(2R)-1-[[4-[[3-甲基-5-[(苯磺酰基)甲基]苯氧基]甲基]苯基]甲基]-2-吡咯烷甲醇柠檬酸盐
中文名称:
(2R)-1-[[4-[[3-甲基-5-[(苯磺酰基)甲基]苯氧基]甲基]苯基]甲基]-2-吡咯烷甲醇柠檬酸盐
中文同义词:
(2R)-1-[[4-[[3-甲基-5-[(苯磺酰基)甲基]苯氧基]甲基]苯基]甲基]-2-吡咯烷甲醇柠檬酸盐;SPHK1抑制剂(PF-543 CITRATE)
英文名称:
PF-543 (Citrate)
英文同义词:
PF-543 (Citrate);(2R)-1-[[4-[[3-Methyl-5-[(phenylsulfonyl)methyl]phenoxy]methyl]phenyl]methyl]-2-pyrrolidinemethanol 2-hydroxy-1,2,3-propanetricarboxylate (1:1);(2R)-1-[[4-[[3-Methyl-5-[(phenylsulfonyl)methyl]phenoxy]methyl]phenyl]methyl]-2-pyrrolidinemethanol 2-hydroxy-1,2,3-propanetricarboxylate;PWXXWUWKNPXSGW-VQIWEWKSSA-N;PF543 CITRATE; PF 543 CITRATE;Sphingosine Kinase 1 Inhibitor II Citrate
CAS号:
1415562-83-2
分子式:
C33H39NO11S
分子量:
657.72786
EINECS号:
相关类别:
细胞生物学试剂
Mol文件:
1415562-83-2.mol
生物活性
PF-543 Citrate (Sphingosine Kinase 1 Inhibitor II Citrate) 是一种有效，选择性，可逆和鞘氨醇竞争性 SPHK1 抑制剂，IC50 为 2 nM，Ki 为 3.6 nM。PF-543 Citrate 对 SPHK1 的选择性是 SPHK2 的 100 倍以上。PF-543 Citrate 还是有效的全血中 1-磷酸鞘氨醇 (S1P) 形成的有效抑制剂，IC50 为 26.7 nM。PF-543 Citrate 诱导细胞凋亡，坏死和自噬。
靶点
IC50: 2 nM (SPHK1); 26.7 nM (Sphingosine 1-phosphate (S1P))
Ki: 3.6 nM (SPHK1)
体外研究
PF-543 (10-1000 nM; 24 hours; PASM cells) treatment abolishes SK1 expression at nM concentrations.
PF-543 (0.1-10 μM; 24 hours; PASM cells) treatment induces caspase-3/7 activity.
PF-543 inhibits C 17 -S1P formation in 1483 cells with an IC 50 of 1.0 nM.
SphK1 inhibition by PF-543 causes a dose-dependent depletion of the intracellular level of S1P with EC 50 concentration of 8.4 nM and a concomitant elevation of the intracellular level of sphingosine in 1483 cells. The level of endogenous S1P in 1483 cells after a 1 h treatment with 200 nM PF-543 is decreased 10-fold, producing a proportional increase in the level of sphingosine.
Western Blot Analysis
Cell Line: Human pulmonary arterial smooth muscle (PASM) cells
Concentration: 10 nM, 100 nM, 1000 nM
Incubation Time: 24 hours
Result: Abolished SK1 expression at nM concentrations.
Apoptosis Analysis
Cell Line: Human pulmonary arterial smooth muscle (PASM) cells
Concentration: 0.1 μM, 1 μM, 10 μM
Incubation Time: 24 hours
Result: Induced caspase-3/7 activity in cultured human pulmonary smooth muscle cells.
Cell Line:
Human pulmonary arterial smooth muscle (PASM) cells
Concentration:
10 nM, 100 nM, 1000 nM
Incubation Time:
24 hours
Result:
Abolished SK1 expression at nM concentrations.
Cell Line:
Human pulmonary arterial smooth muscle (PASM) cells
Concentration:
0.1 μM, 1 μM, 10 μM
Incubation Time:
24 hours
Result:
Induced caspase-3/7 activity in cultured human pulmonary smooth muscle cells.
体内研究
PF-543 (1 mg/kg; intraperitoneal injection; every second day; for 21 days; female C57BL/6 J mice) treatment has no effect on vascular remodelling but reduces right ventricular hypertrophy. The protection involves a reduction in the expression of p53 and an increase in the expression of anti-oxidant nuclear factor Nrf-2.
Mice are initially dosed (ip) with 10 mg/kg or 30 mg/kg of PF-543 for 24 h and the T 1/2 is 1.2 h in blood samples. Administration of 10 mg/kg PF-543 for 24 h to mice induces a decrease in SK1 expression in pulmonary vessels.
Animal Model: Female C57BL/6 J mice (7-12 week-old) with hypoxic-induced pulmonary arterial hypertension
Dosage: 1 mg/kg
Administration: Intraperitoneal injection; every second day; for 21 days
Result: Reduced right ventricular hypertrophy. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor Nrf-2.
Animal Model:
Female C57BL/6 J mice (7-12 week-old) with hypoxic-induced pulmonary arterial hypertension
Dosage:
1 mg/kg
Administration:
Intraperitoneal injection; every second day; for 21 days
Result:
Reduced right ventricular hypertrophy. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor Nrf-2.
