Asterriquinones produced by Aspergillus candidus inhibit binding of the Grb-2 adapter to phosphorylated EGF receptor tyrosine kinase.
Five new asterriquinone analogs (2-4, 6, 7), together with previously identified neoasterriquinone (1) and isoasterriquinone (5), were isolated from a fermentation broth of the fungus Aspergillus candidus and purified by HSCCC (high speed counter current chromatography) followed by HPLC. The structures were determined by 1D and 2D NMR and MS/MS techniques. All seven showed inhibitory activity against the binding of a recombinant protein containing the SH2 protein domain of Grb-2 to the tyrosine phosphorylated form of the EGF receptor tyrosine kinase. Some of these asterriquinones exhibited specific inhibition of Grb-2 binding compared to Grb-7 and PLC-gamma.
Alvi
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Natural Products Chemistry Services, MDS Panlabs, Bothell, WA 98011, USA.
Pu
H
H
Luche
M
M
Rice
A
A
App
H
H
McMahon
G
G
Dare
H
H
Margolis
B
B
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D001230:Aspergillus / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D005285:Fermentation; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D010766:Phosphorylation; D011485:Protein Binding; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013056:Spectrophotometry, Ultraviolet; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; C409587:GRAP2 protein, human; D007211:Indoles; C035746:asterriquinone; D005982:Glutathione Transferase; D066246:ErbB Receptors