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

Asmaa Sallam, Wael E Houssen, Chris R. Gissendanner, Khaled Y. Orabi, Ahmed I. Foudah, Khalid El Sayed

Research output: Contribution to journalArticle

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Abstract

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.
Original languageEnglish
Pages (from-to)1360-1369
Number of pages10
JournalMedChemComm
Volume4
Issue number10
Early online date6 Aug 2013
DOIs
Publication statusPublished - 1 Oct 2013

Fingerprint

Indole Alkaloids
Diterpenes
Fungi
Alkaloids
Fermentation
Breast Neoplasms
Large-Conductance Calcium-Activated Potassium Channels
Penicillium
MCF-7 Cells
Caenorhabditis elegans
Metabolites
Tumor Cell Line
Tumors
Breast
Cells
tremortin
indole
emindole
paspaline

Cite this

Bioguided discovery and pharmacophore modeling of the mycotoxic indole diterpene alkaloids penitrems as breast cancer proliferation, migration, and invasion inhibitors. / Sallam, Asmaa ; Houssen, Wael E; Gissendanner, Chris R.; Orabi, Khaled Y.; Foudah, Ahmed I.; El Sayed, Khalid.

In: MedChemComm, Vol. 4, No. 10, 01.10.2013, p. 1360-1369.

Research output: Contribution to journalArticle

Sallam, Asmaa ; Houssen, Wael E ; Gissendanner, Chris R. ; Orabi, Khaled Y. ; Foudah, Ahmed I. ; El Sayed, Khalid. / Bioguided discovery and pharmacophore modeling of the mycotoxic indole diterpene alkaloids penitrems as breast cancer proliferation, migration, and invasion inhibitors. In: MedChemComm. 2013 ; Vol. 4, No. 10. pp. 1360-1369.
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