Owing to millions of years of evolution, natural products have emerged with wide-ranging physiological functions and inspired chemists and biologists alike with their complex structures and therapeutic activities. Actinomycete bacteria, in particular, have offered an unparalleled source of antimicrobial and anticancer agents with vancomycin and mitomycin providing but two well-known examples of such therapeutics. Recent advances in DNA sequencing technologies coupled with bioinformatics indicate that the natural products discovered so far merely represent the tip of the iceberg as the products of most biosynthetic gene clusters (BGCs) that can be observed in microbial genomes remain to be identified. Even microbes previously considered exhausted or drained have emerged as valuable reservoirs of untapped metabolites and, with the appropriate discovery methods, these strains can yield new and potentially useful compounds.

Motivated by this untapped potential and the possibility of finding new molecules from well-studied strains, we subjected established antimicrobial producers to antiproliferative assays against persistent cancer cell lines. We discovered five novel natural products including hirocidins A–C that form a new chemotype and are constitutively produced by Streptomyces hiroshimensis. Hirocidin A possesses a carbocyclic maleimide; its structure was established by spectroscopic analysis as well as a concise total synthesis route. Variants B and C contain a bridged azaheterocyclic backbone within a larger macrocyle. Hirocidins display promising cytotoxic activities and subsequent mode of action studies showed that they induce cell death by caspase-9-mediated apoptosis. Our work is in line with the notion that even well-trodden strains remain useful sources of new natural products. The discovery and total synthesis of hirocidin A will facilitate structure activity relationships to better understand and enhance its anticancer activity.

* Reference

- Authors (Pusan National University): Seoung Rak Lee (College of Pharmacy)

- Title of original paper: Hirocidins, Cytotoxic Metabolites from Streptomyces hiroshimensis, Induce Mitochondrion-Mediated Apoptosis

- https://onlinelibrary.wiley.com/doi/10.1002/anie.202405367

- Journal: Angewandte Chemie - International Edition

- DOI: 10.1002/anie.202405367