CN103284987A - Application of propargyl cysteine and analogues thereof in preparation of medicaments for preventing and treating diseases related to cardiovascular system inflammation - Google Patents
Application of propargyl cysteine and analogues thereof in preparation of medicaments for preventing and treating diseases related to cardiovascular system inflammation Download PDFInfo
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- CN103284987A CN103284987A CN2012100445538A CN201210044553A CN103284987A CN 103284987 A CN103284987 A CN 103284987A CN 2012100445538 A CN2012100445538 A CN 2012100445538A CN 201210044553 A CN201210044553 A CN 201210044553A CN 103284987 A CN103284987 A CN 103284987A
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Abstract
The invention belongs to the field of pharmacy, and relates to the application of propargyl cysteine and analogues thereof in preparation of medicaments for preventing and treating diseases related to cardiovascular system inflammation. Through in-vitro cell experiments, the results show that the propargyl cysteine and the analogues thereof can inhibit the expression of the mRNA and the protein of tumor necrosis factor alpha, interleukin-1beta and monocyte chemoattractant protein-1, increase the content of hydrogen sulfide in myocardial inflammation tissues, inhibit the expression of the mRNA of inducible nitric oxide synthase, cyclooxygenase-2 and intercellular adhesion molecule-1 related to the myocardial cells expressed inflammation, inhibit the activation of pathways ERK1/2 and NF-kB related to the inflammation in the myocardial cells, activate protein kinase B (Akt), and inhibit the production of oxygen free radicals in the myocardial cells, and can be prepared into the treatment medicaments for treating the diseases, such as ischemic heart disease, atherosis or myocardial infarction, related to the cardiovascular system inflammation.
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 diseases related medicine of preparation control cardiovascular system inflammation; Described cardiovascular system inflammation is diseases related, comprises the disease that atherosclerosis and inflammation are relevant.
Background technology
Cardiovascular disease is to cause one of dead first cause in developed country and developing country in recent years; Such disease comprises atherosclerosis, coronary heart disease etc.At present, studies confirm that inflammation is one of primary pathogenic factors of cardiovascular disease, and inflammatory reaction reaches in the back of healing all the time with the key player in cardiovascular disease generation evolution; Therefore, intervene its immune related inflammation reaction with generation, the development of effective angiocardiopathy preventing.
At present, known propargyl cysteine 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.Have report to point out, NaHS suppresses the reaction of cardiovascular inflammation, but NaHS t
1/2Too short, effumability, uncontrollable dosage; And propargyl cysteine and analog thereof can produce protective effect to cardiovascular by discharging hydrogen sulfide.
But up to now, the relevant propargyl cysteine of Shang Weijian and analog thereof comprise the report of effects such as coronary heart disease, atherosclerosis to the cardiovascular system diseases associated with inflammation.
Summary of the invention
The purpose of this invention is to provide propargyl cysteine and analog thereof the new purposes in pharmacy, be specifically related to propargyl cysteine and analog thereof the purposes in the diseases related medicine of preparation control cardiovascular system inflammation; Described cardiovascular system inflammation is diseases related, comprises the disease that atherosclerosis and inflammation are relevant.
Propargyl cysteine of the present invention (SPRC) and analog thereof, comprise 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:
Propargyl cysteine of the present invention (SPRC) and analog thereof our experiments show that, can be used as medicine and are applied to treat the cardiovascular system inflammation disease, as ischemic heart desease, atherosclerosis, myocardial infarction etc.
Among the present 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.
The myocardial cell inflammatory model that the present invention induces by lipopolysaccharide (LPS) detects propargyl cysteine SPRC to the influence of the myocardial cell function of described model, and detects the H in the culture supernatant
2The S level: 1. with mRNA and the protein expression of tumor necrosis factor, interleukin-11 β and monocyte chemotactic factor, the 2. mRNA level of inducible nitric oxide synthase, Cycloxygenase-2 and iuntercellular adhesion molecule-1; The result shows that described propargyl cysteine SPRC obviously increases the H in the culture supernatant
2The S level, the mRNA and the protein expression that suppress tumor necrosis factor-alpha, interleukin-11 β and monocyte chemotactic factor-1, and the mRNA level of energy inducible nitric oxide synthase, Cycloxygenase-2 and iuntercellular adhesion molecule-1, simultaneously SPRC can also activated protein kinase B (Akt), suppress that ERK1/2, NF-κ B that lipopolysaccharide causes activate, I κ B α degraded, and suppress the increase of oxygen-derived free radicals (ROS) in the cell that lipopolysaccharide causes; The result shows that described SPRC can be made into medicine and is applied to the inflammatory reaction that cardiovascular disease causes.
