Unified Total Synthesis and Structure-Activity Relationships of Marine Macrolide Natural Products of Cyanobacteria Origin

本项目旨在探索海洋蓝藻大环内酯类天然产物的全合成及构效关系。我们简洁的合成neopeltolide，一个非常有效的抗增殖大环内酯，使我们能够阐明其药效所需的有效活性的结构元素。基于我们的药效团模型，成功设计了几个具有纳摩尔活性的截短新贝内酯类似物。此外，还实现了具有中等细胞毒性的大环内酯苷lyngbyaloside B及其13-去甲基类似物的简洁全合成。嵌合大环内酯的设计、合成和生物学评价表明，聚酮大环内酯提供了独特的结构基序，可用于开发新型抗增殖剂。

This project pursued unified total synthesis and structure-activity relationships of marine macrolide natural products of cyanobateria origin. Our concise synthesis of neopeltolide, a highly potent antiproliferative macrolide, enabled us to elucidate its pharmacophoric structural elements required for potent activity. Several truncated neopeltolide analogues with nanomolar activity were successfully designed on the basis of our pharmacophore model. Concise total synthesis of lyngbyaloside B, a moderately cytotoxic macrolide glycoside, and its 13-demethyl analogue was also achieved. Design, synthesis, and biological evaluation of chimeric macrolides were undertaken to show that polyketide macrolides offer unique structural motifs useful for the development of novel antiproliferative agents.