Characterizing the fragmentation of 2,5-bis (4-amidinophenyl)furan-bis-O-methylamidoxime and selected metabolites using ion trap mass spectrometry

Lian Zhou, Robert D. Voyksner, Dhiren R. Thakker, Chad E. Stephens, Mariappan Anbazhagan, David W. Boykin, James E. Hall, Richard R. Tidwell

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

A novel prodrug [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289)] of the promising antimicrobial agent, 2,5-bis(4-amidinophenyl)furan (DB75), has excellent oral activity. It is currently undergoing phase II clinical evaluation as an orally administered drug candidate against African trypanosomiasis and Pneumocystis carinii pneumonia. The sequential product ion (MSn) fragmentations of DB289 and selected metabolites were characterized using ion trap mass spectrometry with electrospray ionization. An unusual homolytic bond cleavage, formation of an odd-electron ion from an even-electron ion with the loss of a radical, was commonly seen in the fragmentation patterns of DB289 and its metabolites. Both O-ethyl and N-methyl homologues of DB289 were utilized to confirm this fragmentation pathway. The labile hydrogen atoms in DB289 are readily exchanged with deuterium atoms in the solvent containing deuterium oxide (D2O) instead of water. The mass shift patterns displayed in the product ion spectra of DB289 in D2O proved useful in verifying the fragmentation pathway. Octadeuterated DB289 and DB75 (d-labeling on the diphenyl rings) showed unequivocally that the diphenylfuran moiety is not involved in the fragmentation. The fragmentation pathways uncovered in this work will facilitate structural characterization of all the metabolites produced in the metabolic activation of DB289.

Original languageEnglish (US)
Pages (from-to)1078-1085
Number of pages8
JournalRapid Communications in Mass Spectrometry
Volume16
Issue number11
DOIs
StatePublished - Jun 5 2002

Fingerprint

Metabolites
Mass spectrometry
Ions
Deuterium Oxide
Electrospray ionization
Atoms
Electrons
Deuterium
Prodrugs
Anti-Infective Agents
Labeling
Hydrogen
Chemical activation
pafuramidine
Water
Pharmaceutical Preparations
furamidine

ASJC Scopus subject areas

  • Analytical Chemistry
  • Spectroscopy
  • Organic Chemistry

Cite this

Characterizing the fragmentation of 2,5-bis (4-amidinophenyl)furan-bis-O-methylamidoxime and selected metabolites using ion trap mass spectrometry. / Zhou, Lian; Voyksner, Robert D.; Thakker, Dhiren R.; Stephens, Chad E.; Anbazhagan, Mariappan; Boykin, David W.; Hall, James E.; Tidwell, Richard R.

In: Rapid Communications in Mass Spectrometry, Vol. 16, No. 11, 05.06.2002, p. 1078-1085.

Research output: Contribution to journalArticle

Zhou, Lian ; Voyksner, Robert D. ; Thakker, Dhiren R. ; Stephens, Chad E. ; Anbazhagan, Mariappan ; Boykin, David W. ; Hall, James E. ; Tidwell, Richard R. / Characterizing the fragmentation of 2,5-bis (4-amidinophenyl)furan-bis-O-methylamidoxime and selected metabolites using ion trap mass spectrometry. In: Rapid Communications in Mass Spectrometry. 2002 ; Vol. 16, No. 11. pp. 1078-1085.
@article{0c27caaa597c4179af427aa9566012a6,
title = "Characterizing the fragmentation of 2,5-bis (4-amidinophenyl)furan-bis-O-methylamidoxime and selected metabolites using ion trap mass spectrometry",
abstract = "A novel prodrug [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289)] of the promising antimicrobial agent, 2,5-bis(4-amidinophenyl)furan (DB75), has excellent oral activity. It is currently undergoing phase II clinical evaluation as an orally administered drug candidate against African trypanosomiasis and Pneumocystis carinii pneumonia. The sequential product ion (MSn) fragmentations of DB289 and selected metabolites were characterized using ion trap mass spectrometry with electrospray ionization. An unusual homolytic bond cleavage, formation of an odd-electron ion from an even-electron ion with the loss of a radical, was commonly seen in the fragmentation patterns of DB289 and its metabolites. Both O-ethyl and N-methyl homologues of DB289 were utilized to confirm this fragmentation pathway. The labile hydrogen atoms in DB289 are readily exchanged with deuterium atoms in the solvent containing deuterium oxide (D2O) instead of water. The mass shift patterns displayed in the product ion spectra of DB289 in D2O proved useful in verifying the fragmentation pathway. Octadeuterated DB289 and DB75 (d-labeling on the diphenyl rings) showed unequivocally that the diphenylfuran moiety is not involved in the fragmentation. The fragmentation pathways uncovered in this work will facilitate structural characterization of all the metabolites produced in the metabolic activation of DB289.",
author = "Lian Zhou and Voyksner, {Robert D.} and Thakker, {Dhiren R.} and Stephens, {Chad E.} and Mariappan Anbazhagan and Boykin, {David W.} and Hall, {James E.} and Tidwell, {Richard R.}",
year = "2002",
month = "6",
day = "5",
doi = "10.1002/rcm.676",
language = "English (US)",
volume = "16",
pages = "1078--1085",
journal = "Rapid Communications in Mass Spectrometry",
issn = "0951-4198",
publisher = "John Wiley and Sons Ltd",
number = "11",

