Antimony(V) complex formation with adenine nucleosides in aqueous solution.
Despite the clinical use of pentavalent antimonial drugs for over half a century, their mode of action against leishmaniasis remains poorly understood. In this paper, we investigated the ability of Sb(V) to form in aqueous solution complexes with adenine nucleosides and deoxynucleosides, using circular dichroism (CD) and (1)H and (13)C NMR spectroscopies. We report that the ribonucleosides, adenosine (A) and adenosine monophosphate (AMP), form in water complexes with Sb(V), as evidenced by the changes induced in their CD spectra. On the other hand, 2'-deoxyadenosine (dA) did not show such a change. CD titration of the ribonucleosides with Sb(V) suggests the formation of 1:2 Sb(V)-nucleoside complexes. NMR analysis indicates that Sb(V) binds to the sugar moiety at the 2' position. Furthermore, the incubation of the antimonial drug, meglumine antimonate, with adenosine at 37 degrees C led to the transfer of Sb(V) from its original ligand to the nucleoside molecule, at acidic pH (pH 5), but not at neutral pH (7.2). Our data therefore suggests that the formation of such complexes may take place in vivo within the acidic cell compartments, including the phagolysosome of macrophage in which Leishmania resides.
Demicheli
Cynthia
C
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, 31270-901, Belo Horizonte, Minas Gerais, Brazil. demichel@dedalus.lcc.ufmg.br
Frézard
Frédéric
F
Lecouvey
Marc
M
Garnier-Suillerot
Arlette
A
D000241:Adenosine / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D000965:Antimony / Q000737:chemistry / Q000378:metabolism*; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002942:Circular Dichroism; D006863:Hydrogen-Ion Concentration; D007891:Leishmania / Q000187:drug effects; D008024:Ligands; D008264:Macrophages / Q000469:parasitology; D009682:Magnetic Resonance Spectroscopy; D008536:Meglumine / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects / Q000469:parasitology; D011487:Protein Conformation
D000981:Antiprotozoal Agents; D008024:Ligands; D000249:Adenosine Monophosphate; D008536:Meglumine; D000965:Antimony; D000241:Adenosine