Actinomycin Analogs From Streptomyces polyantibioticus S4D258: Structural Elucidation and Antiproliferative Activity Against Triple‐Negative Breast Cancer

ABSTRACT Fifteen new actinomycin analogs were obtained from the marine‐derived Streptomyces polyantibioticus S4D258. Structural elucidation of these compounds was successfully achieved by comprehensive analysis of high‐resolution electrospray ionization mass spectrometry (HR‐ESIMS), nuclear magnetic resonance spectroscopy (NMR), and Marfey's method. Notably, actinomycins H 1 –H 5 ( 1 – 5 ) contain L ‐serine ( L ‐Ser), D ‐2‐aminobutyric acid ( D ‐2‐Aba), and L ‐2‐methylaminobutyric acid ( L ‐2‐MeAba) residues, whereas actinomycin H 6 ( 6 ) comprises a 5 H ‐oxazolo[4,5‐ b ]phenoxazine chromophore. Actinomycins H 7 –H 15 ( 7 – 15 ) are nine truncated actinomycin analogs only containing one pentapeptidolactone unit. Actinomycins H 1 ( 1 ) and H 9 ( 9 ) exhibited inhibitory activities against the proliferation of triple‐negative breast cancer MDA‐MB‐231 cells with IC50 values of 28.00 nM and 4.34 µM, respectively. Mechanistic investigation revealed that the above two actinomycin analogs not only induce S‐phase arrest, mitochondrial membrane potential depolarization, and apoptosis, but also trigger ferroptosis, as revealed by an increase in the level of reactive oxygen species, lipid peroxidation, and malondialdehyde. Collectively, our findings enriched the structural diversity of natural actinomycins and inspired the re‐examination of actinomycin analogs as anticancer leads against triple‐negative breast cancer.