}

TY - JOUR

T1 - Characterizing the fragmentation of 2,5-bis (4-amidinophenyl)furan-bis-O-methylamidoxime and selected metabolites using ion trap mass spectrometry

AU - Zhou, Lian

AU - Voyksner, Robert D.

AU - Thakker, Dhiren R.

AU - Stephens, Chad E.

AU - Anbazhagan, Mariappan

AU - Boykin, David W.

AU - Hall, James E.

AU - Tidwell, Richard R.

PY - 2002/6/5

Y1 - 2002/6/5

N2 - A novel prodrug [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289)] of the promising antimicrobial agent, 2,5-bis(4-amidinophenyl)furan (DB75), has excellent oral activity. It is currently undergoing phase II clinical evaluation as an orally administered drug candidate against African trypanosomiasis and Pneumocystis carinii pneumonia. The sequential product ion (MSn) fragmentations of DB289 and selected metabolites were characterized using ion trap mass spectrometry with electrospray ionization. An unusual homolytic bond cleavage, formation of an odd-electron ion from an even-electron ion with the loss of a radical, was commonly seen in the fragmentation patterns of DB289 and its metabolites. Both O-ethyl and N-methyl homologues of DB289 were utilized to confirm this fragmentation pathway. The labile hydrogen atoms in DB289 are readily exchanged with deuterium atoms in the solvent containing deuterium oxide (D2O) instead of water. The mass shift patterns displayed in the product ion spectra of DB289 in D2O proved useful in verifying the fragmentation pathway. Octadeuterated DB289 and DB75 (d-labeling on the diphenyl rings) showed unequivocally that the diphenylfuran moiety is not involved in the fragmentation. The fragmentation pathways uncovered in this work will facilitate structural characterization of all the metabolites produced in the metabolic activation of DB289.

AB - A novel prodrug [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289)] of the promising antimicrobial agent, 2,5-bis(4-amidinophenyl)furan (DB75), has excellent oral activity. It is currently undergoing phase II clinical evaluation as an orally administered drug candidate against African trypanosomiasis and Pneumocystis carinii pneumonia. The sequential product ion (MSn) fragmentations of DB289 and selected metabolites were characterized using ion trap mass spectrometry with electrospray ionization. An unusual homolytic bond cleavage, formation of an odd-electron ion from an even-electron ion with the loss of a radical, was commonly seen in the fragmentation patterns of DB289 and its metabolites. Both O-ethyl and N-methyl homologues of DB289 were utilized to confirm this fragmentation pathway. The labile hydrogen atoms in DB289 are readily exchanged with deuterium atoms in the solvent containing deuterium oxide (D2O) instead of water. The mass shift patterns displayed in the product ion spectra of DB289 in D2O proved useful in verifying the fragmentation pathway. Octadeuterated DB289 and DB75 (d-labeling on the diphenyl rings) showed unequivocally that the diphenylfuran moiety is not involved in the fragmentation. The fragmentation pathways uncovered in this work will facilitate structural characterization of all the metabolites produced in the metabolic activation of DB289.

UR - http://www.scopus.com/inward/record.url?scp=0036001221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036001221&partnerID=8YFLogxK

U2 - 10.1002/rcm.676

DO - 10.1002/rcm.676

M3 - Article

VL - 16

SP - 1078

EP - 1085

JO - Rapid Communications in Mass Spectrometry

JF - Rapid Communications in Mass Spectrometry

SN - 0951-4198

IS - 11

ER -