adopts and contains the different time of SPRC (100 μ M) cultivation, extracts albumen, and Western blot analyzes p-ERK1/2 and expresses, and HRPT is as confidential reference items albumen;
A:Western blot analyzes the expression of mice RAW264.7 macrophage p-ERK1/2;
B: represent the p-ERK1/2 relative expression quantity with p-ERK1/2/HRPT;
Data are represented (n=3) with mean ± standard deviation,
*P＜0.05 vs control.
Fig. 9 has shown the signal transduction pathway that SPRC starts in macrophage,
Wherein, activity activates ERK1/2 and PPAR-γ simultaneously thereby SPRC activates CSE, and the latter activates STAT3 and nuclear translocation takes place; STAT3 activates and to cause the proinflammatory cytokine and the chemotactic factor that raise anti-inflammatory cytokines IL-10 and reduce other.
The specific embodiment
The influence that the Turnover of Mouse Peritoneal Macrophages of SPRC and mice RAW264.7 macrophage chemotactic factor discharge
1. H
2The mouse macrophage of S donor SPRC discharges the influence of inflammatory/inducibility chemotactic factor
By to former generation macrophage and the research of mice RAW264.7 macrophage, with variable concentrations SPRC (1 μ M, 50 μ M, 100 μ M, 200 μ M) cultivate the different time, collect supernatant at different time points, adopt ELISA to detect MIP-1 α and MIP-1 β level; Along with the prolongation of incubation time, the cell of tranquillization discharges MIP-1 α and MIP-1 β level constantly increases, and illustrates that these chemotactic factors are idiopathic secretions, but and the secretion of the inhibition MIP-1 α of SPRC dosage and time dependence and MIP-1 β.
The result shows that SPRC can suppress RAW264.7 macrophage spontaneous secretion MIP-1 α and MIP-1 β significantly;
2. SPRC is to the influence of former generation macrophage release chemotactic factor
The result shows that SPRC (100 μ M) cultivates the secretion matter (shown in Fig. 2 A, B) that 24h significantly suppresses peritoneal macrophage MIP-1 α and MIP-1 β;
The result shows that SPRC discharges chemotactic factor to above-mentioned two cells all inhibitory action.
The influence of the Turnover of Mouse Peritoneal Macrophages of SPRC and mice RAW264.7 macrophage release of cytokines
Based on the result of above-described embodiment 1, detect the release whether SPRC influences proinflammatory cytokine and anti-inflammatory cytokines; The result shows that the different time of different depth SPRC (1 μ M, 50 μ M, 100 μ M, 200 μ M) cultivation RAW264.7 cell, (24h), ELISA measured TNF-α, IL-1 β, IL-6 and the IL-10 level in the supernatant for 4h, 18h; SPRC (1 μ M, 50 μ M, 100 μ M) but the secretion (shown in Fig. 3 A, B) of the promotion IL-10 of time dependence; SPRC (100 μ M) can significantly promote the release of IL-10 (shown in Fig. 3 C) and IL-6 (shown in Fig. 4 A), and SPRC (1 μ M, 50 μ M, 100 μ M, 200 μ M) can significantly reduce the secretion of TNF-α and IL-1 β simultaneously.
Embodiment 3SPRC improves mice RAW264.7 macrophage STAT-3 transcriptional activity
By detecting transcription factor NF-KB, STAT-3 and AP-1 participate in the influence of the cytokine of SPRC and chemotactic factor release, the result shows, SPRC (1 μ M, 50 μ M, 100 μ M, 200 μ M) with RAW264.7 cell culture 24h, extract nucleoprotein and carry out DNA in conjunction with experiment, the result shows, SPRC (100 μ M) can significantly increase the STAT3 transcriptional activity, and to NF-κ B and the not influence (shown in Fig. 6 A, B, C) of AP-1 transcriptional activity.
Embodiment 4SPRC promotes mice RAW264.7 macrophage CSE to express
Variable concentrations SPRC (1 μ M, 50 μ M, 100 μ M, 200 μ M) cultivates 24h with mice RAW264.7 macrophage, and Western blot analyzes and shows that SPRC (100 μ M) can obviously raise the expression (as shown in Figure 7) of CSE.
