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芬维A胺

芬维A胺用途

Fenretinide 是一种合成的类维生素A衍生物,能够结合视黄酸受体 (RAR) 诱导细胞死亡。

芬维A胺名称

[ CAS 号 ]:
65646-68-6

[ 中文名 ]:
维甲酰酚胺

[ 英文名 ]:
Fenretinide

[中文别名 ]:

[英文别名 ]:

4-Hydroxyphenyl retinamide
Fenretinide
4-HPR
15-[(4-Hydroxyphenyl)amino]retinal
fenretinida
Retinal, 15-[(4-hydroxyphenyl)amino]-
fenretinidum
MFCD00792674

芬维A胺生物活性

[ 描述 ]:

Fenretinide 是一种合成的类维生素A衍生物,能够结合视黄酸受体 (RAR) 诱导细胞死亡。

[ 相关类别 ]:

信号通路 >> 自噬 >> 自噬

信号通路 >> 代谢酶/蛋白酶 >> RAR/RXR

研究领域 >> 癌症

[体外研究]

芬维A胺不仅在选定的T-ALL细胞系中发挥急性而且长期的抗肿瘤活性。芬维A胺以剂量和时间依赖性方式抑制CCRF-CEM白血病细胞中的DES活性,导致内源性细胞dhCer含量的伴随增加。芬维A胺(3μM)诱导dhCer在CCRF-CEM和Jurkat细胞中积累[1]。芬维A胺对神经酰胺的抑制作用可以保护胰岛素信号。芬维A胺可防止脂质诱导的胰岛素刺激的葡萄糖摄取减少[2]。芬维A胺在高于1μM的浓度下抑制OVCAR-5细胞增殖和活力,在10μM时具有70-90％的生长抑制。 Fenretinide(1 microM)在预培养3天后显着抑制OVCAR-5侵袭。用1 microM 4-HPR处理的内皮细胞不能形成管,但形成小的细胞聚集体[4]。

[体内研究]

芬维A胺(10mg/kg,ip)选择性地抑制神经酰胺积聚HFD喂养的雄性C57Bl/6小鼠。芬维A胺治疗通过葡萄糖和胰岛素耐量试验确定了葡萄糖耐量和胰岛素敏感性[2]。在NOD/SCID小鼠中向芬维A胺中添加25mg/kg酮康唑可增加4-HPR血浆水平[3]。

[细胞实验]

标准XTT测定用于确定细胞活力。对于仅芬维A胺处理，将细胞以750,000个细胞/ mL和100μL/孔接种在96孔板中。 4小时后，以50μL/孔加入处理，获得500,000个细胞/ mL的最终密度，最终体积为150μL/孔。每个实验条件使用四次重复。在所选治疗期结束前4小时加入XTT试剂混合物，每孔测定490nm处的吸光度。稍微修改的方案用于分析myriocin（终浓度100nM）或抗氧化剂对芬维A胺治疗的影响。简言之，将细胞接种在60mm培养皿上，4小时后加入myriocin或抗氧化剂。 2小时后加入芬维A胺处理，将细胞一式四份涂布在96孔板（150μL/孔）中。

[动物实验]

雄性小鼠（C57B16）用标准食物或高脂肪饮食（HFD）喂养5至17周，此时一半喂食HFD的小鼠开始在饮用水中接受芬维A胺4周。将芬维A胺溶于100％乙醇中并在水中稀释至10μg/ mL。对照处理水接受等量的乙醇（0.5％）。 FEN水在低光照条件下制备，并在防光瓶中给药。每1-2天更换一次水，并且在任何时候都没有注意到FEN的沉淀。在治疗期的开始和结束时记录动物重量。在4周FEN治疗后，小鼠进行腹膜内葡萄糖和胰岛素耐量试验。对于两种测试，将小鼠禁食6小时并接受葡萄糖（1g / kg体重）或胰岛素（0.75单位/ kg体重）的注射。在BayerContour®血糖仪指示的时间测定血糖，并用大鼠/小鼠胰岛素ELISA试剂盒测量胰岛素。通过使用空腹血糖和胰岛素水平来评估胰岛素抵抗指数以计算胰岛素抵抗的稳态模型评估（HOMA-IR），其中较高的数字代表更大的胰岛素抗性。

[参考文献]

[1]. Apraiz, Aintzane., et al. Dihydroceramide accumulation and reactive oxygen species are distinct and nonessential events in 4-HPR-mediated leukemia cell death. Biochemistry and Cell Biology (2012), 90(2), 209-223.

[2]. Bikman, Benjamin T., et al. Fenretinide Prevents Lipid-induced Insulin Resistance by Blocking Ceramide Biosynthesis. Journal of Biological Chemistry (2012), 287(21), 17426-17437.

[3]. Cooper JP, et al. Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure. Br J Pharmacol. 2011 Jul;163(6):1263-75.

[4]. Golubkov V, et al. Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells. Anticancer Res. 2005 Jan-Feb;25(1A):249-53.

