Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products

Nikolaj L Villadsen; Kristian M Jacobsen; Ulrik B Keiding; Esben T Weibel; Bjørn Christiansen; Thomas Vosegaard; Morten Bjerring; Frank Jensen; Mogens Johannsen; Thomas Tørring; Thomas B Poulsen

doi:10.1038/nchem.2657

Synthesis of ent-BE-43547A₁ reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products

Nat Chem. 2017 Mar;9(3):264-272. doi: 10.1038/nchem.2657. Epub 2016 Nov 21.

Authors

Affiliations

¹ Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
² Department of Forensic Medicine, Aarhus University, 8200 Aarhus N, Denmark.
³ Interdisciplinary Nanoscience Center, iNANO, Aarhus University, 8000 Aarhus C, Denmark.

PMID: 28221346
DOI: 10.1038/nchem.2657

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Bacteria / enzymology
Bacterial Proteins / metabolism
Biological Products / chemistry
Biological Products / metabolism*
Biological Products / toxicity
Cell Hypoxia
Cell Line, Tumor
Cell Survival / drug effects
Depsipeptides / chemical synthesis*
Depsipeptides / toxicity
Humans
Lipopeptides / biosynthesis
Lipopeptides / chemistry
Lipopeptides / toxicity
Molecular Conformation
Peptides, Cyclic / chemistry
Peptides, Cyclic / toxicity
Polyketide Synthases / metabolism
Stereoisomerism
Tandem Mass Spectrometry

Substances

Antineoplastic Agents
BE-43547A1
Bacterial Proteins
Biological Products
Depsipeptides
Lipopeptides
Peptides, Cyclic
Polyketide Synthases
rakicidins

Associated data

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PubChem-Substance/318482279
PubChem-Substance/318482280
PubChem-Substance/318482266
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PubChem-Substance/318482285
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PubChem-Substance/318482275
PubChem-Substance/318482278
PubChem-Substance/318482281
PubChem-Substance/318482268