In vitro evidence for direct complexation of ADR-529/ICRF-187 [(+)-1,2-bis-(3,5-dioxo-piperazin-1-yl)propane] onto an existing ferric-anthracycline complex.
ADR-529 protects against anthracycline cardiotoxicity, possibly by preventing free radical induction. We hypothesize that this occurs by ADR-529 forming a ternary anthracycline-iron-ADR-529 complex. This study used 200-MHz Fourier-transformed NMR to demonstrate the ability of ADR-529 to do this. Peak assignments were by proton-correlated spectroscopy and proton-carbon heteronuclear-correlated spectroscopy. Ga3+ served as a probe for Fe3+, and D2O was the system solvent. Doxorubicin and epirubicin were the studied drugs. Proton spectra of multiple combinations (including pure standards as controls) were obtained. Both Ga3+ plus ADR-529 and Ga3+ plus doxorubicin showed evidence of complexation, as seen by appropriate peak shifts and changes in the associated coupling constants. Ga3+ plus ADR-529 plus epirubicin showed complexation different from that of Ga3+ plus ADR-529 or Ga3+ plus doxorubicin and consistent with the proposed structure. We conclude that ADR-529 would be able to form a ternary complex with an existing anthracycline-Fe3+ complex in an isolated aqueous environment.
Sobol
M M
MM
Department of Medical Oncology and Clinical Haematology, Royal Melbourne Hospital, Australia.
Amiet
R G
RG
Green
M D
MD
D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D003198:Computer Simulation; D004317:Doxorubicin / Q000737:chemistry; D005290:Ferric Compounds / Q000737:chemistry*; D005583:Fourier Analysis; D005609:Free Radicals; D005708:Gallium / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D008968:Molecular Conformation; D011929:Razoxane / Q000737:chemistry*; D013057:Spectrum Analysis / Q000379:methods
D000903:Antibiotics, Antineoplastic; D005290:Ferric Compounds; D005609:Free Radicals; D011929:Razoxane; D004317:Doxorubicin; D005708:Gallium