Aspergiolides C and D: spirocyclic aromatic polyketides with potent protein kinase c-Met inhibitory effects

Lin Du; Jing Ai; Dehai Li; Tianjiao Zhu; Ying Wang; Michael Knauer; Torsten Bruhn; Hongbing Liu; Meiyu Geng; Qianqun Gu; Gerhard Bringmann

doi:10.1002/chem.201001547

Aspergiolides C and D: spirocyclic aromatic polyketides with potent protein kinase c-Met inhibitory effects

Chemistry. 2011 Jan 24;17(4):1319-26. doi: 10.1002/chem.201001547. Epub 2010 Dec 3.

Authors

Lin Du¹, Jing Ai, Dehai Li, Tianjiao Zhu, Ying Wang, Michael Knauer, Torsten Bruhn, Hongbing Liu, Meiyu Geng, Qianqun Gu, Gerhard Bringmann

Affiliation

¹ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P.R. China.

PMID: 21243700
DOI: 10.1002/chem.201001547

Abstract

Variation of the cultivation conditions for Aspergillus glaucus led to the discovery of two novel spirocyclic aromatic polyketides, aspergiolides C (3) and D (4). Their constitutions were elucidated by a combination of spectroscopic methods and isotope-labeling experiments. Aspergiolides C (3) and D (4) occur as racemic mixtures, the resolution of which was succeeded by HPLC on a chiral phase. The absolute configurations of their enantiomers were assigned online, from the peaks in the chromatogram, by a combination of HPLC-CD and quantum chemical CD calculations. Both compounds were found to inhibit the kinase activities of the receptor tyrosine kinases (RTKs) c-Met, Ron, and c-Src with low-micromolar IC(50)s. The enantiomers of 3 were resolved by HPLC on a chiral phase. Both enantiomers showed a comparable inhibition of the HGF-induced autophosphorylation of c-Met and of subsequent cell migration.

Publication types

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

MeSH terms

Anthraquinones / chemistry*
Anthraquinones / isolation & purification
Anthraquinones / pharmacology*
Aspergillus / chemistry
Aspergillus / isolation & purification*
Biological Products / chemistry*
Biological Products / isolation & purification*
Cell Movement / drug effects
Hepatocyte Growth Factor / chemistry*
Hepatocyte Growth Factor / metabolism
Humans
Macrolides / chemistry*
Macrolides / isolation & purification
Macrolides / pharmacology*
Molecular Structure
Phosphorylation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / agonists*
Proto-Oncogene Proteins c-met / chemistry
Proto-Oncogene Proteins c-met / drug effects
Proto-Oncogene Proteins c-met / metabolism
Quantum Theory
Spiro Compounds / chemistry*
Spiro Compounds / pharmacology*
Stereoisomerism

Substances

Anthraquinones
Biological Products
Macrolides
Protein Kinase Inhibitors
Spiro Compounds
aspergiolide C
aspergiolide D
Hepatocyte Growth Factor
Proto-Oncogene Proteins c-met