Novel Bleomycin Analogues: Synthesis,Antitumor Activity,and Interaction with DNA

The novel analogues 11 – 16 of bleomycin A₆ ( 3 ) were obtained by selective protection of the primary‐amine function of the β‐aminoalaninamide moiety of 3 by means of coordination with Cu^II ions, condensation with an aliphatic or aromatic acid R′COOH in the presence of dicyclohexylcarbodiimide, and demetalization (Scheme). The antitumor activity against HeLa and BGC‐823 in vitro, binding property with CT‐DNA, and cleavage potency towards pBR322 DNA were also studied (Tables 1–3). All the compounds 11 – 16 displayed significant antitumor activity, which was enhanced as the hydrophobicity of the C‐terminus substituent R′ increased, but decreased as the DNA‐binding affinity increased. There was a negative relationship between DNA‐cleavage potency and binding affinity to DNA in this series of compounds.