Aspergiolides C and D: spirocyclic aromatic polyketides with potent protein kinase c-Met inhibitory effects.
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.
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P.R. China.
Lin
L
Du
Jing
J
Ai
Dehai
D
Li
Tianjiao
T
Zhu
Ying
Y
Wang
Michael
M
Knauer
Torsten
T
Bruhn
Hongbing
H
Liu
Meiyu
M
Geng
Qianqun
Q
Gu
Gerhard
G
Bringmann
D000880:Anthraquinones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D001230:Aspergillus / Q000737:chemistry / Q000302:isolation & purification*; D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification*; D002465:Cell Movement / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000819:agonists* / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D011789:Quantum Theory; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
D000880:Anthraquinones; D001688:Biological Products; D018942:Macrolides; D047428:Protein Kinase Inhibitors; D013141:Spiro Compounds; C555952:aspergiolide C; C555953:aspergiolide D; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met