Synthesis and evaluation of bis-dipeptide and bis-tripeptide analogues of actinomycin D.

Six-bis-dipeptide analogues of actinomycin D, all containing two threonyl-D-valine side chains, were prepared. Also two bis-tripeptide analogues containing an additional proline or oxoproline residue were synthesized. None of the compounds bound to DNA in a manner similar to actinomycin D. This lack of strong intercalative binding emphasizes the importance of the pentapeptidolactone side chains in the binding of actinomycin D to DNA and also highlights the deficiences inherent in using only small nucleotide sequences in investigating drug-DNA binding. None of the analogues tested showed any antitumor activity, although actinocylbis(threonyl-D-valine methyl ester) did show 10% of the antibacterial activity of actinomycin D vs. Bacillus subtilis.