|
Destruxin B, first isolated from culture filtrates of the
insect pathogenic fungus Metarrhizium anisopliae, is cyclo-(D-
.alpha.-hydroxy-.gamma.-methylvaleryl-L-prolyl-L-isoleucyl-N-
methyl-L-valyl-N-methyl-L-alanyl-.beta.alanyl). According to
the studies of structure-activity relationship, it was believed
that the ester bond and N-methyl groups in the structure of
destruxin B might play an important role in biological
activity. Therefore, the analyogs of destruxin B which had
lactam struxture and des-N- methylation were synthesized and
their biological activities were also studied. In order to
obtain a cyclic monomer in good yield at the cyclization step,
the D-amino acid residue was placed at the N- terminus of
linear precursors, which were synthesized by Fmoc/NMP chemistry
of solid phase automated peptide synthesis. The yields of
cyclization were very effective by BOP/NaHCO3/DMF method.
Unlike natural destruxin B and desmethyldestruxin B, these
analogs including desmethyldestruxin B-amide and
protodestruxin- amide can't suppress hepatitis B surface
antigen gene expression in hepatoma 3B cell line. To build the
tertiary structures of these analogs, NOE restraints from NMR-
ROESY spectra were introduced to the simulation program-
simulated annealing (SA) to calculate ten conformations. By
comparison with the X-ray crystallography of destruxin B, the
conformation of the analogs obtained from preliminary studies
show different configuration in the part of amide bonds and how
the conspicuous difference in the structures correlating with
their biological function remains to be investigated.
|