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金诺芬

金诺芬用途

Auranofin (SKF-39162)是硫氧还蛋白还原酶 (TrxR) 的抑制剂,IC50为0.2 μM。

金诺芬名称

[ CAS 号 ]:
34031-32-8

[ 中文名 ]:
金诺芬

[ 英文名 ]:
auranofin

[中文别名 ]:

醋硫葡金

[英文别名 ]:

auranofin
ridaura
AURANOFINE
Crisinor
Adtil
EINECS 251-801-9
Crisofin
Ridauran

金诺芬生物活性

[ 描述 ]:

Auranofin (SKF-39162)是硫氧还蛋白还原酶 (TrxR) 的抑制剂,IC50为0.2 μM。

[ 相关类别 ]:

信号通路 >> 其他 >> 其他

研究领域 >> 炎症/免疫

[ 靶点 ]

IC50: 0.2 μM (TrxR)[1]

[体外研究]

金诺芬是一种被批准用于治疗类风湿性关节炎的药物,但正在研究其在许多其他疾病(包括癌症,神经退行性疾病)中的潜在治疗应用。金诺芬通过与选择性破坏线粒体氧化还原稳态相关的Bax/Bak依赖性机制诱导细胞凋亡,同时伴随Prx3的氧化[1]。金诺芬以剂量和时间依赖性方式抑制SKOV3细胞的增殖和存活。金诺芬治疗激活促凋亡的caspase-3,增加凋亡诱导蛋白Bax和Bim的蛋白水平,并降低SKOV3细胞中抗凋亡介质Bcl-2的表达[2]。金诺芬是一种具有抗炎和免疫抑制特性的亲脂性金化合物。金诺芬抑制PC3人前列腺癌细胞中的细胞生长和线粒体凋亡的诱导。金诺芬治疗显着抑制细胞活力,24小时后IC50值为2.5μM[3]。

[体内研究]

用金诺芬预防性治疗佐剂诱导的关节炎大鼠,导致爪水肿轻微减少,IL-2产生减少完全正常化,IL-1产生增加,但对抑郁IL-没有影响。 3生产[4]。

[细胞实验]

金诺芬溶解在DMSO中。用金诺芬（0,50,100,200和400nM）处理细胞72小时进行剂量依赖性反应测定，并将100nM金诺芬加入孔中0,24,72和120小时的时间 - 依赖性反应试验。用DMSO处理对照培养物。通过MTT测定法测量细胞活力[2]。

[动物实验]

大鼠：预防性地，从佐剂注射当天开始以每日间隔口服给予金诺芬（6.7至15mg金/ kg），吲哚美辛（2mg / kg）或黄蓍胶载体对照。在第16至17天，分离并测试来自正常或佐剂注射的大鼠的腹膜渗出细胞或脾细胞[4]。

[参考文献]

[1]. Cox AG, et al. The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation. Biochem Pharmacol. 2008 Oct 30;76(9):1097-109.

[2]. Park SH, et al. Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. Int J Oncol. 2014 Oct;45(4):1691-8.

[3]. Park N, et al. Auranofin promotes mitochondrial apoptosis by inducing annexin A5 expression and translocation in human prostate cancer cells. J Toxicol Environ Health A. 2014;77(22-24):1467-76.

[4]. Lee JC, et al. Effect of auranofin treatment on aberrant splenic interleukin production in adjuvant arthritic rats. J Immunol. 1987 Nov 15;139(10):3268-74.

[相关活性小分子]

金诺芬物理化学性质

[ 沸点 ]:
425.5ºC at 760mmHg

[ 熔点 ]:
103 - 105ºC

[ 分子式 ]:
C₂₀H₃₆AuO₉PS

[ 分子量 ]:
680.50

[ 闪点 ]:
298ºC

[ PSA ]:
149.54000

[ LogP ]:
2.79250

[ 外观性状 ]:
针状

[ 储存条件 ]:
通风低温干燥,与库房食品原料存放

[ 水溶解性 ]:
DMSO: ≥5mg/mL

金诺芬毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: MD6500000

CHEMICAL NAME :: Gold, (1-thio-beta-D-glucopyranosato-S)(triethylphosphine)- , 2,3,4,6-tetraacetate

CAS REGISTRY NUMBER :: 34031-32-8

LAST UPDATED :: 199112

DATA ITEMS CITED :: 15

MOLECULAR FORMULA :: C20-H34-Au-O9-P-S

MOLECULAR WEIGHT :: 678.54

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - man

DOSE/DURATION :: 1200 ug/kg/2W-I

TOXIC EFFECTS :: Gastrointestinal - ulceration or bleeding from stomach

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - woman

DOSE/DURATION :: 5400 ug/kg/10D-I

TOXIC EFFECTS :: Behavioral - toxic psychosis Behavioral - muscle weakness Behavioral - muscle contraction or spasticity

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 265 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 25500 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 235 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 39 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 84940 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 33800 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 53600 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 22600 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 3200 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 100 mg/kg

SEX/DURATION :: female 6-15 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 358 mg/kg

SEX/DURATION :: female 6-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 179 mg/kg

SEX/DURATION :: female 6-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth)

MUTATION DATA

TYPE OF TEST :: DNA inhibition

TEST SYSTEM :: Human Cells - not otherwise specified

DOSE/DURATION :: 41 umol/L

REFERENCE :: BCPCA6 Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- Volume(issue)/page/year: 34,3243,1985

金诺芬安全信息

[ 危害码 (欧洲) ]:
Xn

[ 风险声明 (欧洲) ]:
63-22

[ 安全声明 (欧洲) ]:
36/37

[ 危险品运输编码 ]:
UN 2811 6.1 / PGIII

[ RTECS号 ]:
MD6500000

金诺芬制备

吡喃葡糖和乙酸成酯后，再选择性溴化得化合物(I)。2.0g化合物(I)和1.2g硫化钠(或相应的硫化钾)及1.7g三乙基膦氯化金，在氯仿-水的混合液中，室温搅拌1h，得金诺芬。

另外，化合物(I)和硫脲作用，得到化合物(Ⅱ)(其制备方法参见Methods in Carbohydrate Chemistry，vol 2，1963，P．435)。往5.3g(0.011mo1)化合物(Ⅱ)溶于30rnl水所成的溶液中，于-10℃下加入1.66g(0.012mo1)的碳酸钾溶于20ml蒸馏水所成的冷溶液。3.86g(0.011mmol)的三乙基膦氯化金溶于30ml含有数滴二氯甲烷的乙醇，所成的溶液冷却，并加入上述的水溶液中。加完后，在冷却下继续搅拌0.5h。分离出产生的固体，并先后用含水乙醇和水洗涤，真空干燥。得到无色结晶的金诺芬，熔点110～111℃。上述制备中所用的三乙基膦氯化金可通过下述方法来制备：溶于25ml乙醇的10．0g(0.08mo1)的2，2’-二羟基二乙硫醚所成的溶液，和溶于75ml蒸馏水的15.76g(0.04mo1)的氯化金酸三水合物所成的溶液相混合；当橙黄色的溶液变为几乎无色时，冷至-5℃，在搅拌下滴加入-5℃的溶于25ml乙醇的5.0g(0.0425mo1)的三乙基膦；加完后继续搅拌0.5h；过滤出产生的固体后，滤液浓缩至约30ml以产生沉淀，过滤；2次过滤出的固体一起用水：乙醇(2：1)来洗涤；溶于乙醇中，通过加入水至产生混浊后，任其结晶；得到的三乙基膦氯化金为白色针状，熔点85--86℃。

金诺芬