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 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.
Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
Aya
A
Yoshimura
Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
Shinichi
S
Nishimura
Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
Saori
S
Otsuka
Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
Akira
A
Hattori
Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
Hideaki
H
Kakeya
D039903:Actinobacteria / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D047630:Depsipeptides / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000187:drug effects; D061065:Polyketides / Q000494:pharmacology; D013237:Stereoisomerism; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects
D000970:Antineoplastic Agents; D047630:Depsipeptides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D061065:Polyketides; C082424:verucopeptin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases