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盐酸尼莫司汀

盐酸尼莫司汀用途

Nimustine hydrochloride (ACNU) 是一种 DNA 交联剂和 DNA 烷基化剂,能诱导 DNA 复制损伤和 DNA 双链断裂,抑制 DNA 合成,常用于胶质母细胞瘤的化疗中。

盐酸尼莫司汀名称

[ CAS 号 ]:
55661-38-6

[ 中文名 ]:
盐酸尼莫司汀

[ 英文名 ]:
Nimustine HCL

[中文别名 ]:

[英文别名 ]:

cs-439
nimustine monohydrochloride
Nimustine HCL
MFCD01676942
nimustinaclorhidrato
ACNU
Nimustine Hydrochloride
nidran

盐酸尼莫司汀生物活性

[ 描述 ]:

Nimustine hydrochloride (ACNU) 是一种 DNA 交联剂和 DNA 烷基化剂,能诱导 DNA 复制损伤和 DNA 双链断裂,抑制 DNA 合成,常用于胶质母细胞瘤的化疗中。

[ 相关类别 ]:

信号通路 >> 细胞凋亡 >> 细胞凋亡

研究领域 >> 癌症

信号通路 >> 细胞周期/DNA损伤 >> DNA/RNA合成

[参考文献]

[1]. Tomicic MT, et al. Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM. Oncotarget. 2015 Oct 20;6(32):33755-68.

[2]. Kondo N, et al. FANCD1/BRCA2 plays predominant role in the repair of DNA damage induced by ACNU or TMZ. PLoS One. 2011 May 9;6(5):e19659.

[3]. Mineura K, et al. DNA lability induced by nimustine and ramustine in rat glioma cells. J Neurol Neurosurg Psychiatry. 1988 Nov;51(11):1391-4.

盐酸尼莫司汀物理化学性质

[ 熔点 ]:
186 °C

[ 分子式 ]:
C₉H₁₄Cl₂N₆O₂

[ 分子量 ]:
309.152

[ 精确质量 ]:
308.055542

[ PSA ]:
113.57000

[ LogP ]:
2.57310

[ 外观性状 ]:
固体;White to Light yellow powder to crystal

[ 储存条件 ]:
避免光

[ 水溶解性 ]:
可溶于：甲醇；不溶：氯仿,乙醚,苯

盐酸尼莫司汀MSDS

详细MSDS(安全技术说明书)

盐酸尼莫司汀毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: YR8450000

CHEMICAL NAME :: Urea, 3-((4-amino-2-methyl-5-pyrimidinyl)methyl)-1-(2-chlor oethyl)-1-nitroso-, monohydrochloride

CAS REGISTRY NUMBER :: 55661-38-6

LAST UPDATED :: 199410

DATA ITEMS CITED :: 23

MOLECULAR FORMULA :: C9-H13-Cl-N6-O2.Cl-H

MOLECULAR WEIGHT :: 309.19

WISWESSER LINE NOTATION :: T6N CNJ B1 DZ E1MVNNO&2G

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

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

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 113 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Gastrointestinal - hypermotility, diarrhea Nutritional and Gross Metabolic - weight loss or decreased weight gain

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

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 52700 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 :: 60800 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 - rat

DOSE/DURATION :: 15 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 :: 83 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Gastrointestinal - hypermotility, diarrhea Nutritional and Gross Metabolic - weight loss or decreased weight gain

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

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 49300 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 :: 72800 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 :: 59 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Gastrointestinal - hypermotility, diarrhea Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :: LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 5 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Gastrointestinal - hypermotility, diarrhea Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :: LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 5 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Gastrointestinal - hypermotility, diarrhea Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intraperitoneal

DOSE :: 10 mg/kg

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

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - cardiovascular (circulatory) system

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intraperitoneal

DOSE :: 10 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 - Effects on Embryo or Fetus - fetal death Reproductive - Specific Developmental Abnormalities - cardiovascular (circulatory) system

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intraperitoneal

DOSE :: 5 mg/kg

SEX/DURATION :: female 5 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 :: Intravenous

DOSE :: 7 mg/kg

SEX/DURATION :: female 7-20 day(s) after conception

TOXIC EFFECTS :: Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intravenous

DOSE :: 13 mg/kg

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

TOXIC EFFECTS :: Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

MUTATION DATA

TYPE OF TEST :: Mutation test systems - not otherwise specified

TEST SYSTEM :: Rodent - mouse Leukocyte

DOSE/DURATION :: 1 mg/L

REFERENCE :: AMKUDT Acta Medica Kinki University. (Kinki Univ. Medical Assoc., 380 Nishiyama, Sayama-cho, Minami-kawachi-gun, Osaka-fu, Japan) V.1- 1976- Volume(issue)/page/year: 11,57,1986

盐酸尼莫司汀安全信息

[ 符号 ]:

GHS06

[ 信号词 ]:
Danger

[ 危害声明 ]:
H301

[ 警示性声明 ]:
P301 + P310

[ 个人防护装备 ]:
Eyeshields;Faceshields;Gloves;type P2 (EN 143) respirator cartridges

[ 危害码 (欧洲) ]:
T

[ 风险声明 (欧洲) ]:
R25:Toxic if swallowed.

