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

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).

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。

本项目主要取得如下结果：基于邻位诱导加成-环合串联反应、串联脱羧1,3偶极加成环化反应、Lewis Acid或过渡金属催化邻位诱导的炔酰胺、炔烃与N,O-缩醛的加成-环化反应、自由基与醛亚胺加成反应、Lewis Acid催化条件下N,O-缩醛与醛、酮的高选择性一锅Mannich反应等，分别建立了反式不饱和取代哌啶/吡咯酰胺、吡咯里西啶、Isoquinolone、特殊氨基酸等的新方法学。基于以上的合成方法学，完成了项目所申报的Hoiamide A、Lyngbyabellin N，Tubulysins、Symplocin A 的不对称合成及多样性合成及活性评价。基于以上合成方法，我们也完成了Epohelmin A、B及其异构体、(-)-Hapolasin 、(+)-preussinL-733, 060、 CP-122721、(-)-Sedacryptine、苦马豆素、常山酮等活性分子的不对称合成。基于“From Nature to Nature”理念，充分利用废水提取物，首次是实现了一枝蒿酮酸和Apratoxin E的不对称合成，并对天然产物分离的结构进行了矫正。值得一提的是，本项目所建立的合成方法学用于苦马豆素、常山酮的新合成工艺中，并被企业采用用作1类新药研究，目前进入临床前阶段。本项目资助下已公开发表SCI刊物论文22篇，在Org. Lett. J. Org. Chem. Org. Chem. Front.等二区刊物正式发表8篇；1篇被采用为封面文章，1篇被Org. Chem. Highlights 进行Highlights评述。申请国家发明专利15项，授权1项。

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