title: Anti-leukemia selectivity in actinomycin analogues.
abstract: 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.
authors: Department of Molecular Biosciences, University of Kansas, Lawrence 66045-7534, USA. xraymain@ku.edu
authors: F
authors: F
authors: Takusagawa
authors: R G
authors: RG
authors: Carlson
authors: R F
authors: RF
authors: Weaver
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D003609:Dactinomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy*; D012995:Solubility; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003609:Dactinomycin; D004247:DNA; C427203:calf thymus DNA