[相关活性小分子]

维生素A酸；视黄酸 | 4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)甲酰氨基]苯甲酸 | 他米巴罗汀 | 4-[(1E)-2-[5,6,7,8-四氢-5,5,8,8-四甲基-3-(1H-吡唑-1-基甲基)-2-萘基]乙烯基]苯甲酸 | 芳维甲酸 | 厚朴酚 | AGN 194310 | AGN 193109 | CD 437 | 阿达帕林 | AR7 | 他扎罗汀 | UVI 3003 | (R)-氟比洛芬(Tarenflurbil) | AGN 195183

芬维A胺物理化学性质

[ 密度 ]:
1.1±0.1 g/cm3

[ 沸点 ]:
597.6±42.0 °C at 760 mmHg

[ 熔点 ]:
162-163°C

[ 分子式 ]:
C₂₆H₃₃NO₂

[ 分子量 ]:
391.546

[ 闪点 ]:
315.2±27.9 °C

[ 精确质量 ]:
391.251129

[ PSA ]:
49.33000

[ LogP ]:
7.41

[ 外观性状 ]:
黄色粉末

[ 蒸汽压 ]:
0.0±1.8 mmHg at 25°C

[ 折射率 ]:
1.607

[ 储存条件 ]:
−20°C

[ 稳定性 ]:
Light Sensitive - Protect from Light Exposure

芬维A胺MSDS

详细MSDS(安全技术说明书)

芬维A胺毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: VH6420000

CHEMICAL NAME :: Retinamide, N-(4-hydroxyphenyl)-

CAS REGISTRY NUMBER :: 65646-68-6

LAST UPDATED :: 199712

DATA ITEMS CITED :: 8

MOLECULAR FORMULA :: C26-H33-N-O2

MOLECULAR WEIGHT :: 391.60

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - man

DOSE/DURATION :: 180 mg/kg/18D-I

TOXIC EFFECTS :: Sense Organs and Special Senses (Eye) - retinal changes (pigmentary depositions, retinitis, other)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - woman

DOSE/DURATION :: 210 mg/kg/2W-I

TOXIC EFFECTS :: Sense Organs and Special Senses (Eye) - retinal changes (pigmentary depositions, retinitis, other)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 8388 mg/kg/21D-I

TOXIC EFFECTS :: Blood - changes in other cell count (unspecified)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 2138 mg/kg/21D-I

TOXIC EFFECTS :: Blood - pigmented or nucleated red blood cells Blood - changes in erythrocyte (RBC) count Blood - changes in leukocyte (WBC) count

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 600 mg/kg

SEX/DURATION :: female 10-11 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 400 mg/kg

SEX/DURATION :: female 11 day(s) after conception

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - musculoskeletal system

MUTATION DATA

TYPE OF TEST :: Morphological transformation

TEST SYSTEM :: Rodent - mouse Mammary gland

DOSE/DURATION :: 10 umol/L

REFERENCE :: NUCADQ Nutrition and Cancer. (Franklin Institute Press, POB 2266, Phildelphia, PA 19103) V.1- 1978- Volume(issue)/page/year: 7,105,1985

芬维A胺安全信息

[ 符号 ]:

GHS07, GHS08

[ 信号词 ]:
Danger

[ 危害声明 ]:
H302 + H312 + H332-H315-H319-H335-H360

[ 警示性声明 ]:
P201-P261-P280-P305 + P351 + P338-P308 + P313

[ 个人防护装备 ]:
Eyeshields;full-face particle respirator type N100 (US);Gloves;respirator cartridge type N100 (US);type P1 (EN143) respirator filter;type P3 (EN 143) respirator cartridges

[ 危害码 (欧洲) ]:
T: Toxic;

[ 风险声明 (欧洲) ]:
R60;R61;R20/21/22;R36/37/38

[ 安全声明 (欧洲) ]:
S53-S26-S36/37/39-S45

[ 危险品运输编码 ]:
NONH for all modes of transport

[ WGK德国 ]:
3

[ RTECS号 ]:
VH6420000

芬维A胺合成路线

详细合成路线

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芬维A胺上游产品

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芬维A胺文献

Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes.

PLoS ONE 10(2) , e0115686, (2015)

Antimetabolites are a class of effective anticancer drugs interfering in essential biochemical processes. 5-Fluorouracil (5-FU) and its prodrug Capecitabine are widely used in the treatment of several...

Enhanced killing of SCC17B human head and neck squamous cell carcinoma cells after photodynamic therapy plus fenretinide via the de novo sphingolipid biosynthesis pathway and apoptosis.

Int. J. Oncol. 46(5) , 2003-10, (2015)

Because photodynamic therapy (PDT) alone is not always effective as an anticancer treatment, PDT is combined with other anticancer agents for improved efficacy. The clinically-relevant fenretinide [N-...

Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia--Impact on enzyme activity and response to cytotoxics.

Biochim. Biophys. Acta 1851 , 919-28, (2015)

The triphenylethylene antiestrogen, tamoxifen, can be an effective inhibitor of sphingolipid metabolism. This off-target activity makes tamoxifen an interesting ancillary for boosting the apoptosis-in...

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