Complexation of antimony (SbV) 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 SbV, 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 SbV, 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 (k1 = 1.67 × 10−3 and 3.43 × 10−3 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 (k2 = 0.16 × 10−3 and 0.21 × 10−3 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.