[Molecular design of apoptosis inducing agents derived from bleomycin]

Abstract

Reactive oxygen species (ROS) are often involved in the mechanism of apoptosis. Bleomycin consists of an oxygen activating domain and a DNA binding domain, and is an antitumour agent that induces double-strand scission in DNA by oxygen activation. However, bleomycin only weakly induces apoptosis in limited conditions. Previously we have reported efficient oxygen activation by iron complexes of synthetic models of bleomycin namely PYML designed by the direct analogy to the BLM metal core. Recently, novel ligands having symmetrized coordination environment consisting of two histidine units and a pyridine (HPH) were prepared. Oxygen activating efficiency of the iron complexes of the synthetic ligands increased by introducing electron donating substituent into the pyridine ring. HPH compounds have no DNA binding region which is present in bleomycin. HPH compounds but not bleomycin induced apoptosis in mouse leukemia L1210 cells.