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去氧氟尿苷

去氧氟尿苷用途

Doxifluridine是胸苷磷酸化酶活化剂,对PC9-DPE2细胞的IC50为0.62 μM。

去氧氟尿苷名称

[ CAS 号 ]:
3094-09-5

[ 中文名 ]:
去氧氟尿苷

[ 英文名 ]:
Doxifluridine

[中文别名 ]:

[英文别名 ]:

5-Fluorodesoxyuridine
RO-21-9738
EINECS 221-440-1
doxifluridine
5'DFURD
Uridine, 5'-deoxy-5-fluoro-
Flutron
Furtulon
1-(5-Deoxy-β-D-ribofuranosyl)-5-fluorouracil
5'-DFUR

去氧氟尿苷生物活性

[ 描述 ]:

Doxifluridine是胸苷磷酸化酶活化剂,对PC9-DPE2细胞的IC50为0.62 μM。

[ 相关类别 ]:

信号通路 >> 细胞周期/DNA损伤 >> 核苷抗代谢药/类似物

研究领域 >> 癌症

[参考文献]

[1]. Dipartimento di Chimica, Università degli Studi della Basilicata, Potenza, In vitro toxicity of N3-methyl-5'-deoxy-5-fluorouridine, a novel metabolite of doxifluridine: a bioanalytical investigation. J Pharm Biomed Anal. 1998 May;17(1):11-6.

[2]. Baek IH, Lee BY, Kim MS, Pharmacokinetic analysis of doxifluridine and its metabolites, 5-fluorouracil and 5-fluorouridine, after oral administration in beagle dogs. Eur J Drug Metab Pharmacokinet. 2013 Apr 7.

[3]. Yoshikawa T, Tsuburaya A, Shimada K, A phase II study of doxifluridine and docetaxel combination chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer. 2009;12(4):212-8.

[相关活性小分子]

去氧氟尿苷物理化学性质

[ 密度 ]:
1.6±0.1 g/cm3

[ 熔点 ]:
188-192 °C(lit.)

[ 分子式 ]:
C₉H₁₁FN₂O₅

[ 分子量 ]:
246.192

[ 精确质量 ]:
246.065201

[ PSA ]:
104.55000

[ LogP ]:
-0.96

[ 外观性状 ]:
白色固体

[ 折射率 ]:
1.605

[ 储存条件 ]:
-20°C Freezer

去氧氟尿苷MSDS

详细MSDS(安全技术说明书)

去氧氟尿苷毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: YU7526000

CHEMICAL NAME :: Uridine, 5'-deoxy-5-fluoro-

CAS REGISTRY NUMBER :: 3094-09-5

LAST UPDATED :: 199612

DATA ITEMS CITED :: 16

MOLECULAR FORMULA :: C9-H11-F-N2-O5

MOLECULAR WEIGHT :: 246.22

WISWESSER LINE NOTATION :: T6NVMVJ EF A- BT5OTJ CQ DQ E1

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 :: 3390 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Skin and Appendages - hair

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

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Skin and Appendages - hair

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >1 gm/kg

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

TYPE OF TEST :: LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 5 gm/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Skin and Appendages - hair

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

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Skin and Appendages - hair

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >1 gm/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

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 18200 mg/kg/13W-I

TOXIC EFFECTS :: Kidney, Ureter, Bladder - proteinuria Endocrine - changes in thymus weight Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 7 gm/kg/5W-I

TOXIC EFFECTS :: Endocrine - changes in thymus weight Skin and Appendages - hair Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 15470 mg/kg/26W-I

TOXIC EFFECTS :: Blood - normocytic anemia Blood - changes in bone marrow (not otherwise specified) Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 2100 mg/kg/7D-I

TOXIC EFFECTS :: Endocrine - changes in thymus weight Blood - changes in bone marrow (not otherwise specified) Blood - changes in leukocyte (WBC) count

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 1365 mg/kg/13W-I

TOXIC EFFECTS :: Behavioral - convulsions or effect on seizure threshold Liver - other changes Related to Chronic Data - death

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 550 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

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

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 1100 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Effects on Newborn - live birth index (measured after birth) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 2200 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 5950 mg/kg