[ 安全声明 (欧洲) ]:
S36/37/39-S45

[ 危险品运输编码 ]:
UN 2811

[ RTECS号 ]:
YR8450000

盐酸尼莫司汀制备

1. 1,3-双(2-氯乙基)脲的制备

在反应瓶中加入尿素90g(1.5mol)、2-氨基乙醇92g(1.5mol) 和DMF750ml, 搅拌加热至回流, 搅拌回流反应8~9h. 减压浓缩回收DMF, 剩余物再加入2-氨基乙醇66g(1.1mol), 搅拌回流2h. 冷至0 ºC, 搅拌下滴加氯化亚砜195ml(319.4g,2.68mol)滴毕, 放置过夜. 将反应混合物再加热至100~120 ºC, 搅拌反应2~3h, 析出固体, 将结块物料小心捣碎, 过滤, 水洗滤饼, 抽干, 粗品用甲醇重结晶, 得白色固体1,3-双(2-氯乙基)脲86g, 三步收率共32%左右,mp120~3 ºC.

2. 1,3-双(2-氯乙基)-1-亚硝基脲的制备

在反应瓶中加入1,3-双(2-氯乙基)脲86g(0.465mol) 和88%甲酸620ml,搅拌混合并在冰水浴冷却下,滴加亚硝酸钠[74g(1.07mol)]的水(680ml)溶液,于4~4.5h内滴加完.滴毕,继续搅拌反应4~5h,用TLC跟踪,确认1,3-双(2-氯乙基)脲消失,反应到终点,停止反应,置于冰箱过夜.过滤,滤饼用冰水洗涤多次,抽干,真空干燥, 得淡黄色固体1,3-双(2-氯乙基)-1-亚硝基脲77g,收率78%左右,mp30~31 ºC.下步用1,3-双(2-氯乙基)-1-亚硝基脲可不干燥,直接用潮品投料.

3. 1-(4-氨基-2-甲基嘧啶-5-基)-甲基-3-(2-氯乙基)脲的制备

在反应瓶中加入乙酰嘧啶(外购品)49.3g(纯度为91.2%,计纯品45g)(.25mol)和13%NaOH水溶液210ml,加热搅拌至回流温度,搅拌回3.5~4h.TLC跟踪乙酰嘧啶消失,则乙酰嘧啶已转化为2-甲基-5-氨基甲基嘧啶. 冷却至室温,用浓盐酸调至pH10左右,加入上步产物1,3-双(2-氯乙基)-1-亚硝基脲潮湿品(测水分后折算干品50g)(0.234mol),搅拌加热至50~55 ºC,在该温度下搅拌反应4~5h.TLC跟踪,确认1,3-双(2-氯乙基)-1-亚硝基脲消失反应达终点, 冷却至室温, 用13%左右NaOH水溶液调至Ph7~8,静置于冰箱过夜.过滤,饼用水洗数次,抽干,干燥,得淡黄色固体1-(4-氨基-2-甲基嘧啶-5-基)-甲基-3-(2-氯乙基)脲30~32g,收率54%左右,mp165~167 ºC.纯度>95%(HPLC归一法).

4. 尼莫司汀的制备

在反应瓶中加入1-(4-氨基-2-甲基嘧啶-5-基)-甲基-3-(2-氯乙基)脲29g(0.12mol)、15%盐酸280ml,搅拌混合溶解,于冰水浴冷却下加入NaNO210g(0.15mol),分批小量加入,加时控制好内温≤0 ºC,加毕,继续在同温度下搅拌反应3~4h,TLC跟踪, 1-(4-氨基-2-甲基嘧啶-5-基)-甲基-3-(2-氯乙基)脲斑点消失反应达终点,终止反应,如果有大量固体产生,加适量水至其溶解,如仍有极少量不溶物时不再加水,加活性炭2~3g,搅拌30mon. 过滤,滤饼用水洗,滤液用20%~25%的NaCO3水溶液中和至pH到8,析出淡黄色固体,过滤,滤饼用水洗涤数次,抽干,干燥,得淡黄色固体尼莫司汀22g左右,收率约68.5%~70.0%,mp124~125 ºC(分解).

5. 盐酸尼莫司汀的合成

在反应瓶中加入尼莫司汀24.8g(0.08mol)、无水乙醇225ml,搅拌悬浮,加入HCl无水乙醇溶液,加量以使悬浮液至澄清透明为准.加毕继续搅拌反应至析出淡黄色固体为止,反应毕,静置于冰箱2~3h.析出大量固体,过滤,得粗品盐酸尼莫司汀18.5g,收率为75%.

取粗品盐酸尼莫司汀15g,加丙酮225ml,搅拌加热回流,加少量稀盐酸至pH呈酸性,溶液变澄清,加入针用活性炭10~15g,轻微加热回流15~20min.趁热抽滤,滤液经微孔滤膜过滤,抽干,除菌,密封,冰箱静置6h. 析出晶体, 抽滤, 真空(70~ 80^。以下)速干燥,得无菌粉10.5g,收率70%(精制收率),mp170~171 ºC (分解).

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