Journal Article

Synthesis of marmycin A and investigation into its cellular activity

Gomes, Filipe, Maestri, Giovanni, Rodriguez, Raphaël, Cañeque, Tatiana, Mai, Trang Thi, Malacria, Max

2015

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 639/638/549/977/974 / 639/638/92/349 / Analytical Chemistry / Anthraquinones - chemical synthesis / Anthraquinones - chemistry / Anthraquinones - toxicity / Autophagy - drug effects / Biochemistry / Catalysis / Cell Line, Tumor / Chemical Sciences / Chemistry / Chemistry/Food Science / Copper - chemistry / Crystallography, X-Ray / Cyclization / Cycloaddition Reaction / Fluorescence microscopy / Humans / Inorganic Chemistry / Lysosomes - metabolism / Microscopy, Fluorescence / Microtubule-Associated Proteins - metabolism / Molecular Conformation / Organic Chemistry / Physical Chemistry / RNA-Binding Proteins - metabolism / Stereoisomerism