The present invention tests by cell in vitro, and the result shows that described propargyl cysteine and analog thereof can suppress the inflammatory mediator in the myocardial cell, comprise mRNA and the protein expression of tumor necrosis factor, il-1 β, monocyte chemoattractant protein-1; Can increase the hydrogen sulfide content in the myocardium inflammation tissue; Can suppress myocardial cell and express the relevant enzyme of inflammation, comprise that the mRNA of inducible nitric oxide synthase, COX-2, iuntercellular adhesion molecule-1 expresses; The activation of inflammation related pathways in the myocardial cell be can suppress, ERK1/2, NF-κ B comprised, and activated protein kinase B (Akt); Can suppress the generation of oxygen-derived free radicals in the myocardial cell; The result shows, propargyl cysteine and analog thereof are as the donor of hydrogen sulfide, comprise that ethyl cystein, propylcysteine, allyl sulfydryl cysteine, butyl cysteine and amyl group cysteine can be made into medicine and be used for the treatment of the cardiovascular system inflammation disease, comprise ischemic heart desease, atherosclerosis, myocardial infarction etc.
Description of drawings
Fig. 1 has shown that SPRC suppresses lipopolysaccharide-induced myocardial cell and discharges inflammatory cytokine,
Wherein, A: monocyte chemoattractant protein-1; B: tumor necrosis factor; C: il-1 β, LPS: lipopolysaccharide, LY:LY294002 (protein kinase B blocker), PAG:DL-PGIY;
#P＜0.05: normal cell vs lipopolysaccharide (LPS) irritation cell;
*P＜0.05,
*P＜0.01:LPS+SPRC treatment cell vsLPS irritation cell;
﹠amp;P＜0.05:LPS+SPRC+LY or PAG group vs LPS+SPRC treatment cell.
Fig. 2 has shown that SPRC suppresses lipopolysaccharide-induced myocardial cell release inflammatory cytokine and transcribes,
Wherein, the influence that the inflammatory mediator of A:LPS is transcribed, iNOS: nitricoxide synthase, MCP-1: monocyte chemoattractant protein-1, ICAM-1: iuntercellular adhesion molecule-1, TNF α: tumor necrosis factor, IL-1 β: il-1 β,
#P＜0.05: normal cell vs lipopolysaccharide (LPS) irritation cell;
*P＜0.05,
*P＜0.01:LPS+SPRC treatment cell vsLPS irritation cell.
Fig. 3 has shown that SPRC suppresses lipopolysaccharide-induced myocardial cell inflammation relevant enzyme and transcribes,
Wherein, iNOS: nitricoxide synthase, ICAM-1: iuntercellular adhesion molecule-1, COX-2: COX-2,
#P＜0.05: normal cell vs lipopolysaccharide (LPS) irritation cell;
*P＜0.05,
*P＜0.01:LPS+SPRC treatment cell vsLPS irritation cell.
Fig. 4 has shown that SPRC activates PI3K/Akt signal path in the H9c2 myocardial cell that LPS induces,
Data represent with means ± SEM,
#P＜0.05:LPS stimulating group vs normal control group;
*Each dosage group vs LPS stimulating group of P＜0.05:SPRC;
﹠amp;P＜0.05:SPRC 1 μ M group vs PAG group/LY294002.
Fig. 5 has shown that SPRC suppresses the degraded of ERK1/2, p65 phosphorylation and I κ B α in the H9c2 myocardial cell that LPS induces,
Data represent with means ± SEM,
#P＜0.05:LPS stimulating group vs normal control group;
*Each dosage group vs LPS stimulating group of P＜0.05:SPRC;
﹠amp;P＜0.05:SPRC 1 μ M group vs PAG group.
Fig. 6 has shown that SPRC suppresses the generation of ROS in the H9c2 myocardial cell that LPS induces,
Control: normal control group; The LPS:LPS stimulating group; LPSSPRC:LPS stimulating group+SPRC.
Fig. 7 has shown that SPRC suppresses that CSE reduces in the H9c2 myocardial cell that LPS induces,
Data represent with means ± SEM,
#P＜0.05:LPS stimulating group vs normal control group; * each dosage group vs LPS stimulating group of P＜0.05:SPRC;
﹠amp;P＜0.05:SPRC 1 μ M group vs PAG group.
