Synthesis of marmycin A and investigation into its cellular activity

Anthracyclines such as doxorubicin are used extensively in the treatment of cancers. Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been proposed to operate via similar mechanisms, including direct genome targeting. Here, we report the chemical synthesis of marmycin A and the study of its cellular activity. The aromatic core was constructed by means of a one-pot multistep reaction comprising a regioselective Diels–Alder cycloaddition, and the complex sugar backbone was introduced through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel–Crafts cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target the nucleus but instead accumulates in lysosomes, thereby promoting cell death independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through which anthraquinone derivatives act in cells, pointing towards unanticipated biological and therapeutic applications. Marmycin A is an anthraquinone natural product with antiproliferative properties. Now the chemical synthesis of marmycin A—through a Diels–Alder cycloaddition, an Ullmann aromatic amination and a Friedel–Crafts cyclization—has enabled a study of its biological activity. Fluorescence microscopy reveals that marmycin A accumulates in lysosomes and promotes cell death independently of genome targeting.