Actinomycin analogues containing pipecolic acid: relationship of structure to biological activity.
Streptomyces antibioticus synthesizes a mixture of actinomycins which differ at the "imino acid" site of the peptide chains. In the presence of exogenous pipecolic acid, several new actinomycins were synthesized and 70% of the proline in the antibiotic mixture was replaced by the analogue. Three new antibiotics (designated Pip 1alpha, Pip 1beta, and Pip 2) were isolated from culture filtrates, purified, and crystallized. The molar ratio of pipecolic acid to proline was: Pip 1alpha, 1:0; Pip 1beta, 1:1; Pip 2, 2:0. These compounds inhibited the growth and cell division of gram-positive, but not gram-negative, bacteria. The relative inhibitory activity against bacteria, Escherichia coli deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase in vitro, and RNA synthesis in Bacillus subtilis and mouse L-929 cells was: actinomycin IV = Pip 1beta > Pip 2 > Pip 1alpha. Protein synthesis in B. subtilis was less affected, and DNA synthesis was inhibited only at higher concentrations of antibiotic tested. In L cells, DNA formation was reduced less than RNA synthesis, whereas protein synthesis was not blocked under the experimental conditions employed. Kinetic studies with B. subtilis revealed that RNA synthesis was inhibited rapidly followed by an inhibition of protein synthesis. All four antibiotics markedly inhibited the replication of vaccinia virus and reovirus in tissue culture cells, but the production of poliovirus was resistant to the antibiotics. These actinomycins bind to DNA, resulting in an elevation of its T(m) and a decrease in the peak extinction of the actinomycins. The mode of action, as well as the structure-activity relationships among the actinomycins, are discussed relative to a previously proposed model of binding.
D001412:Bacillus subtilis / Q000187:drug effects; D001426:Bacterial Proteins / Q000096:biosynthesis; D002247:Carbon Isotopes; D004247:DNA / Q000096:biosynthesis; D004269:DNA, Bacterial / Q000096:biosynthesis; D003609:Dactinomycin / Q000096:biosynthesis / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D007739:L Cells; D010875:Pipecolic Acids / Q000494:pharmacology*; D017955:Poliovirus / Q000187:drug effects; D011392:Proline / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D012316:RNA Nucleotidyltransferases / Q000378:metabolism; D012329:RNA, Bacterial / Q000096:biosynthesis; D012087:Reoviridae / Q000187:drug effects; D012505:Sarcina / Q000187:drug effects; D013053:Spectrophotometry; D013210:Staphylococcus / Q000187:drug effects; D013302:Streptomyces / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014529:Uridine / Q000378:metabolism; D014616:Vaccinia virus / Q000187:drug effects; D014633:Valine / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D001426:Bacterial Proteins; D002247:Carbon Isotopes; D004269:DNA, Bacterial; D010875:Pipecolic Acids; D012329:RNA, Bacterial; D003609:Dactinomycin; D012313:RNA; D004247:DNA; D011392:Proline; D012316:RNA Nucleotidyltransferases; D014633:Valine; D013936:Thymidine; D014529:Uridine