Indole Diketopiperazine Alkaloids from the Marine Sediment-Derived Fungus <i>Aspergillus chevalieri</i> against Pancreatic Ductal Adenocarcinoma
Dina H. El-Kashef,
Deborah D. Obidake,
Katja Schiedlauske,
Alina Deipenbrock,
Sebastian Scharf,
Hao Wang,
Daniela Naumann,
Daniel Friedrich,
Simone Miljanovic,
Takin Haj Hassani Sohi,
Christoph Janiak,
Klaus Pfeffer,
Nicole Teusch
Affiliations
Dina H. El-Kashef
Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Deborah D. Obidake
Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Katja Schiedlauske
Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Alina Deipenbrock
Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Sebastian Scharf
Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Hao Wang
Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China
Daniela Naumann
Department of Chemistry and Biochemistry, University of Cologne, 50939 Cologne, Germany
Daniel Friedrich
Department of Chemistry and Biochemistry, University of Cologne, 50939 Cologne, Germany
Simone Miljanovic
Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Takin Haj Hassani Sohi
Institute of Inorganic Chemistry and Structural Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Christoph Janiak
Institute of Inorganic Chemistry and Structural Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Klaus Pfeffer
Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Nicole Teusch
Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
A new prenylated indole diketopiperazine alkaloid, rubrumline P (1), was isolated along with six more analogues and characterized from the fermentation culture of a marine sediment-derived fungus, Aspergillus chevalieri, collected at a depth of 15 m near the lighthouse in Dahab, Red Sea, Egypt. In the current study, a bioassay-guided fractionation allowed for the identification of an active fraction displaying significant cytotoxic activity against the human pancreatic adenocarcinoma cell line PANC-1 from the EtOAc extract of the investigated fungus compared to the standard paclitaxel. The structures of the isolated compounds from the active fraction were established using 1D/2D NMR spectroscopy and mass spectrometry, together with comparisons with the literature. The absolute configuration of the obtained indole diketopiperazines was established based on single-crystal X-ray diffraction analyses of rubrumline I (2) and comparisons of optical rotations and NMR data, as well as on biogenetic considerations. Genome sequencing indicated the formation of prenyltransferases, which was subsequently confirmed by the isolation of mono-, di-, tri-, and tetraprenylated compounds. Compounds rubrumline P (1) and neoechinulin D (4) confirmed preferential cytotoxic activity against PANC-1 cancer cells with IC50 values of 25.8 and 23.4 µM, respectively. Although the underlying mechanism-of-action remains elusive in this study, cell cycle analysis indicated a slight increase in the sub-G1 peak after treatment with compounds 1 and 4.
