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.
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 123 M-1 min-1. Metal ion-complex promoted hydrolysis may thus contribute to the in 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 cytochrome c oxidase activity of submitochondrial particles. A number of other chelating agents (desferal; penicillamine; 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.
Hasinoff
B B
BB
Department of Chemistry, Memorial University of Newfoundland, St. John's, Canada.
D002316:Cardiotonic Agents; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D005029:Ethylenediamines / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011929:Razoxane / Q000494:pharmacology*; D013237:Stereoisomerism; D013367:Submitochondrial Particles / Q000201:enzymology*
D002316:Cardiotonic Agents; D002614:Chelating Agents; D005029:Ethylenediamines; D009942:Organometallic Compounds; D010879:Piperazines; C053169:doxorubicin-copper(II) complex; C041415:doxorubicin-iron complex; D011929:Razoxane; C059866:ICRF 198; D003300:Copper; D004317:Doxorubicin; D007501:Iron; D003576:Electron Transport Complex IV; D005998:Glycine