Complexation of antimony (Sb(V)) with guanosine 5'-monophosphate and guanosine 5'-diphospho-D-mannose: formation of both mono- and bis-adducts

J Inorg Biochem. 2005 Dec;99(12):2257-63. doi: 10.1016/j.jinorgbio.2005.08.015. Epub 2005 Oct 6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimony / chemistry*
  • Antimony / pharmacology
  • Antimony Sodium Gluconate / chemistry
  • Antimony Sodium Gluconate / pharmacology
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology
  • Chromatography, High Pressure Liquid
  • Guanosine Diphosphate Mannose / chemistry*
  • Guanosine Monophosphate / chemistry*
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Leishmania / drug effects
  • Leishmania / metabolism
  • Leishmaniasis / drug therapy
  • Magnetic Resonance Spectroscopy
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Antiprotozoal Agents
  • Guanosine Diphosphate Mannose
  • Guanosine Monophosphate
  • Antimony
  • Antimony Sodium Gluconate