Recent advances in the Total synthesis and structural modification of Ecteinascidin-743

Ecteinascidin 743 (ET-743), commercially known as Trabectedin, stands as a pioneering marine-derived antitumor agent and a flagship member of the tetrahydroisoquinoline (THIQ) alkaloid family. As the first marine-based drug to achieve clinical approval, ET-743 was authorized by the European Union in 2007 and the U.S. Food and Drug Administration (FDA) in 2015 for the treatment of advanced soft tissue sarcomas, and it is now employed in nearly 80 countries and regions globally. The molecular architecture of ET-743 is distinguished by a highly intricate pentacyclic scaffold, comprising two tetrahydroisoquinoline subunits fused through a central piperazine ring and further embellished with a tetrahydroisoquinoline side chain linked via a thioether bridge. This structural complexity not only underpins its potent biological activity but also presents significant synthetic challenges, rendering ET-743 a focal point of interest in the realm of natural product synthesis. Over the past decades, considerable efforts have been devoted to the total synthesis and structural modification of ET-743, yielding innovative synthetic strategies and analogs with enhanced pharmacological profiles. This review provides a comprehensive analysis of recent advancements in the total synthesis and structural optimization of ET-743, emphasizing key methodologies, synthetic breakthroughs, and structure-activity relationship (SAR) insights. By consolidating these developments, this work aims to furnish a robust scientific foundation for future research endeavors aimed at harnessing the therapeutic potential of tetrahydroisoquinoline-based natural products.