Chemical Diversity of Aspergillus alliaceus Phenotypes: Discovery of Brominated Bianthrones with Activity against Triple‐Negative Breast Cancer Cell Lines

• Published in: Chembiochem : a European journal of chemical biology 2024-10, Vol.25 (20), p.e202400398-n/a
• Main Authors: Mandelare, Paige E., Yee, Samantha S., Icenhour, Daniel G., Kaweesa, Elizabeth N., McCauley, Mark, Risinger, April L., Rudolf, Jeffrey D., Loesgen, Sandra
• Format: Article
• Language: English
• Subjects: Aspergillus; bianthrones; Biosynthesis; Breast cancer; Bromination; Cell culture; Chemical activity; Cytotoxicity; fungal natural products; Fungi; genome mining; Genomic analysis; Marine chemistry; Mass spectrometry; Mass spectroscopy; Metabolites; Metabolomics; NMR; Nuclear magnetic resonance; Phenotypes; Phenotypic variations; Polyketides; triple-negative breast cancer; Tumor cell lines; Two dimensional analysis
• ISSN: 1439-4227; 1439-7633; 1439-7633
• DOI: 10.1002/cbic.202400398

Marine‐derived fungi have emerged as a source for novel metabolites with a broad range of bioactivities. However, accessing the full potential of fungi under standard laboratory conditions remains challenging. LC–MS‐based metabolomics in combination with varied culture conditions is a fast and powerful tool to detect new metabolites. Here, three developmental forms of the marine‐derived fungus Aspergillus alliaceus were analyzed and 14 fungal metabolites, including new brominated polyketides (11‐14) were isolated. Structure elucidation relied mainly on 1D and 2D NMR techniques and was supported by low‐ and high‐resolution mass spectrometry and DFT‐based computations. We sequenced the A. alliaceus genome, identified the bianthrone‐producing biosynthetic gene cluster, and conducted expression analysis on genes involved in sexual development and biosynthesis. The NCI‐60 cell line panel revealed selective in vitro activity against triple‐negative breast cancer (TNBC) for the halogenated allianthrones and their full antiproliferative and cytotoxic effects were evaluated in five TNBC cell lines. The three developmental forms of the marine‐derived fungus Aspergillus alliaceus grown in different media resulted in the isolation and characterization of 14 fungal metabolites, including new brominated polyketides. The allianthrones exhibit selective in vitro activity against triple‐negative breast cancer (TNBC) and the genome of A. alliaceus was sequenced and the bianthrone‐producing biosynthetic gene cluster identified.