Electron scattering from molecules and molecular aggregates of biological relevance

In this Topical Review we survey the current state of the art in the study of low energy electron collisions with biologically relevant molecules and molecular clusters. We briefly describe the methods and techniques used in the investigation of these processes and summarise the results obtained so far for DNA constituents and their model compounds, amino acids, peptides and other biomolecules. The applications of the data obtained is briefly described as well as future required developments

Site selectivity of halogen oxygen bonding in 5- and 6-haloderivatives of uracil

Seven 5-and 6-halogenated derivatives of uracil or 1-methyluracil (halogen = Cl, Br, I) were studied by single crystal X-ray diffraction. In contrast with pure 5-halouracils, where the presence of N-H…O and C-H…O hydrogen bonds prevents the formation of other intermolecular interactions, the general ability of pyrimidine nucleobases to provide electron donating groups to halogen bonding was confirmed in three crystals and cocrystals containing uracil with the halogen atom at the C6 position. In the latter compounds, among the two nucleophilic oxygen atoms in the C=O moiety, only the urea carbonyl oxygen O1 can act as halogen bond acceptor, being not saturated by conventional hydrogen bonds. The halogen bonds in pure 6-halouracils are all rather weak, as supported by Hirshfeld surface analysis. The strongest interaction was found in the structure of 6- iodouracil, which displayed the largest (13%) reduction of the sum of van der Waals (vdW) radii for the contact atoms. Despite this, halogen bonding plays a rol

Ultrafast Dynamics of a Nucleobase Analogue Illuminated by a Short Intense X-ray Free Electron Laser Pulse

Citation: Nagaya, K., Motomura, K., Kukk, E., Fukuzawa, H., Wada, S., Tachibana, T., . . . Ueda, K. (2016). Ultrafast Dynamics of a Nucleobase Analogue Illuminated by a Short Intense X-ray Free Electron Laser Pulse. Physical Review X, 6(2), 9. doi:10.1103/PhysRevX.6.021035Understanding x-ray radiation damage is a crucial issue for both medical applications of x rays and x-ray free-electron-laser (XFEL) science aimed at molecular imaging. Decrypting the charge and fragmentation dynamics of nucleobases, the smallest units of a macro-biomolecule, contributes to a bottom-up understanding of the damage via cascades of phenomena following x-ray exposure. We investigate experimentally and by numerical simulations the ultrafast radiation damage induced on a nucleobase analogue (5-iodouracil) by an ultrashort (10 fs) high-intensity radiation pulse generated by XFEL at SPring-8 Angstrom Compact free electron Laser (SACLA). The present study elucidates a plausible underlying radiosensitizing mechanism of 5-iodouracil. This mechanism is independent of the exact composition of 5-iodouracil and thus relevant to other such radiosensitizers. Furthermore, we found that despite a rapid increase of the net molecular charge in the presence of iodine, and of the ultrafast release of hydrogen, the other atoms are almost frozen within the 10-fs duration of the exposure. This validates single-shot molecular imaging as a consistent approach, provided the radiation pulse used is brief enough

Ionic liquids: A pharmaceutical perspective

In the last decades, ionic liquids (ILs) progressed from chemical curiosities to interesting biological compounds apprehending the attention of researchers of distinct areas, from chemistry to pharmacology. Initially, ILs were explored as materials for diverse applications due to the possibility of synthesize compounds with targeted chemical properties combined with selected physical properties. More recently, the emergence of ILs with biological activity revolutionized the scientific focus of these compounds and opened interesting perspectives regarding their pharmaceutical application. From the pharmaceutical point of view, an IL approach, in the design of novel active pharmaceutical ingredients (APIs), appears to be appropriate as it enables the chemical manipulation of the compounds with specific objectives related with the manufacturing process, the stability of the formulation, bioavailability and eventual adverse effects. Furthermore, even though crystallinity confers advantages during isolation, processing and storage of the drug, it is known that solid forms of APIs often suffer from low solubility and polymorphic conversion which can influence negatively the bioavailability of the drug and ultimately its therapeutic effect. On a distinct perspective, the possibility of engineering the properties of ILs by manipulating anion-cation combinations, in association with their solvent properties and in some cases water-miscibility, are considered promising characteristics regarding the applicability of ILs as solvents or carriers of pharmaceutical drugs. In this chapter it is intended to expose the pharmaceutical potential of ILs through the discussion of their utilization either as APIs or solvents/carriers of pharmaceutical drugs. The discussion will be centered on the benefits of the IL approach for the development of novel drug candidates considering not only physico-chemical aspects but also the pharmaceutical profile of the developed active pharmaceutical ingredients with IL properties. Considering the utilization of ILs as solvents of drugs or as part of drug delivery systems, it is anticipated that the discussion will be focused on the efficiency and toxicity of the systems and on their influence on the pharmacokinetics and pharmacodynamics of the vehiculated drugs. It is also planned to debate the motivations for the pharmaceutical usage of ILs as well as their peculiar properties that launched them in this context. Currently, the pharmaceutical utilization of ILs is one of the most relevant applications of these solvents, with impact on the safety and effectiveness of the involved processes and with benefits in terms of pharmaceutical formulations and pharmacological activity. It is our belief that this chapter is adequate for the book in project and can greatly enhance its acceptance and interest by readers in distinct research areas

5-Halogenated pyrimidine lesions within a CpG sequence context mimic 5-methylcytosine by enhancing the binding of the methyl-CpG-binding domain of methyl-CpG-binding protein 2 (MeCP2)

Perturbations in cytosine methylation signals are observed in the majority of human tumors; however, it is as yet unknown how methylation patterns become altered. Epigenetic changes can result in the activation of transforming genes as well as in the silencing of tumor suppressor genes. We report that methyl-CpG-binding proteins (MBPs), specific for methyl-CpG dinucleotides, bind with high affinity to halogenated pyrimidine lesions, previously shown to result from peroxidase-mediated inflammatory processes. Emerging data suggest that the initial binding of MBPs to methyl-CpG sequences may be a seeding event that recruits chromatin-modifying enzymes and DNA methyltransferase, initiating a cascade of events that result in gene silencing. MBD4, a protein with both methyl-binding and glycosylase activity demonstrated repair activity against a series of 5-substituted pyrimidines, with the greatest efficiency against 5-chlorouracil, but undetectable activity against 5-chlorocytosine. The data presented here suggest that halogenated pyrimidine damage products can potentially accumulate and mimic endogenous methylation signals

Fragmentation processes of ionized 5-fluorouracil in the gas phase and within clusters

We have measured mass spectra for positive ions produced from neutral 5-fluorouracil by electron impact at energies from 0 to 100 eV. Fragment ion appearance energies of this (radio-)chemotherapy agent have been determined for the first time and we have identified several new fragment ions of low abundance. The main fragmentations are similar to uracil, involving HNCO loss and subsequent HCN loss, CO loss, or FCCO loss. The features adjacent to these prominent peaks in the mass spectra are attributed to tautomerization preceding the fragmentation and/or the loss of one or two additional hydrogen atoms. A few fragmentions are distinct for 5-fluorouracil compared to uracil, most notably the production of the reactive moiety CF+. Finally, multiphoton ionization mass spectra are compared for 5-fluorouracil from a laser thermal desorption source and from a supersonic expansion source. The detection of a new fragment ion at 114 u in the supersonic expansion experiments provides the first evidence for a clustering effect on the radiation response of 5-fluorouracil. By analogy with previous experiments and calculations on protonated uracil, this is assigned to NH3 loss from protonated 5-fluorouracil