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

该项目追求蓝藻来源的海洋大环内酯天然产物的统一全合成和构效关系。我们对高效抗增殖性大环内酯新贝内酯的简明合成，使我们能够阐明其有效活性所需的药理作用结构元素。在我们的药效团模型的基础上，我们成功地设计了几个截短的具有纳摩尔活性的新贝母内酯类似物。还实现了具有中等细胞毒性的大环内酯苷B及其13-去甲基类似物的简明全合成。嵌合大环内酯类化合物的设计、合成和生物学评价表明，聚酮大环内酯类化合物为开发新型抗增殖剂提供了独特的结构基序。

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.