MAN-DESIGNED BLEOMYCIN WITH ALTERED SEQUENCE SPECIFICITY IN DNA CLEAVAGE

The synthetic approach to the concerted antitumor mechanism of bleomycin is studied by introducing a dynamic change into the O2-activation moiety and DNA-binding site. A model PYML(6)-bleomycin previously reported, possessing an oxygen-activating methoxypyridine moiety and a DNA-binding bithiazole moiety, exhibits a nucleotide cleavage mode virtually identical with that of bleomycin. Herein reported is a newly designed bleomycin analogue, PYML(6)-(4R-APA)-distamycin, wherein the 4-methoxypyridine moiety and a DNA-binding distamycin component are connected through an (R)-4-aminopentanoic acid linker moiety. Synthesis of PYML(6)-(4R-APA)-distamycin is carried out by condensation of the hydroxyhistidine-pentanoic acid fragment with the methoxypyridine moiety, followed by introduction of the distamycin moiety. PYML(6)-(4RAPA)-distamycin cleaves a G4 phage DNA fragment (100 base pairs) at 1 μ:mM concentration in the presence of Fe(II), oxygen, and dithiothreitol and induces dramatically altered adenine/thymine specificity. It is indicated that the specific recognition of base sequences for the cleavage is mainly controlled by the DNA affinity site and that the (R)-4-aminopentanoic acid linker seems to determine the proper arrangement of the iron-oxygen site and the distamycin moiety on DNA. © 1990, American Chemical Society. All rights reserved.