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)-(4/?-APA)-distamycin, wherein the 4-methoxypyridine moiety and a DNA-binding distamycin component are connected through an (/?)-4-aminopentanoic acid linker moiety. Synthesis of PYML( 6)-(4/?-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)-(4R-APA)-distamycin cleaves a G4 phage DNA fragment (100 base pairs) at 1 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 (/?)-4-aminopentanoic acid linker seems to determine the proper arrangement of the iron-oxygen site and the distamycin moiety on DNA. Bleomycins (BLMs) are chemotherapeutic agents used for the clinical treatment of Hodgkin's lymphoma, carcinomas of the skin, head, and neck, and tumors of the testis.1 The drug was isolated from Streptomyces verticillus as a copper chelate by Umezawa f Synthetic Studies on Antitumor Antibiotic, Bleomycin. 27.
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