Design, Synthesis, and Structure–Activity Optimization of Marine-Inspired Macrolactones as Nanomolar Anticancer Agents

Inspired by the anticancer marine natural product superstolide A, we previously designed and synthesized a truncated analogue, designated ZJ-101, that retains the potent anticancer activity of the original natural product. In this study, using ZJ-101 as a lead compound, we conducted molecular design, convergent synthesis, and structure–activity optimization, resulting in the discovery of new analogues exhibiting anticancer activity approximately 30–80-fold more potent than ZJ-101, with IC50 values predominantly in the single-digit nanomolar range.