Trabectedin
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| Trabectedin
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| Systematic (IUPAC) name | |
| (1'R,6R,6aR,7R,13S,14S,16R)-6',8,14-trihydroxy- 7',9-dimethoxy-4,10,23-trimethyl-19-oxo-3',4',6,7, 12,13,14,16-octahydrospiro[6,16-(epithiopropano oxymethano)-7,13-imino-6aH-1,3-dioxolo[7,8]isoquino [3,2-b][3]benzazocine-20,1'(2'H)-isoquinolin]-5-yl acetate | |
| Identifiers | |
| CAS number | |
| ATC code | L01 |
| PubChem | |
| Chemical data | |
| Formula | C39H43N3O11S |
| Mol. mass | 761.84 g/mol |
| Pharmacokinetic data | |
| Bioavailability | Not applicable (IV only) |
| Protein binding | 94 to 98% |
| Metabolism | Hepatic (mostly CYP3A4-mediated) |
| Half life | 180 hours (mean) |
| Excretion | Mostly fecal |
| Therapeutic considerations | |
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| Pregnancy cat. |
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| Legal status | |
| Routes | Intravenous |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-525-6884
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Phone:617-525-7431
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Overview
Trabectedin (also known as ecteinascidin 743 or by the brand name Yondelis) is an experimental anti-tumor drug. First isolated from aqueous ethanol extract of tunicates in 1969, the complex molecule was found to have impressive cytotoxic activities in the pico- to nanomolar range. It is composed of 3 tetrahydroquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cystine residue, and 7 chiral centers. This structure was not determined until 1984, and was first totally synthesized by Elias James Corey in 1996.
Synthesis
Biosynthesis is also beleieved to involve the dimerization of two tyrosine residues to form the pentacyclic core of the molecule. The total synthesis by E.J. Corey used this proposed biosynthesis in their attempt at the compounds synthetic creation. Their synthesis utilized such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine catalized enantioselective hydrogenation. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multi-component reaction in the synthesis of such a complex molecule.
Mechanism of action
The biological mechanism of action is believed to involve the production of superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes 'activated' into its reactive oxazolidine form.
External links
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
