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 rings-opened 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 preceded 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.
Hasinoff
B B
BB
Department of Chemistry, Memorial University of Newfoundland, St. John's, Canada.
D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D006868:Hydrolysis; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008929:Mitochondria, Heart / Q000201:enzymology; D015394:Molecular Structure; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors; D009942:Organometallic Compounds / Q000378:metabolism* / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism*; D011929:Razoxane / Q000378:metabolism* / Q000494:pharmacology; D013053:Spectrophotometry; D013367:Submitochondrial Particles / Q000201:enzymology
D009942:Organometallic Compounds; D010879:Piperazines; C053169:doxorubicin-copper(II) complex; C041415:doxorubicin-iron complex; D011929:Razoxane; D003300:Copper; D004317:Doxorubicin; D007501:Iron; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV