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.
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, 1 Avenue de la Terrasse, Gif sur-Yvette 91198, France.
Tatiana
T
Cañeque
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, 1 Avenue de la Terrasse, Gif sur-Yvette 91198, France.
Filipe
F
Gomes
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, 1 Avenue de la Terrasse, Gif sur-Yvette 91198, France.
Trang Thi
TT
Mai
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, 1 Avenue de la Terrasse, Gif sur-Yvette 91198, France.|Department of Chemistry, Università degli Studi di Parma, Parco Area delle Scienze 17/a, Parma 43124, Italy.
Giovanni
http://orcid.org/0000-0002-0244-8605
G
Maestri
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, 1 Avenue de la Terrasse, Gif sur-Yvette 91198, France.|Institut Parisien de Chimie Moléculaire, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 8232, Paris CEDEX 05 75252, France.
Max
M
Malacria
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, 1 Avenue de la Terrasse, Gif sur-Yvette 91198, France.|Institut Curie Research Center, Organic Synthesis and Cell Biology Group, 26 rue d'Ulm, Paris Cedex 05 75248, France.|CNRS UMR 3666, Paris 75005, France.
Raphaël
http://orcid.org/0000-0001-7668-446X
R
Rodriguez
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001343:Autophagy / Q000187:drug effects; D002384:Catalysis; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D003500:Cyclization; D061565:Cycloaddition Reaction; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008968:Molecular Conformation; D016601:RNA-Binding Proteins / Q000378:metabolism; D013237:Stereoisomerism
D000880:Anthraquinones; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C118585:P62 protein, human; D016601:RNA-Binding Proteins; C524224:marmycin A; D003300:Copper