THE IRON(III) AND COPPER(II) COMPLEXES OF ADRIAMYCIN PROMOTE THE HYDROLYSIS OF THE CARDIOPROTECTIVE AGENT ICRF-187 ((+)-1,2-BIS(3,5-DIOXOPIPERAZINYL-1-YL)PROPANE)

ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane) has shown promise (Speyer et al., N. Engl. J. Med. 319, 745 (1988)) as a cardioprotective agent against what may be an iron-based adriamycin-induced cardiotoxicity. ICRF-187, which is membrane permeable, likely exerts its action through its ringsopened hydrolysis product which has a structure similar to EDTA and which, likewise, strongly binds metal ions. Both Fe3+-adriamycin and Cu2+-adriamycin reacted directly with ICRF-187, promoting a ring-opening hydrolysis of ICRF-187 that resulted in the displacement of the metal ion from its complex with adriamycin. Thus ICRF-187 can be considered to be acting as a "suicide protective agent" in its reaction with metal ion-adriamycin complexes. That this metal ion complex-promoted hydrolysis was preceeded by mixed ligand complex formation is evidenced by the fact that the first-order rate constant for loss of metal ion from the adriamycin complex exhibits saturation behaviour at high ICRF-187 concentrations. Also direct spectroscopic evidence was obtained both for a Cu2+-adriamycin-ICRF-187 mixed ligand complex and a Cu2+ (ICRF-187)2 complex. The Fe3+-adriamycin complex inactivates the cytochrome c oxidase and NADH cytochrome c reductase activity on submitochondrial particles. The protection that ICRF-187 affords against this loss of activity may be explained both on the basis of simple Fe3+ removal from Fe3+-adriamycin and also on formation of a less active Fe3+-adriamycin-ICRF-187 mixed ligand complex. © 1990 Birkhäuser Verlag.