Trabectedin

Trabectedin

File:Trabectedin .png
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
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: Yondelis
Routes of administration	Intravenous
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
Identifiers
CAS Number	114899-77-3
ATC code	L01CX01 (WHO)
PubChem	CID 108150
Chemical data
Formula	C39H43N3O11S
Molar mass	761.84 g/mol[[]]

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.

In 2008 it was announced the submission 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.

Discovery and development

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. 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. Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies. The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994 and attempted to farm the sea squirt with limited success. Yields from the sea squirt are extremely low - it takes 1 tonne of animals to isolate 1 gram of trabectidin - and about 5 grams were believed to be needed for a clinical trial 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. This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar. 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. PharmaMar have entered into an agreement with Johnson and Johnson to market the compound outside Europe.

Trabectidin was first dosed in humans in 1996. In 2007, the EMEA gave authorisation for the marketing of trabectidin, 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 trabectidin had not been evaluated in an adequately designed and analysed randomised 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 trabectidin treatment regimens, and due to the rarity of the disease the CHMP considered that marketing authorisation could be granted under exceptional circumstances. 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 trabectidin. Trabectidin is also approved in South Korea and Russia.

Trabectidin is also in phase II trials for prostate, breast and paediatric cancers.

Structure

Trabectidin is composed of 3 tetrahydroisoquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cystine residue, and 7 chiral centers.

Synthesis

The biosynthesis of trabectidin is believed 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 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

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.

References

es:Trabectedina pt:Trabectedina