Chemical Identity

Property	Value
Chemical Formula	C39H43N3O11S
Molecular Weight	761.8 Da
CAS Number	114899-77-0
Peptide Class	Tetrahydroisoquinoline Alkaloid
Origin	Ecteinascidia turbinata (tunicate)

Structure

Trabectedin (ecteinascidin 743) is a tetrahydroisoquinoline alkaloid originally isolated from the tunicate Ecteinascidia turbinata, now produced semi-synthetically. It consists of three fused tetrahydroisoquinoline rings (A, B, C subunits) with a bridged structure. The molecule contains a bridging sulfide bond and multiple stereocenters.

Mechanism of Action

Trabectedin binds to the minor groove of DNA, with the A-ring portion alkylating the N2 of guanine. This induces a bend toward the major groove, disrupting transcription factor binding (particularly NF-Y), blocking cell cycle progression, and inducing apoptosis. It also affects DNA repair pathways by interfering with nucleotide excision repair.

Clinical Applications

• Soft tissue sarcoma: After failure of anthracyclines and ifosfamide (Yondelis)
• Ovarian cancer: Platinum-sensitive relapse in combination with PEG-liposomal doxorubicin
• BRCA-mutated tumors: Enhanced sensitivity due to DNA repair deficiency
• Liposarcoma and leiomyosarcoma: Specific activity in these subtypes

Pharmacokinetics

• Half-life: 180 hours (terminal)
• Protein binding: 97%
• Metabolism: CYP3A4 (primary)
• Elimination: Primarily fecal
• Route: IV infusion over 24 hours every 3 weeks

Safety and Side Effects

Neutropenia (dose-limiting), hepatotoxicity (elevated transaminases), nausea, fatigue, constipation, and rhabdomyolysis (rare). Premedication with dexamethasone reduces hepatotoxicity risk. Avoid with strong CYP3A4 inhibitors.

References

• Demetri, G.D., et al. (2009). Trabectedin for soft tissue sarcoma. Lancet Oncology, 10, 1049-1057.
• Monk, B.J., et al. (2010). Trabectedin plus PLD for ovarian cancer. Journal of Clinical Oncology, 28, 3107-3114.