Fast‐Atom bombardment mass spectrometry of the organometallic parasiticide, meglumine antimonate

Abstract

The mass spectrometry of an organometallic parasiticide used for treatment of leishmaniasis was studied using primarily fast-atom bombardment with complementary studies conducted using electrospray ionization. The positive-ion mass spectrum of meglumine antimonate contained ions with characteristic antimony isotope ratios (57:43) at mlz 6271629, 5071509, 4061408 and 3141316. There was also evidence of ion clusters containing antimony atoms (Sb,-3), which decompose to the mass 5071509 species under acid pH conditions. For meglumine antimonate, an empirical formula CIJIH,Ol,,N,Sb (molecular weight 507) is proposed with a structure containing four Sb-0 bonds in a symmetrical geometry.Following the return of soldiers from the Gulf war, there was concern about possible infection of leishrnaniasi~,'-~ and new interest in the characterization of various parasiticides. Organometallics containing toxic levels of pentavalent antimony have received extensive use as parasiticides or drugs for treatment of leishmaniasis-infected cattle and human beings. lLS Although the structure of the parasiticide, meglumine antim~natel-~ is not established, it is believed that the drug contains a polar gluconate or gluconate-derived functionality (Fig. 1). The organometallic is thus susceptible to thermal degradation and, upon heating, readily transforms to involatile salts. This has limited its study using gas chromatography/mass spectrometry with electron impact ionization, and hampered the elucidation of mechanistic pathways of the parasiticide. Consequently, little is known about the structure of the intact organometallic, its metabolites and subsequent degradation products.Although conventional analytical methodologies such as atomic absorption and inverse voltametry have been used for study of the drug, these methods are not well suited to the determination of the intact organometallic and metabolites excreted in urine. Reported chemotherapy and clinical trials have therefore relied on the determination of pentavalent antimony metal resulting from samples subjected to acid digestion.IL3In this work, the intact parasiticide, meglumine antimonate was studied, using primarily fast-atom bombardment (FAB) mass spectrometry, with complementary studies employing electrospray ionization, as part of an on-going program to develop mass spectrometric tools for broad spectrum analysis (BSA) of pesticides.'-' BSA is used in the context of optimizing * Author for correspondence the information obtainable from analyses of environmental samples. We report new mass spectral data of relevance to understanding the efficacy of organoantimony parasiticides. EXPERIMENTALStudies were conducted using a VG 70s instrument (Manchester, UK) which was followed by detailed studies using a VG Autospec Q mass spectrometer of EBEQ geometry. For the FAB experiments, suspensions of pharmaceutical grade meglumine antimonate were prepared in glycerol and the target bombarded using argon atoms (6 keV energy). Studies were also conducted using samples acidified with hydro...

Pentavalent organoantimonial derivatives: two simple and efficient synthetic methods for meglumine antimonate

“…NMG and antimony pentachloride (SbCl 5 , 99%) were obtained from Aldrich Chemical Co. (Milwaukee, WI, USA). Potassium hexahydroxoantimonate (KSb(OH) 6 ) was obtained from Fluka Chemie GmbH (Switzerland). A commercial sample of meglumine antimonate (Glucantime, also known as RP2168) was obtained from Rhône-Poulenc SA (Paris, France) in powder form.…”

“…0.004 mol of NMG was dissolved in about 25 ml of water under stirring at 55 • C. 0.004 mol of KSb(OH) 6 was then added to the solution and the mixture was kept at 55 • C at pH 7 until the mixture remained clear. After cooling, precipitation was induced by the addition of 75 ml of acetone.…”

“…Fast-atom bombardment (FAB) mass spectrometry (MS) data on the commercially available meglumine antimonate (Glucantime) suggested a structure in which two molecules of N-methyl-D-glucamine (NMG) coordinate with a single antimony atom in a symmetrical geometry. 6 FAB-MS and positive-ion electrospray ionization (ESI(+)) MS indicated a polymeric structure with the general formula (NMG-Sb) n -NMG. 7 Despite this recent progress in structural characterization using MS techniques, the exact structure and binding sites of NMG to antimony still need further investigation.…”

New insights into the chemical structure and composition of the pentavalent antimonial drugs, meglumine antimonate and sodium stibogluconate

“…A proton NMR study allowed the assignment of proton resonances in MA and established the existence of two main distinct environments for NMG, indicating that NMG molecules coordinate Sb in two different fashions [7]. Based on MS data, Headley et al [5] and Roberts et al [6] considered the cationic species with a molecular mass of 507 Da as the main Sb complex in MA and postulated a structure, in which two deprotonated NMG molecules are coordinated with a single positively-charged Sb atom. Even though this model is now generally accepted [3], several conflicting data are encountered in the literature.…”

“…Mass spectrometric and NMR techniques have been used to get information on the structure of MA. Fast-atom bombardment mass spectrometry (FAB-MS) and positive electrospray ionization mass spectrometry (ESI(+)-MS) suggested the existence of a mixture of oligomeric structures with the general formula (NMG-Sb) n -NMG and (NMGSb) n [5][6][7], where NMG represents N-methyl-D-glucamine. A proton NMR study allowed the assignment of proton resonances in MA and established the existence of two main distinct environments for NMG, indicating that NMG molecules coordinate Sb in two different fashions [7].…”