A convergent solid-phase synthesis of actinomycin analogues--towards implementation of double-combinatorial chemistry.
The actinomycin antibiotics bind to nucleic acids via both intercalation and hydrogen bonding. We found this 'double-action attack' mechanism very attractive in our search for a novel class of nucleic acid binders. A highly convergent, solid-phase synthetic strategy has been developed for a class of peptide-aryl-peptide conjugates modeled upon natural actinomycins. The features of this method include the use of Fmoc solid-phase peptide synthesis, side-chain to side-chain cyclization on the solid phase, a chemoselective cleavage step and segment condensation. The synthetic scheme is consistent with the requirements for combinatorial synthesis and furthermore, the final segment condensation allows, for the first time, double-combinatorial chemistry to be performed where two combinatorial libraries can be reacted with each other.
Tong
G
G
Technical University of Denmark, Department of Organic Chemistry, Lyngby, Denmark.
Nielsen
J
J
D000596:Amino Acids / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D003609:Dactinomycin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D008401:Gas Chromatography-Mass Spectrometry; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D012313:RNA / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D007364:Intercalating Agents; D003609:Dactinomycin; D012313:RNA; D004247:DNA