Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anthraquinones / chemical synthesis*
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Anthraquinones / chemistry
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Anthraquinones / toxicity
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Autophagy / drug effects
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Catalysis
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Cell Line, Tumor
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Copper / chemistry
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Crystallography, X-Ray
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Cyclization
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Cycloaddition Reaction
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Humans
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Lysosomes / metabolism
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Microscopy, Fluorescence
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Microtubule-Associated Proteins / metabolism
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Molecular Conformation
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RNA-Binding Proteins / metabolism
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Stereoisomerism
Substances
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Anthraquinones
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MAP1LC3A protein, human
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Microtubule-Associated Proteins
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P62 protein, human
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RNA-Binding Proteins
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marmycin A
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Copper
Associated data
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PubChem-Substance/251973875
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PubChem-Substance/251973876
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PubChem-Substance/251973877
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PubChem-Substance/251973878
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PubChem-Substance/251973879
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PubChem-Substance/251973880
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PubChem-Substance/251973881
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PubChem-Substance/251973882
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PubChem-Substance/251973883
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PubChem-Substance/251973884
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PubChem-Substance/251973885
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PubChem-Substance/251973886
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PubChem-Substance/251973887
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PubChem-Substance/251973888
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PubChem-Substance/251973889
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PubChem-Substance/251973890
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PubChem-Substance/251973891
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PubChem-Substance/251973892
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PubChem-Substance/251973893
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PubChem-Substance/251973894
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PubChem-Substance/251973895
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PubChem-Substance/251973896
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PubChem-Substance/251973897
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PubChem-Substance/251973898
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PubChem-Substance/251973899
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PubChem-Substance/251973900
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PubChem-Substance/251973901
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PubChem-Substance/251973902
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PubChem-Substance/251973903