Strategic scaffold redesign of ecteinascidins: An approach for generating anticancer macrocycles

Strategies for rational design and scaffold diversification of therapeutically valuable yet synthetically challenging natural products remain elusive, often overshadowed by structural simplification approaches. Herein, we report the molecular redesign of an antitumor drug, ecteinascidin 743, which achieves three pivotal objectives: (1) strategic shift of the bridgehead position from C4 to C5, (2) systematic customization of macrocycle size, and (3) incorporation of functional groups for further modification. Our approach generates diverse 14- to 17-membered macrocyclic frameworks bridged at C5, expanding the accessible chemical space beyond that of conventional C1- to C4-bridged scaffolds, while preserving the core structure essential for covalent DNA interactions. These novel macrocycles induce DNA double-strand breaks and exhibit sub-nanomolar anticancer efficacy comparable to ecteinascidins. This method shortens the conventional 21-step semi-synthetic protocol into a streamlined 6- to 10-step process, cutting the synthetic burden by over 50%.