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表阿霉素

表阿霉素用途

Epirubicin是半合成的doxorubicin衍生物,能通过抑制拓扑异构酶起到抗肿瘤的作用。

表阿霉素名称

[ CAS 号 ]:
56420-45-2

[ 中文名 ]:
表阿霉素

[ 英文名 ]:
Epirubicin

[中文别名 ]:

表柔比星

[英文别名 ]:

farmorubicin
4'-EPIDOXORUBICIN
epi-dx
Epirubicin
4'-epi-DX
WP 697
Pidorubicin
Epirubicin Ebewe
Epiadriamycin
4'-Epidoxorubiein

表阿霉素生物活性

[ 描述 ]:

Epirubicin是半合成的doxorubicin衍生物,能通过抑制拓扑异构酶起到抗肿瘤的作用。

[ 相关类别 ]:

研究领域 >> 癌症

[ 靶点 ]

Topoisomerase

[体外研究]

与阿霉素一样,表柔比星通过与DNA的复合物发挥其抗肿瘤作用,导致DNA损伤并干扰DNA,RNA和蛋白质的合成。表柔比星也可能影响细胞膜的完整性和活性。表柔比星引起的最大细胞杀伤发生在细胞周期的S期。随着浓度的增加,早期G2以及G1期和M期也会出现影响[1]。表柔比星显示出对抗大多数癌细胞的抗肿瘤活性。表柔比星对肝癌G2细胞具有细胞毒性,24小时IC50为1.6μg/ mL。 1.6μg/ mL表阿霉素诱导Hep G2细胞凋亡,过氧化氢酶活性增加50％,Se依赖型谷胱甘肽过氧化物酶活性增加110％,Cu,Zn超氧化物歧化酶增加172％,Mn-超氧化物歧化酶增加135％。 Epirbicin可增加NADPH-CYP 450还原酶的细胞表达,并降低GST-π的表达[2]。

[体内研究]

表柔比星对多种肿瘤类型具有临床活性,包括乳腺癌,恶性淋巴瘤,软组织肉瘤,肺癌,胸膜间皮瘤,胃肠癌,头颈癌,卵巢癌,前列腺癌,膀胱移行癌等[ 3]。剂量为3.5mg/kg的表柔比星抑制人乳腺肿瘤异种移植物R-27的肿瘤质量达74.4％[4]。

[细胞实验]

将Hep G2细胞（500个细胞/孔，单层）接种在96孔板中。第二天，在培养基中用表柔比星处理细胞。在孵育期结束时，加入15％体积的MTT染料溶液。在37℃温育1小时后，向每个孔中加入等体积的溶解/终止溶液（二甲基亚砜 - 氧化物），再孵育1小时。记录反应溶液在570nm处的吸光度。

[参考文献]

[1]. Cersosimo RJ, et al. Epirubicin: a review of the pharmacology, clinical activity, and adverse effects of an adriamycin analogue. J Clin Oncol. 1986 Mar;4(3):425-39.

[2]. Ozkan, A., et al. Epirubicin HCl toxicity in human-liver derived hepatoma G2 cells. Pol J Pharmacol, 2004. 56(4): p. 435-44.

[3]. Bonadonna, G., et al. Drugs ten years later: epirubicin. Ann Oncol, 1993. 4(5): p. 359-69.

[4]. Asanuma, F., et al. Antitumor activity of paclitaxel and epirubicin in human breast carcinoma, R-27. Folia Microbiol (Praha), 1998. 43(5): p. 473-4.

[相关活性小分子]

表阿霉素物理化学性质

[ 密度 ]:
1.6±0.1 g/cm3

[ 沸点 ]:
810.3±65.0 °C at 760 mmHg

[ 分子式 ]:
C₂₇H₂₉NO₁₁

[ 分子量 ]:
543.519

[ 闪点 ]:
443.8±34.3 °C

[ 精确质量 ]:
543.174072

[ PSA ]:
206.07000

[ LogP ]:
2.82

[ 蒸汽压 ]:
0.0±3.0 mmHg at 25°C

[ 折射率 ]:
1.710

[ 储存条件 ]:
2-8℃

表阿霉素毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: QI9295840

CHEMICAL NAME :: 5,12-Naphthacenedione, 10-((3-amino-2,3,6-trideoxy-beta-L-arabino-hexopyrano syl)oxy)- 7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacety l)-1-methoxy-, (8S-cis)-

CAS REGISTRY NUMBER :: 56420-45-2

LAST UPDATED :: 199709

DATA ITEMS CITED :: 16

MOLECULAR FORMULA :: C27-H29-N-O11

MOLECULAR WEIGHT :: 543.57

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 14270 ug/kg

TOXIC EFFECTS :: Nutritional and Gross Metabolic - weight loss or decreased weight gain

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 16070 ug/kg

TOXIC EFFECTS :: Nutritional and Gross Metabolic - weight loss or decreased weight gain

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

ROUTE OF EXPOSURE :: Unreported

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 29300 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 :: 2 mg/kg

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea Gastrointestinal - nausea or vomiting Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 28800 ug/kg/12W-I

TOXIC EFFECTS :: Cardiac - changes in coronary arteries Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 31200 ug/kg/13W-I

TOXIC EFFECTS :: Cardiac - changes in heart weight Blood - leukopenia Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 7800 ug/kg/5D-I

TOXIC EFFECTS :: Blood - changes in bone marrow (not otherwise specified) Blood - changes in other cell count (unspecified) Blood - changes in leukocyte (WBC) count

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 15600 ug/kg/13W-I

TOXIC EFFECTS :: Blood - normocytic anemia Blood - leukopenia Biochemical - Metabolism (Intermediary) - other proteins

TYPE OF TEST :: Cytogenetic analysis

TYPE OF TEST :: Cytogenetic analysis

MUTATION DATA

TEST SYSTEM :: Rodent - mouse

DOSE/DURATION :: 10 mg/kg

REFERENCE :: MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- Volume(issue)/page/year: 160,39,1986

表阿霉素制备

化合物(I)经三氟乙酸酐N-酰化，以对氨基进行保护，得到化合物（Ⅱ)。再氧化为酮(Ⅲ)，然后还原为醇(Ⅳ)。在酸作用下去除醚键，再经三氟乙酸酐酯化为化合物(Ⅵ)，然后进行选择性氯代，得到所需的侧链(VII)。
化合物(Ⅷ)经二甲缩丙酮反应成缩酮(Ⅸ)，然后和上述制得的侧链(Ⅶ)反应，得到的化合物(X)水解，即得表柔比星。