title: 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 genusPenicilliumis recognized as a rich source of chemically diverse bioactive secondary metabolites. This study reports the fermentation, isolation and identification of a marine-derivedPenicilliumspecies. Bioassay-guided 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 nematodeCaenorhabditis eleganswas used to assess the BK channel inhibitory activity and toxicity of select compounds. A pharmacophore model was generated to explain the structural relationships of1-9with 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.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana 71201 USA.
authors.forename: Asmaa A
authors.initials: AA
authors.lastname: Sallam
authors.forename: Wael E
authors.initials: WE
authors.lastname: Houssen
authors.forename: Chris R
authors.initials: CR
authors.lastname: Gissendanner
authors.forename: Khaled Y
authors.initials: KY
authors.lastname: Orabi
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Foudah
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed