Indole Diketopiperazine Alkaloids from the Marine Sediment-Derived Fungus Aspergillus chevalieri against Pancreatic Ductal Adenocarcinoma
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Published:2023-12-20
Issue:1
Volume:22
Page:5
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ISSN:1660-3397
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Container-title:Marine Drugs
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language:en
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Short-container-title:Marine Drugs
Author:
El-Kashef Dina H.12ORCID, Obidake Deborah D.1, Schiedlauske Katja1, Deipenbrock Alina1, Scharf Sebastian3ORCID, Wang Hao4ORCID, Naumann Daniela5, Friedrich Daniel5ORCID, Miljanovic Simone1, Haj Hassani Sohi Takin6ORCID, Janiak Christoph6ORCID, Pfeffer Klaus3ORCID, Teusch Nicole1ORCID
Affiliation:
1. Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany 2. Department of Pharmacognosy, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt 3. Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany 4. 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 5. Department of Chemistry and Biochemistry, University of Cologne, 50939 Cologne, Germany 6. Institute of Inorganic Chemistry and Structural Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Abstract
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.
Funder
Deutsche Forschungsgemeinschaft
Subject
Drug Discovery,Pharmacology, Toxicology and Pharmaceutics (miscellaneous),Pharmaceutical Science
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