{"title":"Recent advances in the Total synthesis and structural modification of Ecteinascidin-743.","authors":"Yang Yang, Ju Guo, Yancheng Liu","doi":"10.1016/j.bioorg.2025.109047","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109047"},"PeriodicalIF":4.7000,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1016/j.bioorg.2025.109047","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍：
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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