Bioguided discovery and pharmacophore modeling of the mycotoxic indole diterpene alkaloids penitrems as breast cancer proliferation, migration, and invasion inhibitors

Abstract

Marine-derived fungi have proven to be important sources of bioactive natural organohalides. The genus <i>Penicillium</i> is recognized as a rich source of chemically diverse bioactive secondary metabolites. This study reports the fermentation, isolation and identification of a marine-derived <i>Penicillium</i> species. Bioassay-guided fractionation afforded the indole diterpene alkaloids penitrems A, B, D, E and F as well as paspaline and emnidole SB (<b>1</b>-<b>7</b>). Supplementing the fermentation broth of the growing fungus with KBr afforded the new 6-bromopenitrem B (<b>8</b>) and the known 6-bromopenitrem E (<b>9</b>). These compounds showed good antiproliferative, antimigratory and anti-invasive properties against human breast cancer cells. Penitrem B also showed a good activity profile in the NCI-60 DTP human tumor cell line screen. The nematode <i>Caenorhabditis elegans</i> was used to assess the BK channel inhibitory activity and toxicity of select compounds. A pharmacophore model was generated to explain the structural relationships of <b>1</b>-<b>9</b> with respect to their antiproliferative activity against the breast cancer MCF-7 cells. The structurally less complex biosynthetic precursors, paspaline (<b>6</b>) and emindole SB (<b>7</b>), were identified as potential hits suitable for future studies.