Abstract
AD-2-1 is an antitumor fungal mutant obtained by diethyl sulfate mutagenesis of a marine-derived Penicillium purpurogenum G59. The G59 strain originally did not produce any metabolites with antitumor activities in MTT assays using K562 cells. Tracing newly produced metabolites under guidance of MTT assay and TLC analysis by direct comparison with control G59 extract, seven new (1–7) and two known (8–9) lipopeptides were isolated together with five known polyketides 10–14 from the extract of mutant AD-2-1. Structures of the seven new compounds including their absolute configurations were determined by spectroscopic and chemical evidences and named as penicimutalides A–G (1–7). Seven known compounds were identified as fellutamide B (8), fellutamide C (9), 1′-O-methylaverantin (10), averantin (11), averufin (12), nidurufin (13), and sterigmatocystin (14). In the MTT assay, 1–14 inhibited several human cancer cell lines to varying extents. All the bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses demonstrated that the production of 1–14 in the mutant AD-2-1 was caused by the activated production of silent metabolites in the original G59 fungal strain. Present results provided additional examples for effectiveness of the chemical mutagenesis strategy using diethyl sulphate mutagenesis to discover new compounds by activating silent metabolites in fungal isolates.
Highlights
Activating silent secondary metabolites of fungal isolates have attracted considerable attention and various strategies have been developed for this purpose in the past decade [1,2,3,4]
All the bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses demonstrated that the production of 1–14 in the mutant AD-2-1 was caused by the activated production of silent metabolites in original fungal G59 strain
By tracing newly produced metabolites in the mutant AD-2-1 extract under the guidance of MTT assay and thin layer chromatography (TLC) analysis using the parent G59 extract as control, seven new lipopeptides 1–7 were isolated together with two known lipopeptides 8 and 9 and the five known polyketides 10–14
Summary
Activating silent secondary metabolites of fungal isolates have attracted considerable attention and various strategies have been developed for this purpose in the past decade [1,2,3,4]. As further extension of that work, we have just recently developed a practical strategy to discover new antitumor agents by activating silent fungal metabolite production using a modified method of diethyl sulphate (DES) mutagenesis on P. purpurogenum G59 [12]. Using this strategy, several new antitumor agents including some with novel structures have been discovered [12,13]. We report here our recent work on another bioactive mutant AD-2-1, including the discovery of seven new lipopeptides from activated production of silent metabolites in the original G59 fungal strain. All the bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses demonstrated that the production of 1–14 in the mutant AD-2-1 was caused by the activated production of silent metabolites in original fungal G59 strain
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