Electrospray ionization mass spectrometry and tandem mass spectrometry of clodronate and related bisphosphonate and phosphonate compounds.
The bisphosphonate family with a P-C-P structure is a broad class of drugs, widely investigated as potential inhibitors in bone diseases and calcium metabolic disorders. In this study, the mass spectrometric (MS) behavior and fragmentation of clodronate and related bisphosphonate and phosphonate compounds was studied by using negative ion electrospray ionization (ESI) with triple quadrupole and ion trap instruments. The effect of pH on the degree of deprotonation of the polyprotic bisphosphonic and phosphonic acids in negative ion ESI-MS was investigated, and the degree of deprotonation in the ESI mass spectra and the dissociation in the liquid phase were compared. The results provide evidence that the measured ESI mass spectra do not correlate with the chemistry in the liquid phase owing to the decrease in the pH of the solvent droplets during the ion evaporation process and the charge state neutralization in the gas phase. Ion trap MS(n) provided useful information on the fragmentation study of clodronate and related bisphosphonate and phosphonate compounds, in which interesting fragmentation pathways including the direct elimination of carbon monoxide from deprotonated bisphosphonates and formation of a P-P bond were observed. Reactions between the product ions with a -PO(2) group and residual water in the ion trap or in the high-pressure region of the triple quadrupole instrument formed other unexpected fragmentation paths for all the bisphosphonates studied.
Huikko
Katri
K
Viikki Drug Discovery Technology Center, Department of Pharmacy, P.O. Box 56, FIN-00014 University of Helsinki, Helsinki, Finland.
Kotiaho
Tapio
T
Yli-Kauhaluoma
Jari
J
Kostiainen
Risto
R
D000963:Antimetabolites / Q000032:analysis*; D004002:Clodronic Acid / Q000032:analysis*; D006863:Hydrogen-Ion Concentration; D021241:Spectrometry, Mass, Electrospray Ionization / Q000295:instrumentation / Q000379:methods*
D000963:Antimetabolites; D004002:Clodronic Acid