Discovery of Bioactive Indole-Diketopiperazines from the Marine-Derived Fungus Penicillium brasilianum Aided by Genomic Information

Abstract

Identification and analysis of the whole genome of the marine-derived fungus Penicillium brasilianum HBU-136 revealed the presence of an interesting biosynthetic gene cluster (BGC) for non-ribosomal peptide synthetases (NRPS), highly homologous to the BGCs of indole-diketopiperazine derivatives. With the aid of genomic analysis, eight indole-diketopiperazines (1−8), including three new compounds, spirotryprostatin G (1), and cyclotryprostatins F and G (2 and 3), were obtained by large-scale cultivation of the fungal strain HBU-136 using rice medium with 1.0% MgCl2. The absolute configurations of 1−3 were determined by comparison of their experimental electronic circular dichroism (ECD) with calculated ECD spectra. Selective cytotoxicities were observed for compounds 1 and 4 against HL-60 cell line with the IC50 values of 6.0 and 7.9 μM, respectively, whereas 2, 3, and 5 against MCF-7 cell line with the IC50 values of 7.6, 10.8, and 5.1 μM, respectively.

Classification of Aspergillus, Penicillium, Talaromyces and related genera (Eurotiales): An overview of families, genera, subgenera, sections, series and species

“…Extrolites : Penicillium araracuarense produces pulvilloric acid, P . brasilianum produces aspterric acid, austins, brasilianoids and berkeleytrione ( Hayashi et al., 1994 , Matsuda et al., 2016 , Zhang et al., 2018 , Zhang et al., 2019 ), brasiliamides ( Fujita et al., 2002 , Fujita and Hayashi, 2004 , Fill Taicia et al., 2009 ), fischerin, fumitremorgsins, verruculogen, spirotryprostatins and cyclotryprostatins ( Frisvad, 1989 , Zhang et al., 2019 ), JBIR 113, 114 & 115 ( Koyama et al. 2012 ), neosartorin, penicillic acid ( Frisvad et al., 1989 , Kang and Kim, 2004 , Schürmann et al., 2010 ), viridicatumtoxin and spirohexalines ( Frisvad et al., 1989 , Hayashi et al., 1994 , Inokoshi et al., 2013 , Inokoshi et al., 2016 ), and xanthoepocin ( Tuthill et al., 2001 , Bazioli et al., 2017 ), P .…”

Marine-derived fungi as a source of bioactive indole alkaloids with diversified structures

“…Another spirocyclic DKP, spirotryprostatin G (117), highly homologous to the biosynthetic gene clusters (BGCs) of DKP derivatives, was obtained by large-scale cultivation of the marine-derived fungus P. brasilianum HBU-136 using rice medium with 1.0% MgCl 2 . In addition, cytotoxicity was observed for compound 117 against HL-60 cell line with an IC 50 value of 6.0 μmol/L (Zhang et al 2019). Using direct analysis in real time (DART) mass spectrometry, (-)-spiromalbramide (118), (+)-isomalbrancheamide B (119), (+)-malbrancheamide C (120), and (+)-isomalbrancheamide C (121) were initially detected from hyphae of the fungus Malbranchea graminicola (Watts et al 2011).…”

“…Furthermore, compounds 123 and 125 exhibited most potent activities against U937 cell lines with IC 50 values of 25.3 and 18.2 μmol/L, respectively (Wang et al 2012a). With the aid of genomic analysis, two DKPs, namely cyclotryprostatins F and G (127 and 128) were obtained from the marinederived fungus P. brasilianum, with cytotoxicity against the MCF-7 cell line with IC 50 values of 7.6 and 10.8 μmol/L, respectively (Zhang et al 2019). Prenylated DKP peroxides, 24-hydroxyverruculogen (129), 26-hydroxyverruculogen (130), and 13-O-prenyl-26-hydroxyverruculogen (131) were isolated and identified from the culture extract of the marine sediment-derived fungus P. brefeldianum SD-273.…”

Structures and Biological Activities of Diketopiperazines from Marine Organisms: A Review

“…Spirotryprostatin G ( 231 ), cyclotryprostatins F ( 232 ) and G ( 233 ), three new DKPs alkaloids, were isolated from the fungus Penicillium brasilianum HBU-136 separated from the Bohai Sea. Compound 231 showed excellent cytotoxic activity against HL-60 cell lines with an IC 50 value of 6.0 μM and compounds 232 and 233 exhibited remarkable cytotoxic activity against MCF-7 cell lines with IC 50 values of 7.6 and 10.8 μM, respectively [ 109 ]. A new DKP alkaloid namely penilline C ( 234 ) was obtained from the fungus Penicillium chrysogenum SCSIO 07007, which was isolated from a deep-sea hydrothermal vent environment sample of Western Atlantic [ 110 ].…”