Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem

Area of Science:

• Marine natural products chemistry
• Medicinal chemistry
• Drug discovery and development

Background:

• Ecteinascidins are marine compounds with potent antiproliferative activity.
• Yondelis (trabectedin) is the first marine-derived anticancer drug approved in the EU for soft tissue sarcoma.
• Recent positive Phase III trial results in ovarian cancer highlight its therapeutic potential.

Purpose of the Study:

• To review the original total synthesis of ecteinascidins.
• To present a novel semi-synthetic process for ecteinascidin production.
• To address the challenge of limited supply from natural sources.

Main Methods:

• Review of the original total synthesis of ecteinascidins.
• Development of a semi-synthetic route utilizing cynosafracin B.
• Analysis of ecteinascidin structure and function.

Main Results:

• The original total synthesis of ecteinascidins is detailed.
• A new semi-synthetic process from cynosafracin B has been established.
• This semi-synthetic approach resolves the supply issue for ecteinascidins.

Conclusions:

• Efficient synthetic strategies are crucial for developing marine-derived anticancer agents.
• Semi-synthesis offers a viable solution to the natural scarcity of ecteinascidins.
• These advancements facilitate the broader clinical application of ecteinascidin-based therapies.