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Sunshinamide, a cyclodepsipeptide, has demonstrated significant potential in inhibiting cancer cell proliferation. Our prior research established the total synthesis and anticancer properties of sunshinamide. However, a deeper understanding of the structure–activity relationship (SAR) of sunshinamide remained imperative. In this study, we aimed to elucidate the SAR and mechanistic insights underlying sunshinamide action, both in vitro and in vivo. SAR studies confirm the crucial roles of both the bicyclic-ring and disulfide moiety in the anticancer activity of sunshinamide. Our recent findings unveil that sunshinamide targets TrxR1, leading to ROS generation and ER-stress-mediated apoptosis, while also promoting lipid peroxidation by targeting Gpx4, rendering cancer cells vulnerable to ferroptosis. In vivo, experiments demonstrated the effectiveness of sunshinamide in reducing tumor growth by inducing both apoptosis and ferroptosis. The dual efficacy of sunshinamide in eliciting apoptosis and ferroptosis positions it as a promising candidate for breast cancer therapy, addressing the challenge of chemoresistance.

A convergent route for the asymmetric total synthesis of antibacterial macrolide sorangiolide A has been developed for the first time. The key feature of this synthesis includes Krische iridium-catalyzed anti-diastereoselective carbonyl crotylation, Crimmins acetate aldol, Yamaguchi esterification, Julia–Kocienski olefination, Horner–Wadsworth–Emmons olefination, and ring-closing metathesis. The origin of the low intensity of the 13C{1H} NMR signals of the C1 and C2 centers of the natural product has been investigated, disclosing possible forms of existence for the natural product in the solution phase.