Nucleic acid base complexes with thiotepa as revealed by field ionization mass spectrometry

Rapid Comm Mass Spectrometry

Heuvel

et al. 2006

Self Cite

The effect of cone voltage (CV) variation on the mass spectral pattern of the bisquaternary ammonium salt decamethoxinum in the electrospray ionization (ESI) mode was studied. The advantage of decamethoxinum as a test compound in ESI mass spectrometry lies in the production of two types of precursor ions, i.e. the doubly charged organic dication Cat 2R and its singly charged cluster with a Cl S counterion, Cat Á Cl R . This makes it possible to monitor the fragmentation patterns of these ions under identical experimental conditions. Pronounced qualitative and quantitative changes in the ESI mass spectra were observed upon a gradual increase of the CV. The model compound decamethoxinum allowed us to reveal the extreme situation, in which the mass spectra at a CV below and over approximately 100 V look quite different, in that they contain different product ions of Cat 2R and Cat Á Cl R . While this effect may be much less pronounced for other classes of organic compounds, it should be properly taken into account for the adequate description of fragmentation pathways of bisquaternary ammonium compounds with ESI. Comparison of ESI, FAB-SIMS and MALDI mass spectra of decamethoxinum shows that taking into account CV effects also permits us to gain information on energy deposition into ions generated with the different ionization techniques. 10,[37][38][39][40][41][42] It is believed that the CV effect is due to an in-source collision-induced dissociation (CID) (up-front CID) process. The initially sprayed charged species can undergo collisions with the residual or bath gas on their path between the nozzle and the skimmer, and the change of the ion velocity caused by CV variation affects their kinetic energy and, consequently, their collision energy. 18The possibility of controlling the charge state of the ions, the desolvation process and the degree of fragmentation of the ions by CV variation offers the prospect of many useful applications of this technique, mainly in studies of supramolecular noncovalent complexes. [25][26][27][28][29][30][31][32][33][34][35][36] For example, a method was suggested for evaluating the stability of chemotherapeutic non-intercalating drugs binding to DNA on the basis of monitoring DNA-drug complex decomposition upon CV increase, which correlates with the thermal decomposition of the complex. 25,26 CV adjustment is also of critical importance in probing the structures of surfactant micelles generated under ESI conditions. 30,31 In-source CID is used along with collision-cell tandem mass spectrometric (MS/MS) CID in studies of protein structures. [19][20][21][32][33][34][35][36] Comparison of in-cell CID and in-source CID 32 permits us to obtain more comprehensive information on the molecular structures of analytes. A method, denoted as energydependent ESI mass spectrometry (EDESI-MS), employing CV variation, has been reported for fragmentation studies of metalloorganic compounds.

Section: Resultssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 99%

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The effect of cone voltage on electrospray mass spectra of the bisquaternary ammonium salt decamethoxinum

Pashynska

Rapid Comm Mass Spectrometry

Heuvel

et al. 2006

Self Cite

“…In our earlier mass spectrometric study on molecular mechanisms of action of antimicrobial drugs based on bisquaternary ammonium compounds,31 we studied decamethoxinum which has shown strong dependence of the types of several precursor ions produced and of their fragmentation patterns on the desorption/ionization technique applied and on the variation of some experimental parameters within one technique 32. In this connection we have suggested that a more detailed study of this particular compound can contribute to clarification of the mechanism of the fragmentation of bisquaternary compounds and throw light on the question of the stability of the organic dications in the gas phase.…”

mentioning

confidence: 99%

On the stability of the organic dication of the bisquaternary ammonium salt decamethoxinum under liquid secondary ion mass spectrometry

