Bio-Activity and Dereplication-Based Discovery of Ophiobolins and Other Fungal Secondary Metabolites Targeting Leukemia Cells

Abstract

Abstract:The purpose of this study was to identify and characterize fungal natural products (NPs) with in vitro bioactivity towards leukemia cells. We based our screening on a combined analytical and bio-guided approach of LC-DAD-HRMS dereplication, explorative solid-phase extraction (E-SPE), and a co-culture platform of CLL and stromal cells. A total of 289 fungal extracts were screened and we tracked the activity to single compounds in seven of the most active extracts. The novel ophiobolin U was isolated together with the known ophiobolins C, H, K as well as 6-epiophiobolins G, K and N from three fungal strains in the Aspergillus section Usti. Ophiobolins A, B, C and K displayed bioactivity towards leukemia cells with induction of apoptosis at nanomolar concentrations. The remaining ophiobolins were mainly inactive or only slightly active at micromolar OPEN ACCESSMolecules 2013, 18 14630 concentrations. Dereplication of those ophiobolin derivatives possessing different activity in combination with structural analysis allowed a correlation of the chemical structure and conformation with the extent of bioactivity, identifying the hydroxy group at C3 and an aldehyde at C21, as well as the A/B-cis ring structure, as indispensible for the strong activity of the ophiobolins. The known compounds penicillic acid, viridicatumtoxin, calbistrin A, brefeldin A, emestrin A, and neosolaniol monoacetate were identified from the extracts and also found generally cytotoxic.

Sesterterpenoids with Anticancer Activity

“…In this study, ophiobolins A, B (Fig. 3), C and K displayed antiproliferative activity towards leukemia cells with the induction of apoptosis at nanomolar concentrations [39]. The remaining ophiobolins were mainly inactive or only moderately active at micromolar concentrations [39].…”

“…3, Table 1) as well as 6- epi -ophiobolins G, K and N from three fungal strains in the Aspergillus section Usti [39]. This ophiobolin differs from ophiobolin A by the absence of the tetrahydrofuran ring D with the corresponding modifications in the hydrocarbon tail C15-C19, also present in ophiobolins P, Q, R, S and T as mentioned above.…”

“…3), C and K displayed antiproliferative activity towards leukemia cells with the induction of apoptosis at nanomolar concentrations [39]. The remaining ophiobolins were mainly inactive or only moderately active at micromolar concentrations [39]. Interestingly, 6- epi -ophiobolins G and N isolated previously from the fungus Emericella variecolor had been reported to be active at concentrations of 1–3 µM against the neuroblastoma cell line Neuro 2A, inducing cell shrinkage and chromatin condensation in these cells [40].…”

Fast Screening of Antibacterial Compounds from Fusaria

“…Several antibacterial compounds have been isolated from fungi, with penicillin, produced by Penicillium and Aspergillus species, being the most famous [1]. In the search for novel antibacterial secondary metabolites, several bio-guided approaches can be applied such as fractionating the secondary metabolome by reverse-phase liquid chromatography [2,3] or by explorative solid-phase extraction [4,5]. The fractions are then often assessed for bioactivity through traditional techniques (e.g., spectrophotometry).…”

Chemical investigations of fungicolous and coprophilous fungi

“…The known metabolites cladoacetal A (2.11) and 1-(1,3-dihydro-4-hydroxy- 144 This compound was identified as an antagonist of the chemokine receptor CCR-5, which mediates entry of HIV-I into cells (IC50 = 40 µM) 145 and was also found to be selectively cytotoxic to chronic lymphatic leukemia cells (LC50 = 8 nM). 146 However, no antifungal activity has been reported for ophiobolin C. Other members of the ophiobolin family, however, have been reported to display antifungal effects. 147…”