The specific embodiment
Grouping: with 1 * 10
5Individual myocardial cell kind is gone into the 6cm culture dish and is cultivated and to reach 85-90% in 3 days, and cell synchronization 6-12h is divided into 6 groups at random, that is: 1. normal control group; 2. model group; 3. propargyl cysteine low dose group; 4. dosage group in the propargyl cysteine; 5. propargyl cysteine high dose group; 6. instrument medicine group (PAG or LY).Administration: 3.-5. adding final concentration is the propargyl cysteine of 0.01 μ M, 0.10 μ M, 1 μ M, and 6. PAG or LY shift to an earlier date administration 30min, and SPRC cultivates 30min.Add LPS (10 μ g/ml) cultivation and induce the inflammatory reaction of H9c2 myocardial cell; Extract mRNA, adopt RT-PCR to measure the transcriptional level of inflammation related gene; The inflammation related gene of measuring: mRNA and the protein expression of tumor necrosis factor-alpha, interleukin-11 β and monocyte chemotactic factor-1, and the generation of the mRNA level of inducible nitric oxide synthase, Cycloxygenase-2 and iuntercellular adhesion molecule-1 and the interior ROS of cell; Experimental data is carried out one factor analysis of variance, p＜0.05, and the result shows, mRNA and the protein expression of propargyl cysteine energy inflammation-inhibiting tumor necrosis factor-alpha, il-1 β and monocyte chemotactic factor-1; And the mRNA level of inducible nitric oxide synthase, Cycloxygenase-2 and iuntercellular adhesion molecule-1 and suppress the generation of ROS in the cell; The result shows, the transcript and expression of the obvious inflammation-inhibiting related gene of propargyl cysteine, and described propargyl cysteine has significant protective effect to the myocardial cell inflammatory reaction that LPS induces, and can be used for preparing the medicine of preventing and treating inflammation related disease.
Grouping: with 1 * 10
5Individual H9c2 myocardial cell kind is gone into the 6cm culture dish and is cultivated and to reach 85-90% in 3 days, and cell synchronization 6-12h is divided into 6 groups at random, that is: 1. normal control group; 2. model group; 3. propargyl cysteine low dose group; 4. dosage group in the propargyl cysteine; 5. propargyl cysteine high dose group; 6. instrument medicine group.Administration: 3.-5. adding final concentration is the propargyl cysteine of 0.01 μ M, 0.10 μ M, 1 μ M for adding final concentration, and 6. PAG or LY shift to an earlier date administration 30min, and SPRC cultivates 30min.After adding LPS body (10 μ g/ml) effect 15min, collecting cell albumen, adopt Western blotting to measure the activation of ERK1/2Akt, MAPK and NF-κ B p65, the result shows, the propargyl cysteine suppresses the activation of the signal path ERK1/2 of LPS, suppress the activation of transcription factor NF-KB, and activate Akt, thus the inflammation-inhibiting reaction.
Claims (8)
1. propargyl cysteine and analog thereof are preparing the purposes of preventing and treating in the diseases related medicine of cardiovascular system inflammation.
2. by the described purposes of claim 1, it is characterized in that described cardiovascular system inflammation is diseases related to be ischemic heart desease, atherosclerosis or myocardial infarction.
3. by claim 1 or 2 described purposes, it is characterized in that described allyl cysteine and analog thereof have following molecular formula and structure:
4. by claim 1 or 2 described purposes, it is characterized in that described propargyl cysteine and analog thereof the mRNA and protein expression treatment ischemic heart desease and the relevant cardiovascular system diseases of inflammation by suppressing tumor necrosis factor, il-1 β, monocyte chemoattractant protein-1.
5. by claim 1 or 2 described purposes, it is characterized in that described propargyl cysteine and analog thereof are by increasing hydrogen sulfide content treatment ischemic heart desease and the related cardiovascular system inflammation disease in the myocardium inflammation tissue.
6. by claim 1 or 2 described purposes, it is characterized in that, described propargyl cysteine and analog thereof are expressed inflammation relevant enzyme treatment ischemic heart desease and related cardiovascular system inflammation disease by suppressing myocardial cell, and described relevant enzyme comprises that the mRNA of inducible nitric oxide synthase, COX-2 and iuntercellular adhesion molecule-1 expresses.
7. by claim 1 or 2 described purposes, it is characterized in that, described propargyl cysteine and analog thereof are by suppressing activation treatment ischemic heart desease and the related cardiovascular system inflammation disease of inflammation related pathways in the myocardial cell, and the activation of inflammation related pathways comprises that ERK1/2, NF-κ B and protein kinase B (Akt) activate in the described myocardial cell.
8. by claim 1 or 2 described purposes, it is characterized in that oxygen-derived free radicals produces treatment ischemic heart desease and related cardiovascular system inflammation disease in the myocardial cell by suppressing for described propargyl cysteine and analog thereof.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110041239A (en) * | 2019-05-13 | 2019-07-23 | 南方医科大学 | N- (benzoyl)-L-cysteine methyl esters analog derivative and its preparation method and application |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101467991A (en) * | 2007-08-02 | 2009-07-01 | 复旦大学 | Uses of allyl cysteine and analogue thereof in preparing medicament for treating myocardial damage |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101467991A (en) * | 2007-08-02 | 2009-07-01 | 复旦大学 | Uses of allyl cysteine and analogue thereof in preparing medicament for treating myocardial damage |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110041239A (en) * | 2019-05-13 | 2019-07-23 | 南方医科大学 | N- (benzoyl)-L-cysteine methyl esters analog derivative and its preparation method and application |
| CN112618531A (en) * | 2019-10-08 | 2021-04-09 | 复旦大学 | Application of propargyl cysteine in preparation of receptor agonist preparation |
| 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 |
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Application publication date: 20130911 |