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

• Published in: MedChemComm Vol. 4; no. 10; pp. 1360 - 1369
• Main Authors: Sallam, Asmaa A, Houssen, Wael E, Gissendanner, Chris R, Orabi, Khaled Y, Foudah, Ahmed I, El Sayed, Khalid A
• Format: Journal Article
• Language: English
• Published: England 01.10.2013
• Subjects: Alkaloids; Caenorhabditis
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c3md00198a

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