The interaction of the cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane); its hydrolysis product (ICRF-198); and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin

Abstract

Membrane-permeable ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane) has shown promise as a cardioprotective agent against adriamycin-induced cardiotoxicity. ICRF-187 may act through its rings-opened hydrolysis product (ICRF-198) which has an EDTA-type structure and, likewise, strongly binds metal ions. The reactions of these compounds with Fe³⁺-adriamycin, and Cu²⁺-adriamycin complexes were examined. ICRF-198 quickly and completely removed both Fe³⁺ and Cu²⁺ from their complexes with adriamycin. ICRF-187 also reacted directly., but more slowly, with Fe³⁺-adriamycin to remove Fe³⁺ from the complex. This reaction was first order in ICRF-187 and Fe³⁺-adriamycin and yielded a second order rate constant of 123M ⁻¹ min⁻¹. Metal ion-complex promoted hydrolysis may thus contribute to thein vivo hydrolysis of ICRF-187 to its metal ion-chelating active rings-opened form. Both ICRF-187 and ICRF-198 were very effective in preventing the Fe³⁺-adriamycin induced inactivation of the cytochromec oxidase activity of submitochondrial particles. A number of other chelating agents (desferal; pencillamine; DTPA; EDTA; TPEN; bathophenanthroline sulfonic acid; 2,2'-bipyridine; 1,10-phenanthroline, glutathione and 2-mercaptoethanol) were also examined for their ability to remove Fe³⁺ and Cu²⁺ from their complexes with adriamycin.