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Although natural or artificial modified pyrimidine nucleobases represent important molecules with valuable properties as constituents of DNA and RNA, no systematic analyses of the structural aspects of bromo derivatives of cytosine have appeared so far in the literature. In view of the biochemical and pharmaceutical relevance of these compounds, six different crystals containing proton-transfer derivatives of 5-bromocytosine are prepared and analyzed in the solid-state by single crystal X-ray diffraction. All six compounds are organic salts, with proton transfer occurring to the Nimino atom of the pyridine ring. Experimental results are then complemented with Hirshfeld surface analysis to quantitively evaluate the contribution of different intermolecular interactions in the crystal packing. Furthermore, theoretical calculations, based on different arrangements of molecules extracted from the crystal structure determinations, are carried out to analyze the formation mechanism of halogen bonds (XBs) in these compounds and provide insights into the nature and strength of the observed interactions. The results show that the supramolecular architectures of the six molecular salts involve extensive classical intermolecular hydrogen bonds. However, in all but one proton-transfer adducts, weak to moderate XBs are revealed by C–Br…O short contacts between the bromine atom in the fifth position, which acts as XB donor (electron acceptor). Moreover, the lone pair electrons of the oxygen atom of adjacent pyrimidine nucleobases and/or counterions or water molecules, which acts as XB acceptor (electron donor).

Epigenetic modifications in DNA are strongly linked to the triggering and development of pathophysiological disorders and cancer diseases. The halogenation of DNA via radical species, particularly the formation of 5-chlorocytosine (ClC), has recently emerged as epigenetic modification. This work deals for the first time with the exploration of the electrochemical behaviour of ClC on different carbon electrodes such as glassy carbon and boron-doped diamond using cyclic voltammetry and square wave voltammetry. When comparing both carbon materials, the use of glassy carbon turned out to be the appropriate in terms of a more well-defined anodic wave and higher sensitivity. The electrochemical oxidation potential of ClC resulted to be linearly dependent on the pH with a maximum current intensity in acetic acid buffer solution under the conditions used. Moreover, a linear response between peak current intensity and ClC concentration was obtained within the range of 200 and 1000 μM with a limit of detection of 200 μM. In order to elucidate the reaction mechanism of the process, the main oxidation products after a preparative electrolysis were detected by HPLC-MS. Simultaneous detection of ClC in the presence of the unmodified cytosine and mixtures containing other nucleic bases such as guanine, adenine and thymine was also addressed. Finally, the effect of the halogen atom (X = F, Cl, Br) located at position C-5 of the cytosine entity upon the electrooxidation process was examined by theoretical calculations, too. [ABSTRACT FROM AUTHOR]

Highlights: [•] The spectra of 5-BrC in the solid and in the isolated state were simulated. [•] In the IR Ar matrix spectrum were identified the bands related to the two tautomers. [•] The scaled wavenumbers of our tetramer model are in accordance to the experimental. [•] The effect of the Br atom is more notorious in 5-BrC than in 5-bromouracil. [•] All the cytosine tautomers have relative energies lower than those in uracil. [Copyright &y& Elsevier]

We isolated an intrastrand crosslink product from the Pyrex-filtered UV light irradiation of 5-BrdCpdC in aqueous solution. ESI-MS, MS/MS, and 2-D nuclear Overhauser effect spectroscopy (NOESY) results showed that the C5 carbon atoms of the two cytosines are covalently bonded. The same cross-link product can also be induced from the similar UV irradiation of dCp5-BrdCpdA and dCp5-BrdCpdT. [ABSTRACT FROM AUTHOR]

Oxidative modification of nucleic acids has been implicated in carcinogenesis. One potential mechanism involves halogenation by the myeloperoxidase and eosinophil peroxidase systems of phagocytes. In the current studies, three mass spectrometric methods for the in vitro and in vivo analysis of halogenated cytosines and deoxycytidines were compared: gas chromatography–electron ionization–mass spectrometry (GC-EI-MS) with a quadrupole instrument, fast atom bombardment or electrospray ionization (ESI) tandem MS with a four-sector magnetic instrument, and liquid chromatography ESI tandem MS (HPLC-ESI-MS/MS) with an ion-trap instrument. GC-EI-MS with selected ion monitoring of dimethyl-tert-butylsilyl derivatives of nucleobases was the most sensitive method. High-energy collisionally induced dissociation MS/MS analysis with a four-sector magnetic instrument yielded detailed structural information about halogenated nucleoside adducts but required relatively large amounts of material. The most sensitive analysis of intact halogenated deoxycytidine was achieved with extracted ion chromatograms using HPLC-ESI-MS/MS with an ion-trap instrument. Our results indicate that GC-EI-MS is the methodology of choice for ultrasensitive analysis of halogenated cytosines. HPLC-ESI-MS/MS provides greater structural detail for these compounds and may rival GC-EI-MS in sensitivity with more advanced liquid chromatography applications. The mass spectrometric methods we have developed should be useful for evaluating the role of phagocyte-derived oxidants in halogenating nucleobases, nucleosides, and DNA at sites of inflammation. [Copyright &y& Elsevier]

The relative stability of three intratriplex DNAs with substitution of 5-bromocytosines for cytosines in different strands and the corresponding unsubstituted intratriplex have been respectively investigated by molecular mechanics calculation. The results showed that intratriplex YTC with substitution occurring in strand III is the most stable and YTCY with substitution occurring in both strand I and III is the most unstable. Sugar conformations of the four intratriplexes are mainly C3’-endo. However, there are more C2’-endo sugar conformations in YTCY than in other intratriplexes, especially in strand I and III. Thus intratriplex YTCY is the combination of A-DNA and B-DNA, the other three intratriplexes are classical A-type DNA. [ABSTRACT FROM AUTHOR]

Although natural or artificial modified pyrimidine nucleobases represent important molecules with valuable properties as constituents of DNA and RNA, no systematic analyses of the structural aspects of bromo derivatives of cytosine have appeared so far in the literature. In view of the biochemical and pharmaceutical relevance of these compounds, six different crystals containing proton-transfer derivatives of 5-bromocytosine are prepared and analyzed in the solid-state by single crystal X-ray diffraction. All six compounds are organic salts, with proton transfer occurring to the Nimino atom of the pyridine ring. Experimental results are then complemented with Hirshfeld surface analysis to quantitively evaluate the contribution of different intermolecular interactions in the crystal packing. Furthermore, theoretical calculations, based on different arrangements of molecules extracted from the crystal structure determinations, are carried out to analyze the formation mechanism of halogen bonds (XBs) in these compounds and provide insights into the nature and strength of the observed interactions. The results show that the supramolecular architectures of the six molecular salts involve extensive classical intermolecular hydrogen bonds. However, in all but one proton-transfer adducts, weak to moderate XBs are revealed by C–Br...O short contacts between the bromine atom in the fifth position, which acts as XB donor (electron acceptor). Moreover, the lone pair electrons of the oxygen atom of adjacent pyrimidine nucleobases and/or counterions or water molecules, which acts as XB acceptor (electron donor). [ABSTRACT FROM AUTHOR]