Muricadienin analogs as potent triggers of mitochondrial apoptosis and replicative stress in P53-deficient Cancer cells: A structure-activity relationship study.

Muricadienins, the biosynthetic precursors of Annonaceous acetogenins, represent a promising but under-explored scaffold for overcoming p53-deficiency-mediated drug resistance. This study describes the total synthesis and deep mechanistic profiling of a muricadienin analog library featuring strategically shifted diene systems, accessed via a novel Ti-catalyzed cross-cyclomagnesiation of 1,2-dienes. Biological evaluation against p53-deficient Jurkat cells using real-time cell analysis and multiplex signaling assays revealed that structural tuning of the muricadienin core enables precise control over cell fate. Structural optimization identified the short-chain analog 15a and natural muricadienin 15d as potent triggers of mitochondrial apoptosis, inducing Caspase-9 levels up to 15-fold, significantly surpassing clinical benchmarks staurosporine and valinomycin. Notably, natural 15d provoked extreme replicative stress, characterized by a 55-fold increase in Chk2 phosphorylation, dwarfing the effects of camptothecin. A defining structure-activity relationship (SAR) feature of the series was the near-total collapse of the PI3K/Akt survival axis (5-14% of control), mimicking the potency of rapamycin. While aliphatic analogs induced cytotoxic autophagy (LC3-II > 90%), the phenyl-substituted derivative 15 g functioned as a selective mitochondrial stressor with minimal genotoxicity. These findings demonstrate that the muricadienin scaffold can be chemically modulated to bypass conventional chemoresistance through simultaneous mitochondrial stress and survival signaling blockade, establishing these polyketides as a highly promising class of p53-independent antitumor agents.