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Characterization and biotransformation in the plasma and red blood cells of VIVO2+ complexes formed by ceftriaxone

Sanna, Daniele and Fabbri, Davide and Serra, Maria and Buglyó, Péter and Bíró, Linda and Ugone, Valeria and Micera, Giovanni and Garribba, Eugenio (2015) Characterization and biotransformation in the plasma and red blood cells of VIVO2+ complexes formed by ceftriaxone. Journal of Inorganic Biochemistry , in press. ISSN 0162-0134. Article.

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DOI: 10.1016/j.jinorgbio.2014.12.021


The coordination mode and geometry in aqueous solution of oxidovanadium(IV) complexes formed by a thirdgeneration cephalosporin, ceftriaxone (H3cef), were studied by spectroscopic (EPR, electron paramagnetic resonance), pH-potentiometric and computational (DFT, density functional theory) methods. The behavior of the model systems containing 6-hydroxy-2-methyl-3-thioxo-3,4-dihydro-1,2,4-triazine-5(2H)-one (H2hmtdt) and 3-benzylthio-6-hydroxy-2-methyl-1,2,4-triazine-5(2H)-one (Hbhmt) was examined for comparison. The stability of the tautomers of ceftriaxone and 6-hydroxy-2-methyl-3-thioxo-3,4-dihydro-1,2,4-triazine-5(2H)-one in the neutral,mono- and bi-anionic form was calculated by DFT methods, both in the gas phase and in aqueous solution, and the electron density on the oxygen atoms of the hydroxytriazinone ring was related to the pKa of the ligands. The data demonstrate that ceftriaxone coordinates VIVO2+ forming mono- and bis-chelated complexes with (Oket, O) donor set and formation of five-membered chelate rings. The geometry of the bis-chelated complex, cis-[VO(Hcef)2(H2O)]2−, is cis-octahedral and this species can deprotonate, around physiological pH, to form the corresponding mono-hydroxido cis-[VO(Hcef)2(OH)]3−. The interaction of cis-[VO(Hcef)2(H2O)]2− with apo-transferrin (apo-hTf) was studied and the results suggest that VIVO2+ distributes between (VO)apohTf/(VO)2apo-hTf and cis-[VO(Hcef)2(H2O)]2−, whereas mixed complexes are not formed for charge and steric effects. The interaction of cis-[VO(Hcef)2(H2O)]2− with red blood cells shows that ceftriaxone helps VIVO2+ ion to cross the erythrocyte membrane. Inside the cell cis-[VO(Hcef)2(H2O)]2− decomposes and the same species formed by inorganic VIVO2+ are observed. The relationship between the iotransformation in the plasma and red blood cells and the potential pharmacological activity of VIVO2+ species of ceftriaxone is finally discussed.

Item Type:Article
ID Code:10642
Status:In Press
Uncontrolled Keywords:Vanadium, ceftriaxone, blood, EPR spectroscopy, density functional theory calculations
Subjects:Area 03 - Scienze chimiche > CHIM/03 Chimica generale e inorganica
Divisions:001 Università di Sassari > 02 Centri > Centro di eccellenza interdisc. sviluppo ricerca biotecnologica e studio biodiversità della Sardegna e dell'area mediterranea
001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Chimica e Farmacia
002 Altri enti e centri di ricerca del Nord Sardegna > CNR-Consiglio Nazionale delle Ricerche > Istituto di chimica biomolecolare, Sassari
Publisher:Elsevier Science
Deposited On:19 Jan 2015 14:05

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