Synthesis of marmycin A and investigation into its cellular activity

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.

Salinomycin kills cancer stem cells by sequestering iron in lysosomes

“…In particular, the closely related derivative AM4, devoid of a protonable amine, also accumulated in lysosomes lending strong support to the notion that Sal targets this organelle. Lowering the temperature to block endocytic processes reduced the uptake of a Texas Red (TR)-dextran and the lysosomotropic small molecule artesumycin26, but had no effect on the cellular distribution of AM5 (Supplementary Fig. 9).…”

Marine natural products

“…138 The unusual anthracycline marmoycin 139 has been successfully synthesised and uorescent microscopy studies indicated that it accumulates in the lysosomes and not the cell nucleus. 140 The synthesis of immunoaffinity uorescent probes of chlorizidine A 141 established that two cystolic proteins, part of the glycolytic cycle, were the targets for chlorizidine, 142 while studies on the mechanism of action of thalassospiramides 143 conrmed that the nanomolar activity of this group of lipopeptides against human calpain 1 protease can be ascribed to the rigid 12-membered ring containing the a,b-unsaturated amide moiety that is conserved across the group. 144 Annotations of the dra genome sequence of the Streptomyces sp.…”

A Synthetic Study towards the Marmycins and Analogues

“…We recently reported the total synthesis of marmycin A and B and identified a rather unexpected mechanism of action for this class of natural products. 10 Herein, we describe a full account of our methodological efforts to access these structures and related analogues.…”

“…Additionally, we expected that such a synthetic route would exclusively yield the β-epimer at C7 stereo-and regioselectively, imposed by favourable geometrical factors. To determine the feasibility of this approach, we previously described a convenient method to access triflate 7, 10 which involved an expeditious one-pot multistep reaction involving a Diels-Alder cycloaddition to form key junctions between previously described dieno-phile 11 and diene. 11,12 Aminoglycoside 6 was obtained from the commercially available methyl-α-L-rhamnopyranoside 9.…”