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

On the Giant Octopus (Octopus giganteus) and the Bermuda Blob: Homage to A. E. Verrill

Volume: 188Start Page: 219End Page: 23

The hazards of love: Sterilization and lethality in interspecies crosses

Because sexual selection is weak in selfing species, hermaphrodites may evolve greater susceptibility to the harmful effects of mating. In addition, more specific ‘gene-for-gene’ mismatches might also be evident in interspecies crosses, even between species with the same reproductive mode. We examined heterospecific matings between and within a given sexual mode. Hermaphrodites of C. briggsae, C. elegans, and C. sp. 11 mated to gonochoristic males produce far fewer self-progeny than controls. In C. briggsae, one mating with a gonochoristic male is sufficient for sterilization, and this is likely due to premature oocyte maturation. C. sp. 9 males also greatly accelerate the mortality of C. briggsae hermaphrodites. Dying hermaphrodites often have sperm outside of the uterus and spermatheca (“sperm metastasis”). Germline-feminized C. sp. 9 males deposit copulatory plugs, but fail to sterilize or reduce the lifespan of C. briggsae hermaphrodites, indicating sperm are necessary for both effects. These patterns of asymmetrical sterilization and mortality are also evident in crosses between selfing and gonochoristic Pristionchus species. Matings between different hermaphroditic or gonochoristic species also reduce brood sizes, but to a lesser extent. Collectively, our findings are consistent both with a general ‘weak inbreeder’ susceptibility of hermaphrodites in matings with males of outcrossing species, and with mating system-independent accumulation of reproductive incompatibilities. The latter may represent resolutions of species-specific conflicts that do not ‘complement’ each other in interspecific crosses. Sperm size differences between sexes and species may also contribute. The relaxation of the evolutionary arms race between males and females in hermaphrodites may make them especially susceptible to harm by gonochoristic males. This could accelerate and/or reinforce reproductive isolation between hermaphroditic species and outcrossing relatives