Trabectedin

L01CX01

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Ecteinascidin 743 (also trabectedin or ET -743 ) is a chemotherapy drug for the treatment of soft tissue sarcoma and ovarian cancer. It is also being studied in clinical trials for the suitability for the treatment of breast and Prostatasarkomen.

Discovery

In 1969 was discovered in the framework of a broader research program of the National Cancer Institute of ingredients of plant and marine life that an extract of the ascidian Ecteinascidia turbinata anticarcinogenic properties exhibited. The characterization of the active component Ecteinascidin 743 was granted in 1984 by Kenneth L. Rinehart at the University of Illinois. The structure of Ecteinascidin 743 is complex and has three tetrahydroisoquinoline units, 8 rings, including a ten-membered ring heteocyclischer with a cysteine ​​residue and seven chiral centers. The effect of ecteinascidin 743 is based on the binding of deoxyribonucleic acid and a disturbance of the cell cycle.

Synthesis

After attempts to breed the sea squirt failed and the yield was only in the ppm range, the group of EJ Corey was charged with the synthesis of the natural product. The synthetic route was published in 1996. A simplified synthesis was also later developed into Corey's group.

It is believed that the biosynthesis of ecteinascidin 743, the dimerization of two tyrosine residues included to form the core of the pentacyclic molecule. The synthetic strategy to the total synthesis of EJ Corey was inspired by the proposed biosynthetic route. The synthesis uses such reactions such as the Mannich reaction, the Pictet -Spengler reaction, the Curtius rearrangement, and a reaction catalyzed by a chiral diphosphine - rhodium enantioselective hydrogenation.

Another synthetic route via the Ugi reaction, a multi-component one-pot reaction, which is quite unusual for the synthesis of a complex molecule.