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  • SB 203580
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SB 203580

SB 203580是p38-MAPK(有丝分裂原活化蛋白激酶)通路的特异性抑制剂

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¥575-2650
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460-2120
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  • 货号: ajci11432
  • CAS: 152121-47-6
  • 别名: 4-(4-氟苯基)-2-(4-甲基亚磺酰基苯基)-5-(4-吡啶基)-1H-咪唑,SB 203580; RWJ 64809
  • 分子式: C21H16FN3OS
  • 分子量: 377.44
  • 纯度: >98%
  • 溶解度: ≥ 18.872mg/mL in DMSO, ≥ 3.28 mg/mL in EtOH with ultrasonic
  • 储存: Desiccate at 4°C
  • 库存: 现货

Background

SB 203580 is a specific inhibitor of p38-MAPK (Mitogen-activated Protein Kinase) pathway [1,2]. SB 203580 inhibits p38 kinase in a manner competitive with ATP with a Ki of 21 nm [2].


SB 203580 inhibit the proliferation of human breast cancer cell line MDA-MB-231 with the IC50 value of was 85.1 μM [3]. SB 203580 inhibited IL-10 production by monocytic WEHI 274.3 cells expressing WT-p38α MAPK in a dose-dependent manner with greater than 95% inhibition at 5 μm and with an IC50 of 0.1μM [4]. IL-2-induced proliferation of primary human T cells, murine CT6 T cells, or BAF F7 B cells is prevented by the p38 MAP kinase inhibitor SB 203580 with an IC50 of 3-5μM [5].


SB-203580 demonstrated moderate to high clearance in all species tested in vivo, with non-linear elimination observed in the rat at plasma concentrations > 1000ng ml -1. Although good solution bioavailability was observed in non-rodents (78% in dog, 32% in monkey), lower and more variable bioavailability was observed in the rat and mouse (3-48%) [6]. SB 203580 treatment significantly improve the white blood cell (WBC) and platelet counts decreased significantly in the DENV-infected mice, suggesting leucopenia and thrombocytopenia, respectively [7].


SB 203580是p38-MAPK(有丝分裂原活化蛋白激酶)通路的特异性抑制剂。它以与ATP竞争的方式抑制p38激酶,Ki值为21纳摩尔。


SB 203580可以抑制人乳腺癌细胞系MDA-MB-231的增殖,其IC50值为85.1微米[3]。在表达WT-p38α MAPK的单核WEHI 274.3细胞中,SB 203580以剂量依赖方式抑制IL-10的产生,在5微米时可达到95%以上的抑制率,并且其IC50为0.1微米[4]。 SB 203580是p38 MAP激酶抑制剂,可以防止IL-2诱导的原代人T细胞、小鼠CT6 T细胞或BAF F7 B细胞增殖,其IC50为3-5μM [5]。


在所有测试的物种中,SB-203580在体内表现出中等到高度的清除能力,在大鼠血浆浓度>1000ng ml -1时观察到非线性消除。尽管非啮齿动物(狗78%,猴子32%)观察到良好的溶液生物利用度,但在大鼠和小鼠中观察到较低且更为不稳定的生物利用度(3-48%)[6]。 SB 203580治疗显着改善了DENV感染小鼠的白细胞计数和血小板计数明显下降,分别提示粒细胞减少和血小板减少[7]。

参考文献:
[1]. Barancik M, Bohacova V, Kvackajova J, Hudecova S, Krizanova O, Breier A: SB 203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. Eur J Pharm Sci. 2001, 14: 29-36. 10.1016/S0928-0987(01)00139-7.
[2]. Peter R. Young, Megan M. McLaughlin, Sanjay Kumar, et al. Pyridinyl Imidazole Inhibitors of p38 Mitogen-activated Protein Kinase Bind in the ATP Site. The Journal of Biological Chemistry, 1997, 272(18): 12116-12121.
[3]. Duzgun SA, Yerlikaya A, Zeren S, Bayhan Z, Okur E, Boyaci I. Differential effects of p38 MAP kinase inhibitors SB 203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line. Cytotechnology. 2017;69(4):711-24.
[4]. Guo, X., R.E. Gerl, and J.W. Schrader. 2003. Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. J. Biol. Chem. 278:22237-22242.
[5]. Lali, F. V., Hunt, A. E., Turner, S. J., and Foxwell, B. M. The pyridinyl imidazole inhibitor SB 203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. J. Biol. Chem.,275: 7395-7402,?2000
[6]. Ward KW, Prokscht JW, Azzaranot LM, et al. Preclinical pharmacokinetics of SB-203580, a potent inhibitor of p38 mitogen-activated protein kinase. Xenobiotica 2001; 31: 783-97
[7]. Sreekanth GP, Chuncharunee A, Sirimontaporn A, Panaampon J, Noisakran S, Yenchitsomanus PT, et al. SB 203580 modulates p38 MAPK signaling and Dengue virus-induced liver injury by reducing MAPKAPK2, HSP27, and ATF2 phosphorylation. PLoS One. 2016;11:e0149486.

Protocol

Cell experiment [1]:

Cell lines

MDA-MB-231 human breast cancer cell line

Preparation Method

Cells were treated at the logarithmic phase of the growth with various doses of SB 203580 (0.1, 0.5, 1, 5, 10, 25, 50, 100 μM) for 24 h

Reaction Conditions

0.1, 0.5, 1, 5, 10, 25, 50, 100 μM for 24 h

Applications

SB 203580 did not cause significant cytotoxicity on human MDA-MB-231 breast cancer cell line at low concentrations (0.1-10 μM) as compared to vehicle-treated (0.5% DMSO) control cells. However, the cytotoxic effects of both inhibitors were observed with higher concentrations of 25, 50 and 100 μM..

Animal experiment [2]:

Animal models

Male Balb/c mice

Preparation Method

Treatments with 2% DMSO alone or SB 203580 dissolved in 2% DMSO were given 1 h before and 1 h and 24 h after DENV infection intravenously. The volume of all injections was 0.4 ml. At 7 days after infection, the mice were euthanized with an overdose intraperitoneal injection of sodium pentobarbital anesthesia.

Dosage form

5 mg/kg/d for 7 days, infection intravenously

Applications

After the DENV-infected mice were treated with SB 203580, their liver AST levels were significantly reduced, but the changes in ALT were failed to reach statistical significance

参考文献:

[1]: Duzgun SA, Yerlikaya A, Zeren S, Bayhan Z, Okur E, Boyaci I. Differential effects of p38 MAP kinase inhibitors SB 203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line. Cytotechnology. 2017;69(4):711-24.
[2]: Sreekanth GP, Chuncharunee A, Sirimontaporn A, Panaampon J, Noisakran S, Yenchitsomanus PT, et al. SB 203580 modulates p38 MAPK signaling and Dengue virus-induced liver injury by reducing MAPKAPK2, HSP27, and ATF2 phosphorylation. PLoS One. 2016;11:e0149486.

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