Interaction of the anticancer gallium(III) complexes of 8-hydroxyquinoline and maltol with human serum proteins.
Tris(8-quinolinolato)gallium(III) (KP46) and tris(maltolato)gallium(III) (GaM) are promising orally active antitumor metallodrugs currently undergoing clinical trials. Their interaction with human serum albumin (HSA) and transferrin (Tf) was studied in detail in aqueous solution by the combination of various methods such as spectrofluorometry, UV-vis spectrophotometry, (1)H and saturation transfer difference NMR spectroscopy, and ultrafiltration-UV-vis spectrophotometry. Binding data were evaluated quantitatively. Tf was found to replace the original ligand much less efficiently in KP46 than in GaM, whereas a significant noncovalent binding of KP46 with HSA (log K' = 4.04) retaining the coordination environment around gallium(III) was found. The interaction between HSA and KP46 was also confirmed by protein-complex modeling calculations. On the basis of the conditional stability constants, the distribution of gallium(III) in serum was computed and compared for these metallodrugs under physiological conditions, and revealed the prominent role of HSA in the case of KP46 and that of Tf for GaM.
Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, Szeged, 6720, Hungary. enyedy@chem.u-szeged.hu.
Éva A
ÉA
Enyedy
Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, Szeged, 6720, Hungary.|MTA-SZTE Bioinorganic Chemistry Research Group, Dóm tér 7, Szeged, 6720, Hungary.
Orsolya
O
Dömötör
Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, Szeged, 6720, Hungary.
Krisztina
K
Bali
Department of Medical Chemistry, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary.
Anasztázia
A
Hetényi
Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
Tiziano
T
Tuccinardi
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090, Vienna, Austria.
Bernhard K
BK
Keppler
D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000737:chemistry*; D015125:Oxyquinoline / Q000031:analogs & derivatives* / Q000737:chemistry; D011485:Protein Binding; D011753:Pyrones / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry*; D012995:Solubility; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011753:Pyrones; D012709:Serum Albumin; C408502:tris(8-quinolinolato)gallium (III); C512662:gallium maltolate; C008316:maltol; D015125:Oxyquinoline