title: A Novel and Intuitive Method of Displaying and Interacting with Mass Difference Information: Application to Oligonucleotide Drug Impurities.
abstract: A new method is presented for determining relationships between components in complex analytical systems. The method uses the mass differences between peaks in high resolution electrospray ionization (ESI) mass spectra. It relates peaks that share common mass differences. The method is based on the fundamental assumption that peaks in the spectra having the same exact mass difference are related by the same chemical moiety/substructure. Moreover, the presence (or absence/loss) of the same chemical moiety from a series of molecules may reflect similarities in the mechanisms of formation of each molecule. The determined mass differences in the spectra are used to automatically differentiate the types of components in the samples. Contour plots and summary plots of the summed total ion signal as a function of the mass difference are generated, which form powerful tools for the rapid and automated determination of the components in the samples and for comparisons with other samples. For the first time, in this work a unique profile contour plot has been developed that permits the interactive interrogation of the mass range by mass difference data matrix to obtain valuable information about components that share a common mechanism of formation, and all possible mechanisms of formation linked to a selected precursor molecule. The method can be used as an additional and complementary method to the existing analytical methods to determine relationships between components in complex chemical systems.
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA, 92008, USA, sroussis@isisph.com.
authors.forename: Stilianos G
authors.initials: SG
authors.lastname: Roussis
mesh_terms: D004340:Drug Contamination; D008970:Molecular Weight; D009841:Oligonucleotides / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
chemical_list: D009841:Oligonucleotides
references.citation: Bioorg Med Chem Lett. 2004 Sep 20;14(18):4683-90
references.pmid: 15324888
references.citation: Anal Chem. 1996 Jul 1;68(13):1989-99
references.pmid: 9027217
references.citation: Bioorg Med Chem Lett. 2005 Sep 15;15(18):4118-24
references.pmid: 16002284
references.citation: Nucleic Acids Res. 1994 Nov 25;22(23):4997-5003
references.pmid: 7800492
references.citation: Int J Mass Spectrom. 2011 Jul 1;304(2-3):98-104
references.pmid: 21811394
references.citation: Bioorg Med Chem Lett. 2006 Feb;16(3):607-14
references.pmid: 16274991
references.citation: Anal Chem. 2009 Dec 15;81(24):10106-15
references.pmid: 19904912
references.citation: J Org Chem. 2005 Sep 30;70(20):7841-5
references.pmid: 16277303
references.citation: Rapid Commun Mass Spectrom. 2008 Jun;22(12):1871-81
references.pmid: 18470869
references.citation: J Am Soc Mass Spectrom. 2010 Jan;21(1):1-13
references.pmid: 19897384
references.citation: Anal Chem. 2006 Jul 1;78(13):4363-73
references.pmid: 16808443
references.citation: Anal Chem. 2011 Jun 15;83(12):4924-9
references.pmid: 21526851
references.citation: Eur J Mass Spectrom (Chichester). 2011;17(4):415-21
references.pmid: 22006638
references.citation: J Pharm Biomed Anal. 2012 Oct;69:148-73
references.pmid: 22521633
references.citation: Antisense Nucleic Acid Drug Dev. 2000 Apr;10(2):117-21
references.pmid: 10805163
references.citation: Anal Chem. 2012 Sep 4;84(17):7431-5
references.pmid: 22880549
references.citation: J Am Soc Mass Spectrom. 2010 Apr;21(4):580-91
references.pmid: 20129797
references.citation: J Res Natl Inst Stand Technol. 2002 Feb 01;107(1):1-17
references.pmid: 27446716
references.citation: Nucleic Acids Res. 1997 Sep 15;25(18):3615-20
references.pmid: 9278481
references.citation: Nucleic Acids Res. 1999 Jan 15;27(2):389-95
references.pmid: 9862956
references.citation: Annu Rev Biochem. 1998;67:99-134
references.pmid: 9759484
references.citation: J Am Soc Mass Spectrom. 1998 Mar;9(3):225-33
references.pmid: 9879360
references.citation: Oligonucleotides. 2003;13(4):229-43
references.pmid: 15000838
references.citation: Anal Chem. 1997 Apr 1;69(7):1320-5
references.pmid: 21639339
references.citation: Annu Rev Pharmacol Toxicol. 2010;50:259-93
references.pmid: 20055705
references.citation: Anal Chem. 2008 Oct 1;80(19):7414-21
references.pmid: 18729471
references.citation: Methods Enzymol. 2009;468:289-309
references.pmid: 20946775
references.citation: Cell. 2009 Feb 20;136(4):577-80
references.pmid: 19239877
references.citation: Anal Biochem. 2008 Aug 15;379(2):196-207
references.pmid: 18485883
references.citation: Anal Chem. 2013 Jun 4;85(11):5288-96
references.pmid: 23590404
references.citation: J Pharm Biomed Anal. 1997 Dec;16(4):619-30
references.pmid: 9502158
references.citation: Rapid Commun Mass Spectrom. 2009 Nov;23(21):3423-30
references.pmid: 19813281