Trabectedin

Drugbox
IUPAC_name = (1'"R",6"R",6a"R",7"R",13"S",14"S",16"R")-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-6a"H"-1,3-dioxolo [7,8] isoquino
[3,2-"b"] [3] benzazocine-20,1'(2"'H")-isoquinolin] -5-yl acetate

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CAS_number = 114899-77-3
ATC_prefix = L01
ATC_suffix = CX01
PubChem = 108150
DrugBank =
C=39|H=43|N=3|O=11|S=1
molecular_weight = 761.84 g/mol
bioavailability = Not applicable (IV only)
protein_bound = 94 to 98%
metabolism = Hepatic (mostly CYP3A4-mediated)
elimination_half-life = 180 hours (mean)
excretion = Mostly fecal
pregnancy_AU =
pregnancy_US =
pregnancy_category=
licence_EU = Yondelis
legal_AU =
legal_CA =
legal_UK = POM
legal_US =
legal_status =
routes_of_administration = Intravenous

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 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 US Food & Drug Administration have granted orphan drug status to trabectedin for soft tissue sarcomas and 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. [cite journal|author=Lichter et al.|title=Food-drugs from the sea. Proc: Aug 20–23, 1972.|editor=Worthen LW|publisher= Marine Tech Soc| volume=173|pages=117–127] 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. cite journal |author=Rinehart KL |title=Antitumor compounds from tunicates |journal=Med Res Rev |volume=20 |issue=1 |pages=1–27 |year=2000 |month=January |pmid=10608919] . Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies.cite web|url=http://www.hno.harvard.edu/gazette/2000/05.04/cancersquirt.html|title=Potent cancer drugs made -- Sea squirts provide recipe] The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994Fact|date=July 2008 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 cite web|url=http://www.newscientist.com/article/mg15120473.600-hostages-of-the-deep--prospectors-are-taking-to-the-seas-in-search-of-new-and-promising-chemicalsbut-the-better-the-drugs-turn-out-to-be-the-greater-the-threat-to-the-animalsthat-produce-them-itstephanie-painit-investigates.html|title=New Scientist] soRinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method andpublished it in 1996. [cite journal | journal=J. Am. Chem. Soc. |volume=118|issue=38|year=1996| pages=9202-9203|title=Enantioselective Total Synthesis of Ecteinascidin 743|author=E. J. Corey, David Y. Gin, and Robert S. Kania ] . 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. [cite article|author=C. Cuevas et al.|title=Synthesis of ecteinascidin ET-743 and phthalascidin PT-650 from cyanosafracin|journal=B. Org. Lett. 2|year=2000|pages=2545–2548] PharmaMar have entered into an agreement with Johnson and Johnson to market the compound outside Europe.Fact|date=July 2008

Trabectidin was first dosed in humans in 1996 Fact|date=July 2008. In 2007, the EMEA gave authorisationfor 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 thattrabectidin had not been evaluated in an adequately designed and analysed randomised trialagainst current best care, and that the clinical efficacy data was mainly based on patients withliposarcoma 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. [cite web|title=CHMP evaluation|url=http://www.emea.europa.eu/humandocs/PDFs/EPAR/yondelis/H-773-en6.pdf] 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. [cite web|url=http://www.pharmamar.com/en/press/news_release.cfm?newsReleaseID=179&year=2008|title=PharmaMar website] Trabectidin is also approved in South Korea. [ [http://www.reuters.com/article/rbssHealthcareNews/idUSB73735320080508 S.Korea approves Zeltia cancer drug Yondelis] , Reuters.com, May 8, 2008]

Trabectidin is also in phase III trials for ovarian cancer and phase II trials for prostate, breast and paediatric cancers. [cite web|url=http://www.pharmamar.com/en/about/|title=PharmaMar website]

tructure

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

ynthesis

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