SEMICOCHLIODINOL-A AND SEMICOCHLIODINOL-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 didemethylasterriqui none D and isocochliodinol as well as the new metabolites' semicochlio dinol A and B have been isolated as inhibitors of HIV-1 protease from the culture broth of the fungus Chrysosporium merdarium P-5656. The st ructures 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 mu M and epidermal growth f actor receptor protein tyrosine kinase at 15 to 60 mu M and are theref ore 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 is ocochliodinol 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.