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4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)甲酰氨基]苯甲酸

用途

AM580是选择性的 RARα 激动剂,IC50 和 EC50 分别为8 nM,0.36 nM。

名称

[ CAS 号 ]:
102121-60-8

[ 中文名 ]:
4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)甲酰氨基]苯甲酸

[ 英文名 ]:
AM580

[英文别名 ]:

Ro 40-6055
MFCD00673916
CD 336
AM580

生物活性

[ 描述 ]:

AM580是选择性的 RARα 激动剂,IC50 和 EC50 分别为8 nM,0.36 nM。

[ 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]

在G-CSF存在下,AM580(10-8M)在NB4细胞的LAP mRNA中产生显着的诱导。在浓度为10-5M时,AM580和ATRA与G-CSF组合诱导几乎相同水平的LAP转录物。 AM580(在10-8M)导致NB4细胞中编码G-CSF受体的转录物的稳态水平增加约6倍[1]。 AM580(50 nM)增加所有菌落中的caspase-3表达,并且在30％的菌落中诱导腺泡样空化[2]。使用shRARγ1然后通过Am580处理敲除原代Myc细胞中的RARγ1导致更高水平的CRBP1表达,表明在这些细胞中RARγ对RARα靶基因CRBP1具有抑制作用。 Am580(200 nM)增强了在MCF-10A和MCF-7细胞系中RARγ敲低所显示的抗增殖作用,但在MDA-MB-231细胞中没有[3]。

[体内研究]

Am580(0.3mg/kg /天)治疗对MMTV-wnt1小鼠的无肿瘤存活具有更深远的影响,即使在早期出现的肿瘤中也显着,并且在肝,肺,肾和脾。 Am580治疗可显着降低两种转基因腺体的增生水平[2]。用RARα选择性激动剂Am580处理MMTV-Myc小鼠导致显着抑制乳腺肿瘤生长,肺转移并延长63％小鼠的肿瘤潜伏期[3]。

[激酶实验]

收获大约1×106 NB4，HL-60和APL新鲜白血病细胞或CML嗜中性粒细胞，通过以400g离心10分钟沉淀，用0.9％NaCl洗涤一次，并再次离心。将洗涤的细胞沉淀重悬于匀浆缓冲液（1mM MgCl 2,1mM CaCl 2,20mM ZnCl 2,0.1mM NaCl，0.1％[vol / vol] Triton X-100,50mM Tris / HCl，pH 7.4）中并通过有力的移液。匀浆用于LAP测定，其根据制造商的说明用对硝基苯酚磷酸盐作为底物进行。将LAP活性标准化为样品中蛋白质的含量。使用BSA级分V作为标准，根据Bradford方法测量蛋白质。一个单位的LAP活性定义为能够在25℃下在1分钟内转化1nmol底物的酶量。在相对于底物和蛋白质浓度的线性条件下进行酶测定。

[细胞实验]

将MCF-10A（2×104）对照细胞或过表达RARγ在6孔培养皿中一式三份接种。 24小时后，用PBS洗涤细胞，在2mL DMEM-F12培养基中孵育，分离并每24小时计数。统计显着性通过t检验确定。使用针对IHC分析描述的相同抗体，通过用pSG5-RARγ表达载体稳定转染的对照MCF-10A单层和单层的免疫荧光分析来测试pRB和p27表达。

[动物实验]

4个月大的单胎（1个妊娠/哺乳期）MMTV-neu和6周龄未经产的MMTV-wnt1雌性小鼠（50只小鼠/组）用RARα激动剂AM580（每只小鼠每天0.3mg / kg体重）处理。饮食（Purina 5053）加入1.5 mg AM580 / kg Purina 5053饮食。在治疗的第一个月内发生肿瘤的小鼠从研究中移除。每周两次触诊小鼠并记录肿瘤外观。一旦触及，每周测量肿瘤的大小。从Kaplan-Meier曲线计算无肿瘤存活率，并且通过生存研究的Log-rank检验和肿瘤生长研究的t检验确定统计学显着性。通过去除所有麻醉小鼠的肺来评估转移，每组随机选择20只小鼠并使用立体镜检查肺表面的病变。

[参考文献]

[1]. Gianní M, et al. AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells. Blood. 1996 Feb 15;87(4):1520-31.

[2]. Lu Y, et al. Mechanism of inhibition of MMTV-neu and MMTV-wnt1 induced mammary oncogenesis by RARalpha agonist AM580. Oncogene. 2010 Jun 24;29(25):3665-76.

[3]. Bosch A, et al. Reversal by RARα agonist Am580 of c-Myc-induced imbalance in RARα/RARγ expression during MMTV-Myc tumorigenesis. Breast Cancer Res. 2012 Aug 24;14(4):R121.

[相关活性小分子]

维生素A酸；视黄酸 | 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 | 芬维A胺 | 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

物理化学性质

[ 密度 ]:
1.2±0.1 g/cm3

[ 沸点 ]:
461.0±45.0 °C at 760 mmHg

[ 分子式 ]:
C₂₂H₂₅NO₃

[ 分子量 ]:
351.439

[ 闪点 ]:
232.6±28.7 °C

[ 精确质量 ]:
351.183441

[ PSA ]:
66.40000

[ LogP ]:
6.48

[ 蒸汽压 ]:
0.0±1.2 mmHg at 25°C

[ 折射率 ]:
1.593

[ 储存条件 ]:
室温，干燥

毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: DH6834890

CHEMICAL NAME :: Benzoic acid, 4-((5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthal enyl)carbonyl)amino-

CAS REGISTRY NUMBER :: 102121-60-8

LAST UPDATED :: 199706

DATA ITEMS CITED :: 4

MOLECULAR FORMULA :: C22-H25-N-O3

MOLECULAR WEIGHT :: 351.48

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 2 mg/kg

SEX/DURATION :: female 8-9 day(s) after conception

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - eye/ear Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :: TOLED5 Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- Volume(issue)/page/year: 70,299,1994

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 5 mg/kg

SEX/DURATION :: female 8 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Specific Developmental Abnormalities - Central Nervous System Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue)

REFERENCE :: TJADAB Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- Volume(issue)/page/year: 53,158,1996

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 5 mg/kg

SEX/DURATION :: female 8 day(s) after conception

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Specific Developmental Abnormalities - urogenital system Reproductive - Specific Developmental Abnormalities - other developmental abnormalities

REFERENCE :: TJADAB Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- Volume(issue)/page/year: 53,158,1996

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 15 mg/kg

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

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :: TJADAB Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- Volume(issue)/page/year: 53,158,1996

安全信息

[ 个人防护装备 ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

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

[ WGK德国 ]:
3

[ RTECS号 ]:
DH6834890

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