Semicochliodinol A and B: inhibitors of HIV-1 protease and EGF-R protein tyrosine kinase related to asterriquinones produced by the fungus Chrysosporium merdarium.
The known bisalkylated 2,5-dihydroxybenzoquinones didemethylasterriquinone D and isocochliodinol as well as the new metabolites semicochliodinol A and B have been isolated as inhibitors of HIV-1 protease from the culture broth of the fungus Chrysosporium merdarium P-5656. The structures were elucidated by spectroscopic methods. The NMR spectra of two compounds were completely assigned. The metabolites inhibit HIV-1 protease with an IC50 value as low as 0.17 microM and epidermal growth factor receptor protein tyrosine kinase at 15 to 60 microM and are therefore valuable lead compounds for these targets. Molecular modelling of the HIV-1-protease-inhibitor complexes showed hydrogen bonding between the dihydroxybenzoquinone moiety of didemethylasterriquinone D and isocochliodinol to both active-site aspartic acids (Asp25/Asp25') of the protease and the indole parts of the inhibitors filling the P2 and P2' pockets of the protease.
Fredenhagen
A
A
Core Drug Discovery Technologies, Ciba-Geigy Ltd., Basel, Switzerland.
Petersen
F
F
Tintelnot-Blomley
M
M
Rösel
J
J
Mett
H
H
Hug
P
P
D016227:Benzoquinones / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002912:Chrysosporium / Q000378:metabolism; D005285:Fermentation; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D016227:Benzoquinones; D017320:HIV Protease Inhibitors; D007211:Indoles; C107026:semicochliodinol A; C107027:semicochliodinol B