Trabectedin
Encyclopedia
Trabectedin 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
.
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 trabectedin - 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.
Trabectedin was first dosed in humans in 1996. In 2007, the EMEA gave authorisation
for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracycline
s 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. 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. Trabectedin is also approved in South Korea and Russia.
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.
Trabectedin is also in phase II trials for prostate, breast and paediatric cancers.
moieties
, 8 rings including one 10-membered heteocyclic ring containing a cysteine
residue, and 7 chiral centers.
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.
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.
Zeltia
Zeltia is a public company founded and headquartered in Spain which operates through a variety of subsidiaries in the pharmaceutical and chemical industries. As of 2007, Zeltia's research activities in the pharmaceutical area had not resulted in a marketed product...
and Johnson and Johnson
Johnson & Johnson Pharmaceutical Research and Development
Johnson & Johnson Pharmaceutical Research and Development is a subsidiary of Johnson & Johnson that is responsible for discovering and developing pharmaceutical drugs...
under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma
Soft tissue sarcoma
A soft-tissue sarcoma is a form of sarcoma that develops in connective tissue, though the term is sometimes applied to elements of the soft tissue that are not currently considered connective tissue.-Risk factors:...
. 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
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
status to trabectedin for soft tissue sarcomas and ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
.
Discovery and development
During the 1950s and 1960s, the National Cancer InstituteNational Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
carried out a wide ranging program of screening plant and marine organism material. As part of that program extract from the sea squirt
Tunicate
Tunicates, also known as urochordates, are members of the subphylum Tunicata, previously known as Urochordata, a group of underwater saclike filter feeders with incurrent and excurrent siphons that is classified within the phylum Chordata. While most tunicates live on the ocean floor, others such...
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
Tonne
The tonne, known as the metric ton in the US , often put pleonastically as "metric tonne" to avoid confusion with ton, is a metric system unit of mass equal to 1000 kilograms. The tonne is not an International System of Units unit, but is accepted for use with the SI...
of animals to isolate 1 gram of trabectedin - and about 5 grams were believed to be needed for a clinical trial so Rinehart asked the Harvard chemist E. J. Corey
Elias James Corey
Elias James Corey is an American organic chemist. In 1990 he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis...
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.
Trabectedin was first dosed in humans in 1996. In 2007, the EMEA gave authorisation
for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracycline
Anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var...
s and ifosfamide
Ifosfamide
Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...
, 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
Liposarcoma
Liposarcoma is a malignant tumor that arises in fat cells in deep soft tissue, such as that inside the thigh or in the retroperitoneum.They are typically large bulky tumors which tend to have multiple smaller satellites extending beyond the main confines of the tumor.Liposarcomas, like all...
and leiomyosarcoma
Leiomyosarcoma
Leiomyosarcoma , aka LMS, is a malignant cancer of smooth muscle....
. 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. 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. Trabectedin is also approved in South Korea and Russia.
In 2008 the submission was announced of a registration dossier to the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(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
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
. 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.
Trabectedin is also in phase II trials for prostate, breast and paediatric cancers.
Structure
Trabectedin is composed of 3 tetrahydroisoquinolineTetrahydroisoquinoline
Tetrahydroisoquinoline is a secondary amine with the chemical formula C9H11N.-Reactions:Like other secondary amines, tetrahydroisoquinoline can be oxidized to the corresponding nitrone using hydrogen peroxide, catalyzed by selenium dioxide....
moieties
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
, 8 rings including one 10-membered heteocyclic ring containing a cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residue, and 7 chiral centers.
Synthesis
The biosynthesis of trabectedin is believed to involve the dimerization of two tyrosineTyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
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
Mannich reaction
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...
, Pictet-Spengler reaction
Pictet-Spengler reaction
The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine such as tryptamine undergoes ringclosure after condensation with an aldehyde or ketone. Usually an acidic catalyst is employed and the reaction mixture heated, but some reactive compounds give good yields even at...
, the Curtius rearrangement
Curtius rearrangement
The Curtius rearrangement , as first defined by Theodor Curtius, is a chemical reaction that involves the rearrangement of an acyl azide to an isocyanate. Several reviews have been published....
, and chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
rhodium
Rhodium
Rhodium is a chemical element that is a rare, silvery-white, hard and chemically inert transition metal and a member of the platinum group. It has the chemical symbol Rh and atomic number 45. It is composed of only one isotope, 103Rh. Naturally occurring rhodium is found as the free metal, alloyed...
-based diphosphine
Diphosphines
Diphosphines, sometimes called bisphosphanes are organophosphorus compounds that are used as ligands in inorganic and organometallic chemistry. They are identified by the presence of two phosphino groups linked by a backbone and are usually chelating...
-catalyzed
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
enantioselective hydrogenation
Hydrogenation
Hydrogenation, to treat with hydrogen, also a form of chemical reduction, is a chemical reaction between molecular hydrogen and another compound or element, usually in the presence of a catalyst. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically...
. A separate synthetic process also involved the Ugi reaction
Ugi reaction
The Ugi reaction is a multi-component reaction in organic chemistry involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide.The reaction is named after Ivar Karl Ugi, who first published this reaction in 1959....
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 actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is believed to involve the production of superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. 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
Oxazolidine
Oxazolidine is a five-membered ring compound consisting of three carbons, a nitrogen, a hydrogen, and an oxygen. The oxygen and NH are the 1 and 3 positions, respectively. In oxazolidine derivatives, there is always a carbon between the oxygen and the nitrogen . All of the carbons in oxazolidines...
form.