埃博霉素

中文名称:

埃博霉素

中文同义词:

爱博霉素;埃博霉素;埃坡西龙 D;埃博霉素 D(埃坡西龙 D、埃博霉素D、爱博霉素D);埃博霉素D 埃坡西龙 D;埃博霉素D;埃坡霉素D

英文名称:

Epothilone D

英文同义词:

Oxacyclohexadec-13-ene-2,6-dione, 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-, (4S,7R,8S,9S,13Z,16S)-;Oxacyclohexadec-13-ene-2,6-dione, 4,8-dihydroxy-5,5,7,9,13-pentamethyl -16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-, (4S-(4R*,7S,8R*,9R*,1 3Z,16R*(E)))-;(3S,7S,14S,15S,16R)-3,15-Dihydroxy-2,2,10,14,16-pentamethyl-7-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-6-oxacyclohexadec-9-ene-1,5-dione;Epothilone D;Desoxyepothilone B;12;13-DESOXYEPOTHILONE B; DESOXYEPOTHILONE B; KOS 862;13-Desoxyepothilone B;CS-1161

CAS号:

189453-10-9

分子式:

C27H41NO5S

分子量:

491.68

EINECS号:

相关类别:

原料药;医药中间体;医药原料;原料;医药原料药;医用原料;医用原料;Inhibitors;Chiral Reagents;Intermediates Fine Chemicals;Pharmaceuticals;Sulfur Selenium Compounds;Anti-cancerimmunity

Mol文件:

189453-10-9.mol

熔点 

63-66°C

比旋光度 

D22 -61.3° (c = 2.5 in methanol)

沸点 

663.7±55.0 °C(Predicted)

密度 

1.084±0.06 g/cm3(Predicted)

储存条件 

-20°C Freezer

酸度系数(pKa)

13.47±0.70(Predicted)

概述

埃博霉素（Epothilones）是黏细菌纤维堆囊菌产生的大环内酯类次级代谢产物，是一种新型的抗肿瘤药物。其作用机制与紫杉醇相同，通过促微管聚合作用从而抑制肿瘤细胞的增殖，并且与紫杉醇相比，埃博霉素具有毒性更小、水溶性更好、对紫杉醇耐药性细胞作用更强、抗肿瘤谱更广等优点，是最具有潜力的抗肿瘤新药之一，目前对结肠癌、乳腺癌、卵巢癌等治疗效果显著。 图1为埃博霉素B结构式

制备方法

生物发酵法 培养基：CNST 培养基：KNO30.05%，Na2HPO40.025%，MgSO4·7H2O 0.1%，FeC30.001%，琼脂 2%，微量元素液 1 mL/L，pH7.2。1×105Pa 高压蒸汽灭菌 20 min。 M26培养基：土豆淀粉 8.0 g/L，大豆蛋白胨 2.0g/L，葡萄糖 2.0 g/L，酵母粉 2.0 g/L，MgSO4·7H2O1.0 g/L，CaCl21.0 g/L，EDTA-Fe3+1 mL/L，微量元素1 mL/L，以 KOH 调节 pH 值为 7.2。 初始发酵培养基：糊精 0.3%，蔗糖 0.07%，葡萄糖 0.02%，豆饼粉 0.17%，七水硫酸镁 0.17%，无水氯化钙 0.3%，EDTA-Fe3+2 mL/L，微量元素（TE）0.5 mL/L，pH7.2，树脂 XAD-16 2%。1×105Pa 高压蒸汽灭菌 20 min。 培养方法 种子培养：：将保藏在固体斜面培养基的菌种接入放有已灭菌滤纸片的 CNST 平板上，倒置于恒温培养箱中在 30℃条件下培养 5-7 d 后，转接于 M26 培养基中，装液量为 50 mL/250 mL 三角瓶，在 30℃、170 r/min 的条件下摇床培养 72 h 后，得到作为发酵培养的种子液。 发酵培养：以 5%（V/V）接种量将所得种子液接种到发酵培养基中进行摇床培养，发酵体系为300 mL 三角瓶装液量为 50 mL，在 30℃、170 r/min的条件下摇床培养 5 d。

应用

用于结肠癌、乳腺癌、卵巢癌的治疗。 有关埃博霉素B的概述、制备方法、应用是由Chemicalbook的丁红编辑整理。（2015-12-21）

生物活性

Epothilone D (KOS 862) 是有效的微管稳定剂。

靶点

Microtubule/Tubulin

体外研究

Epothilone D (KOS-862) is a more potent microtubule stabilizer in vitro than epothilone A or B. In vitro, Epothilone D has shown potent cytotoxicity in a panel of human tumor cell lines, with similar potency to paclitaxel. Epothilone D also shows a definite advantage over paclitaxel in drug-resistant cell lines, and retained its cytotoxicity against a multidrug resistant cell line over-expressing P-glycoprotein. Epothilone D (EpoD) is a microtubules (MTs)-stabilizing agent.

体内研究

To evaluate whether Epothilone D (EpoD) improves MT and axonal function in PS19 mice, groups of 3-month old male PS19 mice received weekly i.p. injections of vehicle or Epothilone D (EpoD) (1 mg/kg or 3 mg/kg) for a total of 3 months. In addition, 3-month old non-Tg littermates received 3 mg/kg Epothilone D (EpoD) or vehicle. The 3 mg/kg Epothilone D (EpoD) dose corresponds to ~10-fold less than that used in a Phase II clinical study, which should minimize side-effects such as neutropenia that are observed with MT-stabilizing drugs in human subjects. PS19 and WT mice that receive Epothilone D (EpoD) show no signs of drug intolerance. Indeed, all drug-treated mice exhibited weight gain that is indistinguishable from vehicle-treated animals. Likewise, relative organ weights are similar in vehicle- and Epothilone D (EpoD)-treated mice. The motor performance of Epothilone D (EpoD)-treated mice, assessed using a standard rotarod test, is not significantly different from vehicle-treated cohorts. Finally, although there is minor group-to-group variability, there are no significant differences in white blood cell counts or neutrophil content between any of the treatment cohorts. Thus, the low doses of Epothilone D (EpoD) utilized in these studies appeared to be well tolerated.