Synthesis and properties of some peptide analogues of actinomycin D.
Analogues of actinomycin D (AMD) were synthesized in which amino acid replacements were made at various sites in the peptide moieties. These include (i) replacement of both N-methylvalines by N-methylleucine, (ii) replacement of both sarcosines by N-[2-(methoxycarbonyl)ethyl]glycine, and (iii) replacement of one or both D-valines by D-threonine. The purpose of replacements ii and iii was to ascertain the effect upon biological activity of introducing a new side chain which could be functionalized to allow the attachment of carrier molecules such as antibodies. NMR data indicated that none of the analogues had solution conformations significantly different from that of AMD. Difference spectra with DNA revealed that replacement i enhanced binding while the other analogues bound less strongly to DNA. All the analogues had lower antimicrobial activities than AMD. In contrast, 5,5'-(MeLeu)2AMD displayed in vitro antitumor activity comparable with that of AMD at approximately 100-fold lower concentrations.
Mauger
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Medlantic Research Foundation, Washington, D. C. 20010.
Stuart
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OA
Katz
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E
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001412:Bacillus subtilis / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000187:drug effects*; D003609:Dactinomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009842:Oligopeptides; D003609:Dactinomycin; D004247:DNA