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Mass Spectrometry and Theoretical Studies on N-C Bond Cleavages in the N-sulfonylamidino Thymine Derivatives
Mass Spectrometry and Theoretical Studies on N-C Bond Cleavages in the N-sulfonylamidino Thymine Derivatives
- Publication Year :
- 2015
-
Abstract
- The reactivity of new biologically active thymine derivatives substituted with 2-(arylsulfonamidino)ethyl group at N1 and N3 position was investigated in the gas phase using CID experiments (ESI-MS/MS) and by density functional theory (DFT) calculations. Both derivatives show similar chemistry in the negative mode with a retro-Michael addition (Path A(-)) being the most abundant reaction channel, which correlate well with the fluoride induced retro-Michael addition observed in solution. The difference in the fragmentation of N-3 substituted thymine 5 and N-1 substituted thymine 1 in the positive mode relates to the preferred cleavage of the sulfonyl group (m/z 155, Path B) in N-3 isomer and the formation of the acryl sulfonamidine 3 (m/z 309) via Path A in N-1 isomer. Mechanistic studies of the cleavage reaction conducted by DFT calculations give the trend of the calculated activation energies that agree well with the experimental observations. A mechanism of the retro-Michael reaction was interpreted as a McLafferty type of fragmentation, which includes Hβ proton shift to one of the neighboring oxygen atoms in a 1,5-fashion inducing N1(N3)-Cα bond scission. This mechanism was found to be kinetically favorable over other tested mechanisms. Significant difference in the observed fragmentation pattern of N-1 and N-3 isomers proves the ESI-MS/MS technique as an excellent method for tracking the fate of similar sulfonamidine drugs. Also, the observed N-1 and/or N-3 thymine alkylation with in situ formed reactive acryl sulfonamidine 3 as a Michael acceptor may open interesting possibilities for the preparation of other N-3 substituted pyrimidines.
- Subjects :
- Models, Molecular
Spectrometry, Mass, Electrospray Ionization
Hot Temperature
Stereochemistry
N-sulfonylamidines
Thymine
retro-Michael addition
ESI-MS
DFT calculations
Antineoplastic Agents
Alkylation
Medicinal chemistry
Catalysis
Tosyl Compounds
chemistry.chemical_compound
Fragmentation (mass spectrometry)
Drug Stability
Isomerism
Structural Biology
Tandem Mass Spectrometry
Ethyl group
Spectroscopy
Bond cleavage
Sulfonyl
chemistry.chemical_classification
Sulfonamides
Molecular Structure
Chemistry
Quaternary Ammonium Compounds
Energy Transfer
Michael reaction
Density functional theory
Indicators and Reagents
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....530ca686959dd68f7f08a4f8dbdd9f33