Anti-leukemia selectivity in actinomycin analogues Original Research Article

An excellent anti-leukemia activity has been found in a group of actinomycin d analogues derivatized at the 2,2′- or 5,5′-position of the depsipeptides. On the basis of the water solubilities, the DNA binding affinities, the RNA synthesis inhibitory activities, the anticancer activities of actinomycin d (AMD), and the crystal structures of DNA–AMD complexes, it becomes clear that AMD is extremely well designed as an effective poison produced by micro-organisms. The anticancer activity of AMD is mainly due to its selective inhibition of RNA synthesis. We have hypothesized that a modification on the AMD structure at a site not involved in DNA interaction can either increase or decrease the diffusion rate of the analogue into certain cancer cells. Since the i-propyl groups of the d-valine residues at the 2,2′-positions and N-methyl-l-valine residues at the 5,5′-positions in the depsipeptides do not participate in interaction with DNA, these amino acid residues were replaced with other d-amino acid residues and N-methyl-l-amino acid residues, respectively. The cancer screen tests have indicated that AMD analogues 2,2′-d-PheAMD, 2,2′-d-OmeAMD, 5,5′-l-TyrAMD, 5,5′-d-ValAMD, 5,5′-d-TyrAMD, 5,5′-d-PheAMD, and 5,5′-d-OmeAMD, inhibit selectively the growth of leukemia cell lines at about 100- to 500-fold lower drug concentrations than those required to inhibit other cancer cell lines.