Embodiment 5SPRC promotes mice RAW264.7 macrophage ERK1/2 phosphorylation
Analyze the molecular mechanism of the RAW 264.7 of SPRC, Western blot analyzes SPRC (100 μ M) and cultivates the expression that different time points detects p-ERK1/2 and p-JN K1/2, the result shows that SPRC can obviously raise the expression (shown in Fig. 8 A, B, C) of p-ERK1/2.
Claims (5)
1. propargyl cysteine and analog thereof are preparing the purposes for the treatment of in the immune related inflammation disease medicament.
2. propargyl cysteine and analog thereof the purposes in preparation peroxide activator enzyme body proliferator activated receptor-γ medicine.
3. by claim 1 or 2 described purposes, it is characterized in that described propargyl cysteine and analog thereof have following molecular formula and structure:
4. by the described purposes of claim 1, it is characterized in that, propargyl cysteine and analog thereof are by peroxide activator enzyme body proliferator activated receptor-γ, alleviate the inflammatory reaction of macrophage and macrophage system RAW264.7 cell, increasing cystathionie-γ in the cell-lyases expresses, and the generation of promotion anti-inflammatory factors interleukin 10, immune related inflammation disease is treated in the tumor necrosis factor-alpha that the inhibition macrophage discharges, the effect of macrophage inflammatory protein-1 α, macrophage inflammatory protein-1 β.
5. by the described purposes of claim 1, it is characterized in that described propargyl cysteine is synthetic by following route:
The L-cysteine hydrochloride is dissolved in the NH of 2M, 240ml pre-cooling
4In the OH solution, the 3-propargyl bromide that adds 12g, 0.124mol fully stirs; Mixed solution stirs the 2h after-filtration down at 0 ℃, and＜40 ℃ of following filtrate decompression distillation evaporated in vacuo obtain white needle-like crystals behind the water/ethyl alcohol recrystallization of 2: 3 volume ratios, determine through magnetic resonance detection hydrogen spectrum.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111973581A (en) * | 2020-09-02 | 2020-11-24 | 爱赫凯(广东)医疗科技有限公司 | Application of ZYZ-802 in preparation of psoriasis treatment drug |
| CN112521322A (en) * | 2020-12-14 | 2021-03-19 | 上海市第十人民医院 | Amino acid compound and composition and application thereof in treatment of periodontal diseases |
| CN112618531A (en) * | 2019-10-08 | 2021-04-09 | 复旦大学 | Application of propargyl cysteine in preparation of receptor agonist preparation |
| CN114642768A (en) * | 2020-12-18 | 2022-06-21 | 深圳先进技术研究院 | Material for regulating and controlling macrophage polarization and immune function and application thereof |
| CN115501125A (en) * | 2022-10-20 | 2022-12-23 | 澳门科技大学 | H for repairing skin lesions 2 S donor gel and H 2 Preparation method of S donor gel |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112618531A (en) * | 2019-10-08 | 2021-04-09 | 复旦大学 | Application of propargyl cysteine in preparation of receptor agonist preparation |
| CN111973581A (en) * | 2020-09-02 | 2020-11-24 | 爱赫凯(广东)医疗科技有限公司 | Application of ZYZ-802 in preparation of psoriasis treatment drug |
| WO2022048214A1 (en) * | 2020-09-02 | 2022-03-10 | 爱赫凯(广东)医疗科技有限公司 | Use of zyz-802 in preparation of drug for treating psoriasis |
| CN112521322A (en) * | 2020-12-14 | 2021-03-19 | 上海市第十人民医院 | Amino acid compound and composition and application thereof in treatment of periodontal diseases |
| CN114642768A (en) * | 2020-12-18 | 2022-06-21 | 深圳先进技术研究院 | Material for regulating and controlling macrophage polarization and immune function and application thereof |
| CN114642768B (en) * | 2020-12-18 | 2023-01-03 | 深圳先进技术研究院 | Material for regulating and controlling macrophage polarization and immune function and application thereof |
| CN115501125A (en) * | 2022-10-20 | 2022-12-23 | 澳门科技大学 | H for repairing skin lesions 2 S donor gel and H 2 Preparation method of S donor gel |
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Application publication date: 20130911 |