Ion trap collision-induced dissociation of multiply deprotonated RNA: c/y-ions versus (a-B)/w-ions

Therapeutic approaches for treatment of various diseases aim at the interruption of transcription or translation. Modified oligonucleotides, such as 2′-O-methyl-and methylphosphonatederivatives, exhibit high resistance against cellular nucleases, thus rendering application for, e.g., antigene or antisense purposes possible. Other approaches are based on administration of cross-linking agents, such as cis-diamminedichloroplatinum(II) (cisplatin, DDP), which is still the most widely used anticancer drug worldwide. Due to the formation of 1,2-intrastrand cross links at adjacent guanines, replication of the double-strand is disturbed, thus resulting in significant cytotoxicity. Evidence for the gas-phase dissociation mechanism of platinated RNA is given, based on nano-electrospray ionization high-resolution multistage tandem mass spectrometry (MS n ). Confirmation was found by investigating the fragmentation pattern of platinated and unplatinated 2′-methoxy oligoribonucleotide hexamers and their corresponding methylphosphonate derivatives. Platinated 2′-methoxy oligoribonucleotides exhibit a similar gas-phase dissociation behavior as the corresponding DNA and RNA sequences, with the 3′-C-O bond adjacent to the vicinal guanines being cleaved preferentially, leading to w x -ion formation. By examination of the corresponding platinated methylphosphonate derivatives of the 2′-methoxy oligoribonucleotides, the key role of the negatively charged phosphate oxygen atoms in direct proximity to the guanines was proven. The significant alteration of fragmentation due to platination is demonstrated by comparison of the fragment ion patterns of unplatinated and platinated 2′-O-methyl-and 2′-O-methyl methylphosphonate oligoribonucleotides, and the results obtained by H/D exchange experiments.

Section: Fragmentation Of 2′-o-methyl Oligoribonucleotidessupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Tandem Mass Spectrometry of Modified and Platinated Oligoribonucleotides

Nyakas

Stucki

Schürch

2011

“…As has been reported previously, the dissociation of oligonucleotide anions can be highly sensitive to precursor ion charge state [43][44][45]. To investigate the dissociation behavior of the LNA mixmer anions of higher charge states, the [M Ϫ 7H] 7-ions were isolated and subjected to ion trap CID.…”

Section: Ion Trap Collision-induced Dissociation Of Functional Lna-dnmentioning

confidence: 99%

Ion trap collision-induced dissociation of locked nucleic acids

Huang

Kharlamova

McLuckey

2010

Self Cite

Gas-phase dissociation of model locked nucleic acid (LNA) oligonucleotides and functional LNA-DNA chimeras have been investigated as a function of precursor ion charge state using ion trap collision-induced dissociation (CID). For the model LNA 5 and 8 mer, containing all four LNA monomers in the sequence, cleavage of all backbone bonds, generating a/w-, b/x-, c/y-, and d/z-ions, was observed with no significant preference at lower charge states. Base loss ions, except loss of thymine, from the cleavage of N-glycosidic bonds were also present. In general, complete sequence coverage was achieved in all charge states. For the two LNA-DNA chimeras, however, dramatic differences in the relative contributions of the competing dissociation channels were observed among different precursor ion charge states. At lower charge states, sequence information limited to the a-Base/w-fragment ions from cleavage of the 3=C-O bond of DNA nucleotides, except thymidine (dT), was acquired from CID of both the LNA gapmer and mixmer ions. On the other hand, extensive fragmentation from various dissociation channels was observed from post-ion/ion ion trap CID of the higher charge state ions of both LNA-DNA chimeras. This report demonstrates that tandem mass spectrometry is effective in the sequence characterization of LNA oligonucleotides and LNA-DNA chimeric therapeutics. (J Am Soc Mass Spectrom 2010, 21, 144 -153)

“…In the past few decades, continuous efforts have been devoted to the investigation of the dissociation reactions of charged compounds derived from protonation [4][5][6][7][8] or deprotonation [9][10][11][12][13]. On the other hand, the mass spectrometric fragmentations of metal cationized, especially lithiated biomolecules, have attracted much attention because of the desire to measure intrinsic metal ion affinity and identify the binding sites [14,15], and because the interesting dissociation pathways exhibited by these compounds are usually different from the protonated and deprotonated analogues [16,17].…”

mentioning

confidence: 99%

Gas Phase Chemistry of Li⁺with Amides: the Observation of LiOH Loss in Mass Spectrometry

Guo

Zhou

Liu

et al. 2012

of N-phenylbenzamide and N-phenylcinnamide. Loss of LiOH was essentially the sole fragmentation reaction observed for the former. For the latter, both losses of LiOH and H 2 O were discovered. The presence of electron-donating substituents of the phenyl ring of these compounds was found to facilitate elimination of LiOH, while that loss was retarded by electron-withdrawing substituents. Proposed fragment ion structures were supported by elemental compositions deduced from ultrahigh resolution Fourier transform ion cyclotron resonance tandem mass spectrometry (FTICR-MS/MS) m/z value determinations. Density functional theory-based (DFT) calculations were performed to evaluate potential mechanisms for these reactions.