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 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. 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 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.

Astaxanthin and Docosahexaenoic Acid Reverse the Toxicity of the Maxi-K (BK) Channel Antagonist Mycotoxin Penitrem A

“…A PA dose of 2 μM was selected based on previous studies [22,23,24]. Combined treatment of 50 μM DHA with 2 μM PA significantly reduced the number of C. elegans reversals, suggesting the counteraction of PA’s BK channel antagonistic effects (Figure 3).…”

“…This behavior includes an increase in the number of times the worm stops and reverses its direction, which can be easily assessed and quantified. This model was used to assess the PA-induced BK channel antagonistic effects with a broad dose range (1–50 μM) and known documented activity [22,23,24,25]. …”

“…Similarly, combined 10–20 μM treatments of AST with PA at its IC 50 dose prevented its toxicity and raised these cells’ survival to 61.7%–70.5%. The nematode C. elegans was used to assess the PA BK channel inhibition and protective activities of DHA and AST [22,23,24,25]. BK channel inhibition in C. elegans is associated with abnormal worm locomotion behavior: increased reversal locomotion (i.e., increased the number of times in which the worm stops and reverses its direction).…”

“…BK channel inhibition in C. elegans is associated with abnormal worm locomotion behavior: increased reversal locomotion (i.e., increased the number of times in which the worm stops and reverses its direction). This number can be easily recorded and quantified to reflect the degree of BK channel antagonism [22,23,24]. PA showed BK channel inhibitory activity in the C. elegans model in treatment levels as low as 1 μM, based on the observed increased reversals number exhibited by treated worms compared to the vehicle (DMSO) control [22,23].…”

Discovery and Computer-Aided Drug Design Studies of the Anticancer Marine Triterpene Sipholanes as Novel P-gp and Brk Modulators

“…Each of these models contained a maximum of six of the following features: hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic group (H) and aromatic ring (R). Ten pharmacophore models with three different variant combinations (AAADHR, AAAHHR and AADHHR) survived the scoring process (Table 26.3) [51,52]. These represented top-scoring hypotheses with the best alignment of actives [51,[53][54][55].…”