Abstract
Many fungal biosynthetic pathways are silent in standard culture conditions, and activation of the silent pathways may enable access to new metabolites with antitumor activities. The aim of the present study was to develop a practical strategy for microbial chemists to access silent metabolites in fungi. We demonstrated this strategy using a marine-derived fungus Penicillium purpurogenum G59 and a modified diethyl sulphate mutagenesis procedure. Using this strategy, we discovered four new antitumor compounds named penicimutanolone (1), penicimutanin A (2), penicimutanin B (3), and penicimutatin (4). Structures of the new compounds were elucidated by spectroscopic methods, especially extensive 2D NMR analysis. Antitumor activities were assayed by the MTT method using human cancer cell lines. Bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses were used to estimate the activated secondary metabolite production. Compounds 2 and 3 had novel structures, and 1 was a new compound belonging to a class of very rare natural products from which only four members are so far known. Compounds 1–3 inhibited several human cancer cell lines with IC50 values lower than 20 μM, and 4 inhibited the cell lines to some extent. These results demonstrated the effectiveness of this strategy to discover new compounds by activating silent fungal metabolic pathways. These discoveries provide rationale for the increased use of chemical mutagenesis strategies in silent fungal metabolite studies.
Highlights
Natural products are important sources of drugs and drug leads [1,2,3,4]
We reported that the treatment of P. purpurogenum G59 spores at 4 °C with aqueous dimethyl sulfoxide (DMSO) alone did not affect strain growth [20]
The Diethyl sulphate (DES) mutagenesis in the present study was performed on the G59 spores in aqueous DMSO
Summary
Natural products are important sources of drugs and drug leads [1,2,3,4]. Among the small molecule antitumor drugs that were approved from the 1930s to the middle of June 2012, 67% were derived from or inspired by natural products [2]. A significant number of natural product drugs and drug leads are of microbial origin, making cultured microbes crucial sources. Fungal metabolites, especially those derived from marine fungi, are important and have attracted considerable attention [5,6,7]. Especially those derived from marine fungi, are important and have attracted considerable attention [5,6,7] In spite of their roles in drug development, the majority of cultured microbes cannot be used for drug production because the pathways that produce secondary metabolites are silenced in standard culture conditions [8,9,10,11,12]. The one strain-many compounds (OSMAC) strategy [13] and chemical epigenetics methodology [14,15]
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