Synthetic Study toward Man-made Bleomycins by Deeply Contributing to the Anticancer Mechanism of Natural Bleomycins

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) -H2O2 or Fe (II) -O2 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) - (4R-APA) -distamycin which shows dramatically altered AT specific mode in the DNA scission.