Scaffold Redesign Strategy for Ecteinascidin 743

Ecteinascidin 743 is a clinically used marine natural product that exerts potent antitumor activity through DNA alkylation and subsequent ternary complex formation with nuclear proteins. This review summarizes its biosynthesis, total synthesis, and mode of action, while highlighting our scaffold redesign strategy aimed at transforming this structurally complex natural product into a programmable medium-sized macrocyclic molecular platform. By replacing the native C1-C4 macrolactone bridge with C1-C5-bridged macrolactams, a series of 14-17-membered redesigned macrocycles were rapidly synthesized from cyanosafracin B through divergent semisynthesis. Systematic analyses of DNA alkylation, DNA double-strand break induction, and antiproliferative activity demonstrated that subtle macrocycle modifications can modulate biological activity and mode of action while preserving the key DNA-alkylating function of the core scaffold. These findings highlight scaffold redesign as a promising strategy for expanding the chemical and functional space of bioactive natural products.