Complexation of antimony (Sb(V)) with guanosine 5'-monophosphate and guanosine 5'-diphospho-D-mannose: formation of both mono- and bis-adducts.
In spite of the extensive use of pentavalent antimony chemotherapy, the mechanism of its anti-leishmania action is still not clear. Here, we report the interactions of Sb(V), including the clinically used drug stibogluconate, with guanosine 5'-monophosphate (5'-GMP) and guanosine 5'-diphospho-d-mannose (5'-GDP-mannose) in aqueous solution. The deprotonated hydroxyl groups (-OH) of the ribose ring are shown to be the binding site for Sb(V), probably via chelation. Both mono- and bis-adducts were formed as determined by NMR, high performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS), and both of them are stable in the pH range of 4 to around 9.5. The formation of the mono-adduct (k(1)=1.67x10(-3) and 3.43x10(-3) mM(-1) min(-1) for Sb(5'-GMP) and Sb(5'-GDP-mannose), respectively, at 298 K) was 10-fold faster than that of the bis-adduct (k(2)=0.16x10(-3) and 0.21x10(-3) mM(-1) min(-1), for Sb(5'-GMP)(2) and Sb(5'-GDP-mannose)(2), respectively), and the mono-adduct was the major species in solution with the [bis-adduct]/[mono-adduct]<0.5. The reactions of stibogluconate with 5'-GMP and 5'-GDP-mannose were slower than that of antimonate under similar conditions.
Chai
Yi
Y
Department of Chemistry and Open Laboratory of Chemical Biology, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China.
Yan
Siucheong
S
Wong
Iris L K
IL
Chow
Larry M C
LM
Sun
Hongzhe
H
D000818:Animals; D000965:Antimony / Q000737:chemistry* / Q000494:pharmacology; D000967:Antimony Sodium Gluconate / Q000737:chemistry / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006155:Guanosine Diphosphate Mannose / Q000737:chemistry*; D006157:Guanosine Monophosphate / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007891:Leishmania / Q000187:drug effects / Q000378:metabolism; D007896:Leishmaniasis / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
D000981:Antiprotozoal Agents; D006155:Guanosine Diphosphate Mannose; D006157:Guanosine Monophosphate; D000965:Antimony; D000967:Antimony Sodium Gluconate