The one-ring open hydrolysis product intermediates of the cardioprotective agent ICRF-187 (dexrazoxane) displace iron from iron-anthracycline complexes.
The ability of the cardioprotective agent ICRF-187 (dexrazoxane), its one-ring open hydrolysis products, and its two-ring open hydrolysis product, ADR-925, to displace Fe3+ from its complex with doxorubicin, daunorubicin, epirubicin and idarubicin have been studied. At pH 7.4, ICRF-187 at a concentration of 100 microM ICRF-187 slowly but completely displaced Fe3+ from its anthracycline complexes with half-times ranging from 230 to 450 min. The one-ring open intermediate hydrolysis products were also shown to be chelating agents and were also able to displace quickly and completely Fe3+ from its anthracycline complexes with half-times ranging from 1.7 to 16.7 min. Molecular modeling of Fe3+ complexes with the one-ring open intermediates showed that these intermediates were likely acting as tetradentate ligands. Since these intermediates are such good chelating agents, they may also be pharmacologically active species in preventing oxygen-radical derived iron-based anthracycline-induced cardiotoxicity. Since these one-ring open intermediates are produced by hydrolysis from the parent ICRF-187 more quickly than is ADR-925, the formation of pharmacologically active species might be occurring more quickly than previously thought. The displacement of Fe3+ from its anthracycline complexes by the two-ring open hydrolysis product ADR-925 also took place quickly and completely with half-times ranging from 1 to 3 min.
Buss
J L
JL
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
Hasinoff
B B
BB
D000873:Anthracenes / Q000737:chemistry*; D005029:Ethylenediamines / Q000737:chemistry; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry; D006868:Hydrolysis; D007501:Iron / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D011929:Razoxane / Q000737:chemistry*; D013055:Spectrophotometry, Infrared
D000873:Anthracenes; D005029:Ethylenediamines; D011929:Razoxane; C059866:ICRF 198; D007501:Iron; D005998:Glycine