How Fe3+ binds anthracycline antitumour compounds. The myth and the reality of a chemical sphinx.
The interaction of Fe3+ with several anthracycline antitumour antibiotics has been reinvestigated. Absorption and circular dichroism (CD) measurements were carried out (i) in aqueous solution and (ii) in semi-aqueous MeOH to avoid the stacking of the anthracycline molecules. The Fe3+ binding to anthracycline was dependent on the metal-to-ligand molar ratio, antibiotic concentration, ionic strength, and pH. The formation of two major Fe3(+)-anthracycline complexes, I and II, was observed for all the drugs. These species differed in their coordination modes to the anthracycline ligands. Complex I was a monomeric species, where Fe3+ was bound to the anthracycline through the {C(11)-O-; C(12) = O} chelating site. In complex II, Fe3+ was also bound through the {C(5) = O; C(6)-O-} coordination site. Thus, the antibiotic ligand was acting as a bridge between two metal ions, forming oligomeric (or polymeric) structures. The different degree of association of the anthracyclines could be responsible for the reactivity of the metal ion. In fact, complexes I and II could constitute mononuclear, binuclear or polynuclear Fe3+ species depending on the competitive kinetics of both coordination and hydrolysis of the metal ion.
Fiallo
M M
MM
LPBC, CNRS ESA 7033, Université Paris Nord, Bobigny, France. fiallo@smbh.univ-paris13.fr
Garnier-Suillerot
A
A
Matzanke
B
B
Kozlowski
H
H
D000880:Anthraquinones / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002942:Circular Dichroism; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015255:Idarubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D000432:Methanol; D013056:Spectrophotometry, Ultraviolet; D013451:Sulfonic Acids / Q000737:chemistry; D014867:Water
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D013451:Sulfonic Acids; D014867:Water; D004317:Doxorubicin; C034890:1,4-dihydroxyanthraquinone; C027260:pirarubicin; D007501:Iron; D000432:Methanol; C000847:daunorubicinol; D015255:Idarubicin; D003630:Daunorubicin