Pashynska

Rapid Comm Mass Spectrometry

Gömöry

et al. 2005

In the course of a liquid secondary ion mass spectrometric (SIMS) investigation on a bisquaternary ammonium antimicrobial agent, decamethoxinum, unusual pathways of fragmentation of the organic dication M2+ of this bisquaternary salt, with preservation of the doubly charged state of the fragments, were observed. To reveal the structural and electronic parameters of decamethoxinum, which are responsible for the stabilization of its organic dication in the gas phase, a comprehensive SIMS study using metastable decay, collision-induced dissociation and kinetic energy release techniques complemented by ab initio quantum chemical calculations was performed. Pathways of fragmentation of two main precursors originating from decamethoxinum-organic dication M2+ and its cluster with a Cl- counterion [M.Cl]+-and a number of their primary fragments were established and systematized. Differences in the pathways of fragmentation of M2+ and [M.Cl]+ were revealed: the main directions of [M.Cl]+ decay involve dequaternization similar to thermal degradation of this compound, while in M2+ fragmentation via loss of one and two terminal radicals with preservation of the doubly charged state of the fragments dominates over charge separation processes. It was shown that pairing of the dication with a Cl- anion does not preserve the complex from fragmentation via separation of two positively charged centers or neutralization (dequaternization) of one such center. At the same time the low abundance of M2+ in the SIMS spectra is to a larger extent controlled by a probability of M2+ association with an anion than by the decay of the dication per se. Quantum chemical calculations of the structural and electronic parameters of the decamethoxinum dication have revealed at least three features which can provide stabilization of the doubly charged state. Firstly, in the most energetically favorable stretch conformation the distance between the quaternary nitrogens (rN1-N2=1.39 nm) is relatively large. Secondly, an intramolecular solvation of quaternary groups by carbonyl oxygens of the adjacent groups of the dication occurs, which contribute to structural stabilization. Thirdly, an important feature of the electronic structure of the dication is the presence of a partial negative charge on the nitrogen atoms and smearing of a positive charge mainly over the hydrogens of alkyl groups attached to the quaternary nitrogens, which reduces the net repulsion between the quaternary groups. The possible influence of charge smearing on the kinetic energy released on the dication fragmentation is discussed.

“…Proceeding from this, FAB mass spectra of thiotepa mixtures with nucleic acid bases were obtained (the choice of these substances was connected with the continuation of the work started in Ref. 15 dealing with the study of the thiotepa pharmacological activity). It turned out that the mass spectra of the mixtures mentioned contained only the peaks corresponding to thiotepa, i.e.…”

Section: Fast Atom Bombardment Mass Spectra Of Thiotepamentioning

confidence: 99%

Fast atom bombardment mass spectra of thiotepa

Shelkovsky

Boryak

et al. 1991

Org. Mass Spectrom.

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Fast Atom Bombardment Mass Spectra of ThiotepaIn the present paper fast atom bombardment (FAB) mass spectra of both positive and negative ions of the N,N',N"-triethylenethiophosphamide ((DN-),-P-S) used in oncology as the antitumour drug thiotepa are obtained, and some details concerning its behaviour in mixtures are discussed. We should point out at once that in this case our attention was drawn not by one more spectrum of a substance, but by the mechanism of its origin.In Fig. l(a) the FAB mass spectrum of thiotepa dissolved in 0.1 M concentration in glycerol matrix is presented. The mass spectrum consists of the protonated molecular ion [MH]', m/z 190 and fragment ions with m/z 147, 115, 104-106,63 and 42 with appropriate isotope peaks. The peaks mentioned are of high absolute intensity, more than an order of magnitude greater than the background chemical noise, so the latter is omitted in the figure.The distinctive feature of this spectrum is the complete absence of the glycerol matrix signals (m/z 93 and 185).The main peak in the negative-ion FAB mass spectrum of thiotepa is m/z 32, corresponding to sulphur. For negative ions the pronounced effect of background suppression was not detected.To elucidate the formation mechanism of the thiotepa FAB mass spectrum it is of interest to compare it with the spectra obtained in other ionization modes. The comparison of the positive-ion FAB with the chemical ionization (CI)' and the electron impact (EI) mass spectra of thiotepa ( Fig. l(b)) obtained independently in four different laboratories2-' indicates a coincidence of the form of the molecular ion [MH]' in FAB and CI, and complete qualitative, and to a high extent quantitative, coincidence of the fragmentation in FAB and EI. The relation of the molecular ion abundance to the most intensive fragment with m/z 147 in FAB (-40%) is somewhat lower than in EI (-90%). The mentioned peculiarities of the FAB mass spectrum may be explained in the light of the information obtained in recent papers,'*8 in which, by means of tandem mass spectrometry, the direct evidence was obtained proving that for certain substances giving simultaneously molecular M+' and protonated molecular [MH]' ions in FAB the fragment region is represented as superposition of fragments formed by an EI-like mechanism from M", and by ( C ) [M-S]" [M] '* [M-N4]'bM-S]'' [2M]*' 78.5 94.5 318 CL-150 200 loo m / r SO Figure 1. Mass spectra of thiotepa obtained at different ionization modes: (a) FAB; (b) El;=5 and (c) FI.3*6 a chemical ionization (C1)-like mechanism from [MH]'.Moreover, in some cases the intensity of the ion M+' may be vanishingly small because its fragmentation in FAB resembles hard fragmentation in the EI when the energy of the electrons is more than 70 eV.' The picture observed for thiotepa agrees well with this model and it seems reasonable that in this case the FAB mass spectrum may consist of the CI-like [MH]+ ion with negligible fragmentation and the EI-like fragments characteristic of M", which itself is vanishingly small. Of course we...