title: Synthesis of ent-BE-43547A1reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products.
abstract: Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Nikolaj L
authors.initials: NL
authors.lastname: Villadsen
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Kristian M
authors.identifier: 0000-0002-3450-0850
authors.initials: KM
authors.lastname: Jacobsen
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.|Department of Forensic Medicine, Aarhus University, 8200 Aarhus N, Denmark.
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Keiding
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Esben T
authors.initials: ET
authors.lastname: Weibel
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Christiansen
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.|Interdisciplinary Nanoscience Center, iNANO, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vosegaard
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.|Interdisciplinary Nanoscience Center, iNANO, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Bjerring
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Frank
authors.initials: F
authors.lastname: Jensen
authors.affiliation: Department of Forensic Medicine, Aarhus University, 8200 Aarhus N, Denmark.
authors.forename: Mogens
authors.identifier: 0000-0002-2548-7025
authors.initials: M
authors.lastname: Johannsen
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.|Interdisciplinary Nanoscience Center, iNANO, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tørring
authors.affiliation: Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Thomas B
authors.identifier: 0000-0002-0763-9996
authors.initials: TB
authors.lastname: Poulsen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001419:Bacteria / Q000201:enzymology; D001426:Bacterial Proteins / Q000378:metabolism; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000633:toxicity; D006801:Humans; D055666:Lipopeptides / Q000096:biosynthesis / Q000737:chemistry / Q000633:toxicity; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000737:chemistry / Q000633:toxicity; D048630:Polyketide Synthases / Q000378:metabolism; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; C000626368:BE-43547A1; D001426:Bacterial Proteins; D001688:Biological Products; D047630:Depsipeptides; D055666:Lipopeptides; D010456:Peptides, Cyclic; D048630:Polyketide Synthases; C000723972:rakicidins