Contents lists available at ScienceDirect Phytochemistry Letters journal homepage: www.elsevier.com/locate/phytol Cytotoxic secondary metabolites from the endophytic fungus Aspergillus versicolor KU258497 Sherif S. Ebada a,b,f, ⁎ , Mona El-Neketi c,1 , Weaam Ebrahim a,c,1 , Attila Mándi d , Tibor Kurtán d , Rainer Kalscheuer a , Werner E.G. Müller e , Peter Proksch a, ⁎ a Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany b Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Abbasia, 11566 Cairo, Egypt c Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt d Department of Organic Chemistry, University of Debrecen, P. O. B. 400, 4002 Debrecen, Hungary e Institut für Physiologische Chemie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Duesbergweg 6, 55128 Mainz, Germany f Department of Pharmaceutical Chemistry, College of Pharmacy, Mu’tah University, 61710 Al-Karak, Jordan ARTICLE INFO Keywords: Aspergillus versicolor Endophyte Alkaloids Antibacterial Cytotoxicity Tddft-ecd ABSTRACT Two new isocoumarin dimers (1 and 2) and one new dihydroquinolone derivative (3) were isolated from Aspergillus versicolor, an endophyte derived from leaves of the Egyptian water hyacinth Eichhornia crassipes (Pontederiaceae), together with ten other known metabolites. Chemical structures of the isolated metabolites were determined based on HRESIMS, extensive 1D and 2D NMR spectroscopy. The relative and absolute con- figurations of the new natural products were established by ROESY and electronic circular dichroism (ECD) spectroscopy, respectively. The axial chirality of the isocoumarin 7,7′-homodimers (1 and 2) was deduced by TDDFT-ECD calculations. All isolated compounds were assessed for their antimicrobial, antitubercular and cy- totoxic activities. Several tested compounds revealed significant cytotoxic activity against mouse lymphoma L5178Y cell line with IC 50 values ranging from < 0.36 to 16.3 μM. 1. Introduction Endophytic fungi are a renewable source for many new biologically active secondary metabolites and these metabolites have now sky- rocketed (Aly et al., 2011; Ebrahim et al., 2016). Aspergillus versicolor is a wide-spread species of the genus Aspergillus previously isolated from plants, soil and marine habitat or even from air dust (Fomicheva et al., 2006). A. versicolor like other species belonging to this genus can withstand a wide temperature range (4–40 °C), pH and/or salinity. However, it usually reveals optimum growth at a temperature between 22 and 26 °C (Pasanen et al., 1997, Fomicheva et al., 2006, Piontek et al., 2016). It can also survive in very dry habitats due to its moderate xerophillic feature (Pasanen et al., 1997). Aspergillus is a genus comprising about 250 species of highly aerobic fungi growing in almost all oxygen-rich environments (Geiser et al., 2007) with many of them known as oligotrophic species capable of growing in key nutrients-depleted environments (Lee et al., 2013). Moreover, many species have been successfully cultivated over a wide range of temperatures (10–50 °C), pH (2–11) and salinity (0–34%) (Meyer et al., 2011). A. versicolor is known to produce a vast array of structurally diverse bioactive secondary metabolites such as sesquiterpenoid nitrobenzoyl esters (Belofsky et al., 1998), xanthones (sterigmatocystin), anthraqui- nones (averantin, methyl-averantin and nidurufin) (Lee et al., 2010), lipopeptides (fellutamides) (Lee et al., 2011), and isocoumarins (ver- sicoumarin A) (Ye et al., 2014) that exhibited potent antiproliferative activities against several human tumor cell lines. Other metabolites exhibited antibacterial and/or antifungal activities including anthra- quinones (averantin and nidurufin) against Gram-positive bacteria (Lee et al., 2010), diketopiperazine (DKP) alkaloids (brevianamide S) against Bacille Calmette-Guérin (BCG) bacteria with a promising mechanism of action towards tuberculosis (Song et al., 2012), oxepine-containing DKP alkaloids (versicoloids A and B) with a strong antifungal activities against phytopathogenic fungus Colletotrichum acutatum that is even higher than that of cycloheximide (positive control) (Wang et al., 2016), and aspergillomarasmine A (AMA) against metallo-β-lactamases specially NDM-1and VIM-2, which are responsible for carbapenem an- tibiotic resistance (King et al., 2014). Versicoumarin A showed potent anti-tobacco mosaic virus (anti-TMV) activity (Ye et al., 2014), while the aromatic polyketide aspergillin A displayed strong antioxidant https://doi.org/10.1016/j.phytol.2018.01.010 Received 13 October 2017; Received in revised form 13 January 2018; Accepted 19 January 2018 ⁎ Corresponding authors at: Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany. 1 These authors contributed equally to this work. E-mail addresses: sherif_elsayed@pharma.asu.edu.eg (S.S. Ebada), proksch@uni-duesseldorf.de (P. Proksch). Phytochemistry Letters 24 (2018) 88–93 1874-3900/ © 2018 Phytochemical Society of Europe. Published by Elsevier Ltd. All rights reserved. T