Bleomycins (BLMs) are antitumor antibiotics of unusual glycopeptide structure. The potent activity of BLM is attributed to the oxygen activation and the DNA cleavage by the formation of iron-chelate of the peptide moiety.
erythro-β-Hydroxy-
L-histidine, a pivotal amino acid for the oxygen activation, is prepared enantioselectively by aldol reaction of (
R) -3-bromoacetyl-4-isopropyl-1, 3-oxazolidin-2-one with 1-triphenylmethylimidazole-4-carbaldehyde. Model ligands for the metal binding site of BLM with 4-methoxypyridine (PYML-6) and 4-dimethylaminopyridine (PYML-8) show oxygen activation up to 97% and 125% of that of BLM, respectively.
cis-β-Methylstyrene is oxidized either with Fe (III) -H
2O
2 or Fe (II) -O
2 complex systems of BLM and PYML-6 to give the corresponding optically active epoxide. The DNA binding region of BLM is combined with PYML-6 to give the first man-designed BLM, PYML (6) -bleomycin, which shows nucleotide cleavage mode remarkably similar to that of BLM. On the other hand, PYML-6 moiety and distamycin are coupled to afford PYML (6) - (4
R-APA) -distamycin which shows dramatically altered AT specific mode in the DNA scission.
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