基于抗体药物偶联物弹头的具有抗肿瘤活性海洋天然产物Hoiamides A、Lyngbyabellin N等的多样性研究

项目名称： 基于抗体药物偶联物弹头的具有抗肿瘤活性海洋天然产物Hoiamides A、Lyngbyabellin N等的多样性研究

项目编号： No.21472022

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 无机化学

项目作者： 魏邦国

作者单位： 复旦大学

项目金额： 85万元

中文摘要： 本项目以抗体药物偶联物 (antibody drug conjugate, ADC) 的弹头为导向，开展具有重要生理活性Hoiamides A、Lyngbyabellin N，Tubulysins及Symplocin A四类海洋天然产物及其类似物研究。其中，海洋环肽酯Hoiamides A、Lyngbyabellin N为首次全合成研究。本项目具体基于申请人发现的邻位调控的一锅加成-环合串联反应、1,3-迁移新反应，拟开展多种官能化手性邻氨基醇、取代叔亮氨酸的不对称合成方法研究；拟开展环肽酯Hoiamides A、Lyngbyabellin N首次全合成研究；拟开展上述四类分子及含RNH 或NH2基团（与linker链对接）的类似物的合成和评价。本项目的开展不仅能对海洋天然产物的多样性合成做出基础性贡献，也能为进一步开展上述类似物用于ADC弹头的药理学研究奠定基础。

中文关键词： 海洋天然产物；蓝藻；抗肿瘤；多样性合成；抗体药物偶联物

英文摘要： This project will be focused on the syntheses of four marine natural products (Hoiamides A, Lyngbyabellin N, Tubulysins and Symplocin A) and bioactive analogues amied at the drug in antibody drug conjugate (ADC). Due to their important anti- cancer activities, our major efforts will be on the first asymmetric total syntheses of Hoiamides A and Lyngbyabellin N, followed by construction of a small molecular library with natural-product-like structural and biological diversity. In this project, we will conduct the following research: (1) Explore new synthetic methods to prepare functionalized Chiral ortho-amino alcohols and substituted tert-leucine derivatives using our original 'one-pot' temdem reaction through addition-cyclization and migration reactions; (2) Investigate first total syntheses of Hoiamides A、Lyngbyabellin N; (3) Synthesize a series of analogues of Hoiamides A, Lyngbyabellin N, Tubulysins and Symplocin A, which contained the primary or secondary amino group; (4) Study the structure-activity relationship (SAR) of the synthetic natural products and these synthesized analogues. The above systematic research around the marine natural products will provide novel synthetic methodologies to produce Chiral ortho-amino alcohols and substituted tert-leucine derivatives, and new synthetic strategies to construct our well-designed macrocycle library. In addition, the biological evaluation of these natural products and their active analogs will present valuable insights for the high active drug of antibody drug conjugate(ADC).

英文关键词： Marine natural product;Cyanobacteria;Anti-tumor;Diverse synthesis;Antibody drug conjugate