LTQ FT MS Accurate Mass and SRM Data Dependent Exclusion MSn Measurements for Structure Determination of FK228 and Its Metabolites

MS2 fragments are produced by cleavage of all protonated molecules at the lone electron pairs of heteroatoms or the π electrons of double bonds of FK228. Usually, data dependent MS3 measurement cleaves only MS2 fragment of highest intensity that normally does not contain important metabolic sites. New SRM (selected reaction monitoring) data dependent exclusion MSn measurement makes it possible to obtain MS3 fragmentation data for all MS2 fragments, useful for structural determination of FK228 and its metabolites using ESI ion trap. The two different fragmentation pathways of FK228, of which fragment ions had the different elemental composition, were estimated. The accurate masses of FK228 fragment ions Fa1 (or Fb1) and Fa2 (or Fb2) were measured by LTQ FT MS to compare with those calculated exact masses. The fragmentation pathway of formers was correct as the result. LTQ FT MS accurate mass and SRM data dependent exclusion MSn measurements are required for the structure determination of FK228 and its metabolites.

[1]  Y. Mitani,et al.  Strategy for structural elucidation of drugs and drug metabolites using (MS)n fragmentation in an electrospray ion trap. , 2003, Journal of mass spectrometry : JMS.

[2]  M. Grever,et al.  Identification of thiols and glutathione conjugates of depsipeptide FK228 (FR901228), a novel histone protein deacetylase inhibitor, in the blood. , 2003, Rapid communications in mass spectrometry : RCM.

[3]  H. Nakata.  A Fundamental Aspect of The Structure and Fragmentations of Organic Ions in Mass Spectrometry. Protonation of Organic Compounds and The Behavior of Resulting Protonated Molecules. , 2000 .

[4]  D. Dalvie,et al.  Metabolism of CP-195,543, a leukotriene B4 receptor antagonist, in the Long-Evans rat and Cynomolgus monkey. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[5]  W. Wu,et al.  In vitro metabolism of mifepristone (RU-486) in rat, monkey and human hepatic S9 fractions: identification of three new mifepristone metabolites. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[6]  M. Yoshida,et al.  FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. , 1998, Experimental cell research.

[7]  A. Wolffe,et al.  Activators and repressors: making use of chromatin to regulate transcription , 1997, Genes to cells : devoted to molecular & cellular mechanisms.

[8]  M. Okuhara,et al.  FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. , 1994, The Journal of antibiotics.

[9]  H. Tanaka,et al.  FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. II. Structure determination. , 1994, The Journal of antibiotics.

[10]  I. Kawamura,et al.  FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice. , 1994, The Journal of antibiotics.

[11]  J. Rossi,et al.  Influence of the interfunctional distance on the dehydration of amino alcohols in Iso‐butane chemical ionization mass spectrometry , 1979 .

[12]  R. Cooks,et al.  Fragmentation of even electron ions. Protonated ketones and ethers , 1979 .

[13]  C. Perret,et al.  Mécanismes de fragmentation en spectrométrie de masse par ionisation chimique. III—ions formés par cyclisation†‡ , 1978 .

[14]  C. Fenselau,et al.  PROTON LOCALIZATION IN CHEMICAL IONIZATION FRAGMENTATION , 1976 .

[15]  B. Munson,et al.  Studies in chemical ionization mass spectrometry:Steroidal ketones , 1974 .

[16]  G. Milne,et al.  Chemical ionization mass spectrometry of complex molecules. XI. Stereochemical and conformational effects in the isobutane chemical ionization mass spectra of some steroidal amino alcohols. , 1973, Journal of the American Chemical Society.

[17]  B. Munson,et al.  Studies in chemical ionization mass spectrometry: 17‐hydroxy steroids , 1972 .