Structure Elucidation of Verucopeptin, a HIF‑1 Inhibitory Polyketide–Hexapeptide Hybrid Metabolite from an Actinomycete

The transcriptional factor, hypoxia inducible factor-1 (HIF-1), is a promising target for cancer chemotherapy. From an actinomycete, verucopeptin (1) was identified as a HIF-1 signaling inhibitor. By a combination of chemical degradation and spectroscopic analyses, the absolute stereochemistry of me...

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Bibliographic Details
Published in:Organic letters 2015-11, Vol.17 (21), p.5364-5367
Main Authors: Yoshimura, Aya, Nishimura, Shinichi, Otsuka, Saori, Hattori, Akira, Kakeya, Hideaki
Format: Article
Language:English
Subjects:
Actinobacteria - chemistry
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Depsipeptides - chemistry
Depsipeptides - pharmacology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Mechanistic Target of Rapamycin Complex 1
Molecular Structure
Multiprotein Complexes - drug effects
Polyketides - pharmacology
Stereoisomerism
TOR Serine-Threonine Kinases - drug effects
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Summary:The transcriptional factor, hypoxia inducible factor-1 (HIF-1), is a promising target for cancer chemotherapy. From an actinomycete, verucopeptin (1) was identified as a HIF-1 signaling inhibitor. By a combination of chemical degradation and spectroscopic analyses, the absolute stereochemistry of metabolite 1 was determined to be 10R, 15S, 16S, 23S, 27S, 28R, 31S, 33S, 35R. Moreover, metabolite 1 was revealed to attenuate the HIF-1α and mTORC1 pathway, indicating that verucopeptin (1) would be a potent lead compound for anticancer chemotherapy.
ISSN:1523-7060
1523-7052
DOI:10.1021/acs.orglett.5b02718