Clinical data
AHFS/ International Drug Names
License data
Routes of
ATC code L01CX01 (WHO)
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability Not applicable (IV only)
Protein binding 94 to 98%
Metabolism Hepatic (mostly CYP3A4-mediated)
Biological half-life 180 hours (mean)
Excretion Mostly fecal
CAS Number 114899-77-3 N
PubChem (CID) 108150
DrugBank DB05109 YesY
ChemSpider 97236 N
KEGG D06199 N
ECHA InfoCard 100.223.368
Chemical and physical data
Formula C39H43N3O11S
Molar mass 761.84 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Trabectedin (also known as ecteinascidin 743 or ET-743) is an anti-tumor drug. It is sold by Zeltia and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.

Discovery and production

During the 1950s and 1960s, the National Cancer Institute carried out a wide ranging program of screening plant and marine organism material. As part of that program extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969.[1] Separation and characterisation of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984.[2] Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies.[3] Recently, the biosynthetic pathway responsible for producing the drug has been determined to come from Candidatus Endoecteinascidia frumentensis, a microbial symbiont of the tunicate.[4] The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994 and attempted to farm the sea squirt with limited success.[3] Yields from the sea squirt are extremely low - it takes 1 tonne of animals to isolate 1 gram of trabectedin - and about 5 grams were believed to be needed for a clinical trial[5] so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996.[6] This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar.[3] The current supply is based on a semisynthetic process developed by PharmaMar starting from safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens.[7] PharmaMar have entered into an agreement with Johnson & Johnson to market the compound outside Europe.

Approvals and indications

Trabectedin was first trialed in humans in 1996.

Soft tissue sarcoma

In 2007, the EMEA gave authorization for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The agency's evaluating committee, the CHMP, observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized trial against current best care, and that the clinical efficacy data was mainly based on patients with liposarcoma and leiomyosarcoma. However the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease the CHMP considered that marketing authorisation could be granted under exceptional circumstances.[8] As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.[9]

Trabectedin is also approved in South Korea[10] and Russia.

In 2015 (after phase III study comparing with dacarbazine[11]) the US FDA approved trabectedin (Yondelis) for the treatment of liposarcoma and leiomyosarcoma that is either unresectable or has metastasized. Patients must have received prior chemotherapy with an anthracycline.[12]

Ovarian cancer and other

In 2008 the submission was announced of a registration dossier to the European Medicines Agency (EMEA) and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson&Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional Phase III study to be done in support of the submission.[13]

Trabectedin is also in phase II trials for prostate, breast and paediatric cancers.[14]


Trabectedin is composed of 3 tetrahydroisoquinoline moieties, 8 rings including one 10-membered heterocyclic ring containing a cysteine residue, and 7 chiral centers.


Proposed scheme for the biosynthesis of trabecteden

The biosynthesis of trabectedin in Candidatus Endoecteinascidia frumentensis starts with a fatty acid loading onto the acyl-ligase domain of the EtuA3 module. A cysteine and glycine are then loaded as canonical NRPS amino acids. A tyrosine residue is modified by the enzymes EtuH, EtuM1, and EtuM2 to add a hydroxyl at the meta position of the phenol, and adding two methyl groups at the para-hydroxyl and the meta carbon position. This modified tyrosine reacts with the original substrate via a Pictet-Spengler reaction, where the amine group is converted to an imine by deprotonation, then attacks the free aldehyde to form a carbocation that is quenched by electrons from the methyl-phenol ring. This is done in the EtuA2 T-domain. This reaction is done a second time to yeid a dimer of modified tyrosine residues that have been further cyclized via Pictet-Spengler reaction, yielding a bicyclic ring moiety. The EtuO and EtuF3 enzymes continue to post-translationally modify the molecule, adding several functional groups and making a sulfide bridge between the original cysteine residue and the beta-carbon of the first tyrosine to form ET-583, ET-597, ET-596, and ET-594 which have been previously isolated.[4] A third O-methylated tyrosine is added and cyclized via Pictet-Spangler to yield the final product.[4]

Total synthesis

The total synthesis by E.J. Corey [6] used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine-catalyzed 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

Recently, it has been shown that Trabectedin blocks DNA binding of the oncogenic transcription factor FUS-CHOP and reverses the transcriptional program in myxoid liposarcoma. By reversing the genetic program created by this transcription factor, Trabectedin promotes differentiation and reverses the oncogenic phenotype in these cells.[15]

Other than transcriptional interference, the mechanism of action of Trabectedin is complex and not completely understood. The compound is known to bind and alkylate DNA at the N2 position of guanine. It is known from in-vitro work that this binding occurs in the minor groove, spans approximately 3 to 5 bp and is most efficient with CGG sequences. Additional favorable binding sequences are TGG, AGC, or GGC. Once bound, this reversible covalent adduct bends DNA toward the major groove, interferes directly with activated transcription, poisons the transcription-coupled nucleotide excision repair (TCR) complex, promotes degradation of RNA polymerase II, and generates DNA double-strand breaks.[15]


  1. Lichter; et al. Worthen LW, ed. "Food-drugs from the sea. Proc: Aug 20–23, 1972.". 173. Marine Tech Soc: 117–127.
  2. Rinehart KL (January 2000). "Antitumor compounds from tunicates". Med Res Rev. 20 (1): 1–27. doi:10.1002/(SICI)1098-1128(200001)20:1<1::AID-MED1>3.0.CO;2-A. PMID 10608919.
  3. 1 2 3 "Potent cancer drugs made -- Sea squirts provide recipe".
  4. 1 2 3 Rath CM, et al. (November 2011). "Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743". ACS Chemical Biology. 6 (11): 1244–56. doi:10.1021/cb200244t. PMC 3220770Freely accessible. PMID 21875091.
  5. "New Scientist".
  6. 1 2 E. J. Corey; David Y. Gin & Robert S. Kania (1996). "Enantioselective Total Synthesis of Ecteinascidin 743". J. Am. Chem. Soc. 118 (38): 9202–9203. doi:10.1021/ja962480t.
  7. C. Cuevas; et al. (2000). "Synthesis of ecteinascidin ET-743 and phthalascidin PT-650 from cyanosafracin B". Org. Lett. 2 (16): 2545–2548. doi:10.1021/ol0062502. PMID 10956543.
  8. "CHMP evaluation" (PDF).
  9. "PharmaMar website".
  10. S.Korea approves Zeltia cancer drug Yondelis,, May 8, 2008
  11. Trabectedin Superior to Dacarbazine for Leiomyosarcoma, Liposarcoma
  12. FDA Approves Trabectedin (Yondelis) for Advanced Soft-Tissue Sarcoma
  13. Grogan, Kevin (3 May 2011). "J&J pulls submission for Zeltia's Yondelis". PharmaTimes Magazine. London, England. Online PharmaTimes. Archived from the original on 7 May 2011. Retrieved 7 May 2011.
  14. "PharmaMar website".
  15. 1 2 Grohar et. al. (2011). "Ecteinascidin 743 Interferes with the Activity of EWS-FLI1 in Ewing Sarcoma Cells". Neoplasia. 13 (2): 145–153. doi:10.1593/neo.101202. PMC 3033593Freely accessible. PMID 21403840. and works cited therein.
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