Epidithiodioxopiperazine alkaloids possess an astonishing array of molecular architecture and generally exhibit potent biological activity. Nearly twenty distinct families have been isolated and characterized since the seminal discovery of gliotoxin in 1936. Numerous biosynthetic investigations offer a glimpse at the relative ease with which Nature is able to assemble this class of molecules, while providing synthetic chemists inspiration for the development of more efficient syntheses. Herein, we discuss the isolation and characterization, proposed fungal biogeneses, and total syntheses of epidithiodioxopiperazines.

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The LREX’ prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor (NHR), glucocorticoid receptor (GR), which has similar DNA binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein-DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX’ cells, Py-Im polyamide interfered with both androgen receptor- and glucocorticoid receptor-driven gene expression, while enzalutamide interfered with only that of androgen receptor. Genomic analyses indicated immediate interference with the androgen receptor transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer.

The biomimetic total syntheses of both malbrancheamide and malbrancheamide B are reported. The synthesis of the two mono-chloro species enabled the structure of malbrancheamide B to be unambiguously assigned. The syntheses each feature an intramolecular Diels-Alder reaction of a 5-hydroxypyrazin-2(1H)-one to construct the bicyclo[2.2.2]diazaoctane core, which has also been proposed as the biosynthetic route to these compounds.