SEX/DURATION :: male 14 week(s) pre-mating female 2 week(s) pre-mating - 7 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)

MUTATION DATA

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

TEST SYSTEM :: Rodent - mouse Leukocyte

DOSE/DURATION :: 615 umol/L

REFERENCE :: CCCCAK Collection of Czechoslovak Chemical Communications. (Academic Press Inc. Ltd., 24-28 Oval Rd., London NW1 7DX, UK) V.1- 1929- Volume(issue)/page/year: 49,2551,1984

去氧氟尿苷安全信息

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

[ 危害码 (欧洲) ]:
Xi: Irritant;

[ 风险声明 (欧洲) ]:
R36/37/38

[ 安全声明 (欧洲) ]:
26-36

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

[ WGK德国 ]:
2

[ RTECS号 ]:
YU7526000

[ 海关编码 ]:
2934999090

去氧氟尿苷制备

1. 2,4-二(三甲基硅氧基)-5-氟尿嘧啶的制备

在反应瓶中加入5-氟尿嘧啶2g(15.38mmol)、六甲基二硅胺6g(37.04mmol)、硫酸铵0.02g(0.15mmol),搅拌加热至回流,回流反应7h.于60~80 ºC减压蒸除未反应的六甲基二硅胺,得淡黄色油状物2,4-二(三甲基硅氧基)-5-氟尿嘧啶,冷至室温后用甲醇稀释至10ml备用.

2. 2’,3’,5’-三乙酰-5-氟尿嘧啶核苷的制备

在上步盛有5-氟尿嘧啶的反应瓶中加入四乙酰核糖4g(12.58mmol)和二氟甲烷25ml,搅拌15min,(室温下).再向反应瓶中搅拌滴加三氯化铝[2.2g(16.4mmol)]的二氯甲烷(1.8ml)溶液,滴加速度以控制反应温度不超30 ºC为准,滴加时间约45min,滴加毕,继续搅拌反应75~120min.

在搅拌下慢慢向反应瓶中加水1ml,搅拌20min,边搅拌边加入固体NaHCO3 8g,以反应液不溢出为宜,调至pH6.5±1,停止搅拌.抽滤,滤饼用二氯甲烷(5ml×4)洗涤,合并滤液和洗液,于50~70 ºC减压蒸除二氯甲烷,剩余物为糖浆状物2’,3’,5’-三乙酰-5-氟尿嘧啶核苷无需进一步纯化, 直接用于下步反应.

3. 5-氟尿嘧啶核苷的制备

在反应瓶中加入化合物2’,3’,5’-三乙酰-5-氟尿嘧啶核苷和甲醇30ml,加热搅拌溶解#搅拌下加入NaOH[0.8g(19mmol)]的甲醇(10ml)溶液,搅拌均匀后,静置2h,用TLC跟踪[乙酸乙酯/甲醇/水(70:40:5)为展开剂] 检测为单一斑点(R1≈0.6)时,在搅拌下缓慢滴加浓硫酸0.53g(19mmol).滴毕,抽滤,滤饼用甲醇(5ml×4) 洗涤,合并滤液和洗液,置于反应瓶中加热至60~80 ºC,减压(80~96kPa)蒸馏回收甲醇,并浓缩至干,得白色固体5-氟尿嘧啶核苷,不需进一步纯化,直接用于下步反应.取所得粗品1g用无水乙醇10ml重结晶,得5-氟尿嘧啶核苷纯品0.65gmp171~172 ºC.可供分析使用.

4. 2’,3’-异亚丙基-5-氟尿嘧啶核苷的制备

在反应瓶中加入5-氟尿嘧啶核苷和丙酮40ml,搅拌下缓慢滴加浓硫酸0.3ml,加热至回流至瓶中固体溶解.再

加入无水硫酸铜3.0g,继续搅拌回流8h.TLC跟踪[展开剂:乙酸乙酯/甲醇/水(70:40:5)]检测5-氟尿嘧啶核苷斑点消失.分批加入NaCO3 2.4g调至中性,控制加入速度,以反应瓶内反应液不外溢为准.滤除无机盐,并用丙酮10ml洗涤.合并滤液和洗液,加热至70~80 ºC蒸出丙酮,剩余物用甲醇6ml和水6ml溶解(微热),趁热过滤,滤液冷冻结晶,得长针状晶体0.35g, 5-氟尿嘧啶到2’,3’-异亚丙基-5-氟尿嘧啶核苷收率80.3%,mp220~202 ºC.

