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

Marine-derived fungi have proven to be important sources of bioactive natural organohalides. The genus
Penicillium is recognized as a rich source of chemically diverse bioactive secondary metabolites. This study
reports the fermentation, isolation and identification of a marine-derived Penicillium species. Bioassayguided
fractionation afforded the indole diterpene alkaloids penitrems A, B, D, E and F as well as
paspaline and emnidole SB (1–7). Supplementing the fermentation broth of the growing fungus with
KBr afforded the new 6-bromopenitrem B (8) and the known 6-bromopenitrem E (9). 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 Caenorhabditis elegans 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
1–9 with respect to their antiproliferative activity against the breast cancer MCF-7 cells. The structurally
less complex biosynthetic precursors, paspaline (6) and emindole SB (7), were identified as potential hits
suitable for future studies.