Trabectedin Antitumor Drugs

English name：Trabectedin

CAS number：114899-77-3

Molecular formula: C39H43N3O11S

Molecular weight: 761.84

EINECS number:

Related category

Cell apoptosis; Pharmaceutical raw materials; Reagent for scientific research; Household chemicals; General biochemical reagents - natural products; Raw materials; Pharmaceutical raw materials; Chemical reagent; Amines; ChemicalbookHeterocycles; Intermediates&FineChemicals; Pharmaceuticals; API

Mol file：114899-77-3.mol

Structural formula:

Melting point: >143°C(dec.)

Specific rotation: D25+114°(c=0.1inmethanol)

Density: 1.55±0.1g/cm3(20ºC760Torr)

Storage conditions: - 20 ° CFreeChemicalbookzer Underinertatmosphere

Solubility: Soluble in chloroform (a little), methanol (a little)

Acidity coefficient (pKa) : 9.73±0.40(Predicted)

Form: solid

Color: Light yellow to thick yellow

optical activity: -53.824.5 (CHCl3)

InChIKey: PKVRCIRHQMSYJX-HAHYLZASNA-N

Use

Tribetidine is an alkylating agent for patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have received an anthracycline - containing regimen.

Tribetidine, a new drug for the treatment of soft tissue sarcoma

On October 23, 2015, the US FDA approved the drug Trabectedin from Janssen, a subsidiary of Johnson & Johnson, through the priority approval pathway, under the trade name Yondelis. For the treatment of unresectable or metastatic liposarcoma Chemicalbook and leiomyosarcoma in patients who have received chemotherapy containing an anthracycline. Tribetidine, a cytotoxic alkylating agent, was first approved in Europe by the EMEA in 2007 for the treatment of advanced soft tissue sarcoma. Later, it was approved to treat recurrent ovarian cancer in Europe and Canada. The producers are Zeltia, a Spanish biotechnology company, andJohnson & Johnson of the United States.

Biological activity

Trabectedin(Ecteinascidin743; ET-743) is a tetrahydroisoquinoline alkaloid with potent antitumor activity, isolated from Ecteinascidiaturbinata. Trabectedin binds to the small sulci of DChemicalbookNA, blocks transcription of stress-induced proteins, induces DNA skeleton cleavage and apoptosis in cancer cells, and increases ROS production in MCF-7 and MDA-MB-453 cells. Trabectedin can be used in the study of soft tissue sarcoma and ovarian cancer.

Target point

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

Apoptosis

In vitro study

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.

In vivo study

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.

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