5. 2’,3’-异亚丙基-5’-碘代-5-氟尿嘧啶核苷的制备

在反应瓶中加入化合物2’,3’-异亚丙基-5-氟尿嘧啶核苷3.05g(10.1mmol)和DMF9.15ml,搅拌溶解,再加入亚磷酸三苯酯/碘甲烷6.1g(13.5mmol),于25~40ºC搅拌反应4h.TLC跟踪[展开剂:二氯甲烷/甲醇(9:1)]检测2’,3’-异亚丙基-5-氟尿嘧啶核苷斑点消失.再加入甲醇6.1ml,继续搅拌反应30min.将反应液转至分液漏斗,用二氯甲烷15ml和2%NaSO3水溶液10ml与其混合充分振摇10min,分取有机层,用水(20ml×3)洗涤,干燥,有机层

在60~70 ºC/80~90kPa条件下浓缩至原体积的1/3,冷却,放置过夜析晶.抽滤,得短针状晶体2’,3’-异亚丙基-5’-碘代-5-氟尿嘧啶核苷.母液重复前述后处理操作两次,合并得2’,3’-异亚丙基-5’-碘代-5-氟尿嘧啶核苷晶体3.4g, 收率81.7%,mp203~204 ºC.

6. 2’,3’-异亚丙基-5’-脱氧-5-氟尿嘧啶核苷的制备

在氢化反应瓶中加入2’,3’-异亚丙基-5’-碘代-5-氟尿嘧啶核苷3.4g(8.25mmol)、乙酸钠3.4g(41.5mmol)、Raney Ni 1g和甲醇20ml,用N2置换瓶中空气,然后用H2置换瓶中N2,通H2反应5h,直至不再吸收氢气时,停止搅拌,结束反应.过滤,滤饼用甲醇(5ml×2)洗涤,合并滤液和洗液,于70~80 ºC下减压浓缩(80~96kPa)蒸除甲醇,固体剩余物加水10ml和二氯甲烷10ml,于50 ºC下保温搅拌1h.移至分液漏斗中充分剧烈振摇20min,水层用二氯甲烷(20ml×3)提取.合并二氯甲烷相,无水Na2SO4干燥,过滤,滤液于60~70ºC.下蒸除二氯甲烷,得无色透明糖浆状物2’,3’-异亚丙基-5’-脱氧-5-氟尿嘧啶核苷.无需进一步纯化,直接用于下步反应.

7. 去氧氟尿苷的合成

在反应瓶中加入上步产物2’,3’-异亚丙基-5’-脱氧-5-氟尿嘧啶核苷一批量和甲醇10ml,搅拌溶解,再加入H2SO40 3ml和甲醇30ml,搅拌回流反应1.5h.用TLC跟踪[展开剂:二氯甲烷/甲醇(9:1)]确定反应终点.反应毕#用石灰乳中和反应液,调至pH5~6,滤除无机盐.滤液加热至70~80 ºC,减压浓缩至干剩余物加二氯甲烷10ml, 回流1h.冷却,过滤,风干,得粗品1.83g,用无水乙醇33ml重结晶,得白色针状结晶去氧氟尿苷1.52g.母液浓缩后所得固体重结晶得去氧氟尿苷0.17g. 共得去氧氟尿苷1.69g,从2’,3’-异亚丙基-5’-脱氧-5-氟尿嘧啶核苷到去氧氟尿苷的收率83.18%,从5-氟尿嘧啶到去氧氟尿苷总收率为54.6%,mp190~192 ºC.

去氧氟尿苷海关

[ 海关编码 ]: 2934999090

[ 中文概述 ]:
2934999090. 其他杂环化合物. 增值税率:17.0%. 退税率:13.0%. 监管条件:无. 最惠国关税:6.5%. 普通关税:20.0%

[ 申报要素 ]: 品名, 成分含量, 用途

[ Summary ]:
2934999090. other heterocyclic compounds. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

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