曲贝替定

中文名称:

曲贝替定

中文同义词:

他比特定;曲贝替定;他比特啶;TRABECTEDIN曲贝替定;他比特啶?, >95%;曲贝替定/他比特定

英文名称:

ecteinascidin 743

英文同义词:

ecteinascidin 743;Trabectedin;(1R,6R,6aR,7R,13S,14S,16R)-;ET-743;Yondelis;Trabectedin(Ecteinascidin 743,NSC-684766,ET-743, Yondelis);Ecteinascidin;Ecteinascidine 743

CAS号:

114899-77-3

分子式:

C39H43N3O11S

分子量:

761.84

EINECS号:

相关类别:

细胞凋亡;医药原料药;科研试剂;Amines;Heterocycles;Intermediates Fine Chemicals;Pharmaceuticals;API

Mol文件:

114899-77-3.mol

比旋光度 

D25 +114° (c = 0.1 in methanol)

密度 

1.55±0.1 g/cm3 (20 ºC 760 Torr)

酸度系数(pKa)

9.73±0.40(Predicted)

用途

曲贝替定是一种烷化剂药物适用为有不可切除或转移脂肪肉瘤或平滑肌肉瘤患者接受一个以前含蒽环类药物[anthracycline]-方案的治疗。

软组织肉瘤治疗新药-曲贝替定

2015年10月23日，美国FDA通过优先审批途径批准了美国强生旗下杨森（Janssen）公司的药物曲贝替定（Trabectedin）上市，商品名为Yondelis。用于不可切除或转移、曾接受过含一种蒽环类药物化疗的脂肪肉瘤和平滑肌肉瘤患者的治疗。曲贝替定为烷化剂属于细胞毒类药，2007年EMEA批准其在欧洲首次上市，用于治疗晚期软组织肉瘤。后又被批准在欧洲和加拿大等地区治疗复发卵巢癌；生产商是西班牙生物技术公司Zeltia和美国强生（Johnson and Johnson）。

生物活性

Trabectedin (Ecteinascidin 743; ET-743) 是一种四氢异喹啉生物碱，具有有效的抗肿瘤活性，从 Ecteinascidia turbinata 中分离出来。 Trabectedin 与 DNA 的小沟结合，阻断应激诱导的蛋白质的转录，诱导 DNA 骨架裂解和癌细胞凋亡 (apoptosis)，并增加 MCF-7 和 MDA-MB-453 细胞中 ROS 的生成。Trabectedin 可用于软组织肉瘤和卵巢癌的研究。

靶点

IC50: 0.1 nM (MX-1 cells), 1.5 nM (MCF7 cells) and 3.7 nM (MCF7/DXR cells) Reactive oxygen species (ROS) Apoptosis

体外研究

Trabectedin (ET-743; 10 nM; 24-72 hours; MCF7 cells) treatment cells accumulate in late S to G2 phase. Trabectedin (Ecteinascidin 743) inhibits cell growth of MX-1, MCF7 and MCF7/DXR cells with IC 50 values of 0.1 nM, 1.5 nM and 3.7 nM, respectively. Trabectedin induces cytotoxicity and apoptosis in both breast cancer cells in a time and concentration-dependent manner. The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL-R2/DR5, FAS/TNFRSF6, TNF RI/TNFRSF1A, and FADD are significantly increased by 2.6-, 3.1-, 1.7-, 11.2- and 4.0-fold by Trabectedin treatment in MCF-7 cells. In MDA-MB-453 cells, the mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, Smac/DIABLO, and Cleaved Caspase-3 expressions are induced by 4.2-, 3.6-, 4.8-, 4.5-, and 4.4-fold, and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL are reduced by 4.8- and 5.2-fold in MDA-MB-453 cells. In vitro treatment with noncytotoxic concentrations of Trabectedin selectively inhibits the production of CCL2, CXCL8, IL-6, VEGF, and PTX3 by myxoid liposarcoma (MLS) primary tumor cultures and/or cell lines. Cell Cycle Analysis Cell Line: MCF7 cells Concentration: 10 nM Incubation Time: 24 hours, 48 hours, 72 hours Result: Led to pronounced S-G2-M accumulation.

Cell Line:

MCF7 cells

Concentration:

10 nM

Incubation Time:

24 hours, 48 hours, 72 hours

Result:

Led to pronounced S-G2-M accumulation.

体内研究

Trabectedin (ET-743; 30-50 μg/kg; intravenous injection; every three days; female athymic nude mice) treatment increases the antitumor effects in nude mice bearing MX-1 mammary carcinoma xenografts without increasing toxicity. A xenograft mouse model of human myxoid liposarcoma (MLS) shows marked reduction of CCL2, CXCL8, CD68+ infiltrating macrophages, CD31+ tumor vessels, and partial decrease of PTX3 after Trabectedin treatment. Animal Model: Female athymic nude mice bearing the nu/nu gene (5-6 weeks old, 18-20 g) injected with MX-1 cells Dosage: 30 μg/kg, 40 μg/kg, 50 μg/kg Administration: Intravenous injection; every three days Result: Increased the antitumor effects in nude mice bearing MX-1 mammary carcinoma xenografts without increasing toxicity.

Animal Model:

Female athymic nude mice bearing the nu/nu gene (5-6 weeks old, 18-20 g) injected with MX-1 cells

Dosage:

30 μg/kg, 40 μg/kg, 50 μg/kg

Administration:

Intravenous injection; every three days

Result:

Increased the antitumor effects in nude mice bearing MX-1 mammary carcinoma xenografts without increasing toxicity.