Precursor-Directed Biosynthesis of Aminofulvenes: New Chalanilines from Endophytic Fungus Chalara sp.

The plant endophyte Chalara sp. is able to biotransform the epigenetic modifier vorinostat to form unique, aniline-containing polyketides named chalanilines. Here, we sought to expand the chemical diversity of chalaniline A-type molecules by changing the aniline moiety in the precursor vorinostat. In total, twenty-three different vorinostat analogs were prepared via two-step synthesis, and nineteen were incorporated by the fungus into polyketides. The highest yielding substrates were selected for large-scale precursor-directed biosynthesis and five novel compounds, including two fluorinated chalanilines, were isolated, purified, and structurally characterized. Structure elucidation relied on 1D and 2D NMR techniques and was supported by low- and high-resolution mass spectrometry. All compounds were tested for their bioactivity but were not active in antimicrobial or cell viability assays. Aminofulvene-containing natural products are rare, and this high-yielding, precursor-directed process allows for the diversification of this class of compounds.

Automated summary

The plant endophyte Chalara sp. can transform the epigenetic modifier vorinostat into unique polyketides called chalanilines, with the potential to diversify the chemical diversity of these compounds. By synthesizing nineteen different vorinostat analogs and isolating five novel compounds, including two fluorinated chalanilines, this study has demonstrated a precursor-directed process to expand the class of aminofulvene-containing natural products. Although the tested compounds did not show bioactivity in antimicrobial or cell viability assays, this research provides a new approach for studying these compounds.