Uracil Fragment Research Articles

Synthesis of 2-isoxazolines and isoxazoles with uracil fragments

By 1,3-dipolar cycloaddition to nitrile N -oxide obtained from 6-methyluracyl-5-carboxymidoyl chloride, compounds containing an allyl component or propargyl alcohol, a number of 2-isoxazolines and isoxazole with uracil fragments were synthesized.

Synthesis of 4,5-Dihydro-1,2-oxazoles and 1,2-Oxazole Containing Uracil Fragments

Synthesis of 4,5-Dihydro-1,2-oxazoles and 1,2-Oxazole Containing Uracil Fragments

Innovative antimicrobial substances based on uracil S-derivatives.

The problem of antimicrobial resistance is an important global public health challenge. We propose that a development of new antibiotic compounds around known natural substances is a solution to this problem. We investigate reengineer natural products into potent antibiotics. Uracil fragment is abundant in nature and significant to treat infectious diseases due to its affection to the replication of the bacterial chromosome. 12 new uracil S-derivatives were obtained and tested for their in vitro antimicrobial properties. N3 -(thietan-3-yl)- and N3 -(1,1-dioxothietan-3-yl)uracils derivatives were synthesized by thietanylation of 6-methyluracil with 2-chloromethylthiirane and subsequent oxidation of the thietan ring. A method of their alkylation with ethyl-2-chloroacetate was developed and acetohydrazides containing 3-(thietan-3-yl)- and 3-(1,1-dioxothietan-3-yl)uracilyls fragments in the acetyl group were obtained by hydrazinolysis of 2-(thietanyluracil-1-yl)acetic acid ethyl esters. Their interaction with β-dicarbonyl compounds, anhydride of mono- and dicarboxylic acids was studied. Antimicrobial activity was determined by the agar diffusion method on test organisms: S. aureus, E. coli, P. vulgaris, K. pneumoniae, C. diversus, E. aerogenes, P. aeruginosa, S. abosit. N-acyl-5-hydroxypyrazolines and N,N'-diacylhydrazines of 6-methyluracil thietanyl- and dioxothietanyl derivatives showed high antimicrobial activity, which is consistent with the results of structure activity relationship analysis (MIC 0.1-10μg/ml).

Synthesis of Natural Product-Like Tricyclic Higher-Carbon Sugar Nucleosides

Because of the structural novelty and interesting biological profiles, the synthesis of higher-carbon sugars has been highly pursued. In this work, we first synthesized a series of structurally novel bis-uracil containing tricyclic higher-carbon sugar nucleosides (4a–e) using D-xylose as the starting material and the classical Vorbruggen glycosylation as the key synthetic step. The yields of the target compound were good. Unfortunately, despite the presence of pharmaceutically relevant uracil fragment, compounds 4a–e were inactive against the proliferation of several cancer cell lines (EC109, EC9706, PC-3, and MGC-803). Whether and how 4a–e functioned as anticancer agents would be further studied in our laboratory.

Acid-Base Equilibrium of a 6-Methyluracil Derivative with 1,2,3-Triazole Fragment in Aqueous Solutions

The constants and thermodynamic characteristics of the acid-base equilibrium between the first synthesized 6-methyluracil derivative with a 1,2,3-triazole ring at the C(5) atom of the uracil ring—5-(1-pentyl-4-methyl-1,2,3-triazol-4-yl)-6-methyluracil (1)—and its model compound 5,6-dimethyluracil were determined by potentiometric titration in aqueous solutions. It was shown that the 1,2,3-triazole ring does not significantly affect the acid-base properties of the uracil fragment in compound 1. The deprotonation sites of compound 1 in aqueous alkaline and DMSO solutions were suggested. The structure of compound 1 was proved by NMR and IR spectroscopy and elemental analysis.

Position of the Benzene Ring Substituent Regulates the Excited-State Deactivation Process of the Benzyluracil Systems.

A systematic theoretical study of the regulating effect of the substituent position on the photoinduced deactivation process of the benzyluracil systems has been performed based on the high-level static electronic structure calculations and on-the-fly full-dimensional excited-state dynamics simulations. Similarities and differences coexist for the two systems by comparative studies on the photoinduced deactivation process of the 5-benzyluracil (5-BU) and 6-benzyluracil (6-BU) systems. They both obey an S2 → S1 → S0 two-step decay pattern, and the decay coordinates of the S2 → S1 and S1 → S0 processes are mainly driven by the elongation of the bridging bond and the out-of-plane ring deformation motion, respectively. However, the puckering motion occurring at the C2 atom in the uracil fragment dominates the decay pathway of the 5-BU system. On the contrary, the puckering motion at the C5 atom in the benzene fragment mainly drives the decay coordinate of the 6-BU system. Therefore, the substituent position could play significant roles in the deactivation process of the benzyluracil systems. Moreover, the S1 → S0 decay process of the 6-BU system consists of five pathways, possessing a more complex deactivation picture than the 5-BU system. The fitted time scale of the puckering motion is compatible with the experimentally observed lifetimes. This work provides a fundamental understanding of the photophysical and photochemical properties of the benzyluracil systems and can give rational suggestions to further design or regulate the bionic molecular systems.

Ionization and fragmentation of uracil upon microhydration.

We study at the DFT level the ionization and the fragmentation of uracil in the presence of zero, one and two water molecules, to unravel the effect of microhydration on the reactivity of this nucleobase. We show that the microhydration lowers the adiabatic and vertical ionization potentials by 0.41 eV and 0.22 eV, respectively. Furthermore, microhydration increases the activation energies of the different dissociation channels up to 0.5 eV and restricts the formation of some fragments, in particular those corresponding to the C5-C6 fragmentation pathway. For the first time, our theoretical study shows new transition states and minima not found for the gas phase, hence indicating a change in the fragmentation mechanisms, as well as a stabilizing effect of microhydration, confirming previous experimental studies.

Synthesis of Endic Anhydride Adducts with Uracil Fragments

Synthesis of Endic Anhydride Adducts with Uracil Fragments

Multi-temperature study of potassium uridine-5'-monophosphate: electron density distribution and anharmonic motion modelling.

Uridine, a nucleoside formed of a uracil fragment attached to a ribose ring via a β-N1-glycosidic bond, is one of the four basic components of ribonucleic acid. Here a new anhydrous structure and experimental charge density distribution analysis of a uridine-5'-monophosphate potassium salt, K(UMPH), is reported. The studied case constitutes the very first structure of a 5'-nucleotide potassium salt according to the Cambridge Structural Database. The excellent crystal quality allowed the collection of charge density data at various temperatures, i.e. 10, 100, 200 and 300 K on one single crystal. Crystal structure and charge density data were analysed thoroughly in the context of related literature-reported examples. Detailed analysis of the charge density distribution revealed elevated anharmonic motion of part of the uracil ring moiety relatively weakly interacting with the neighbouring species. The effect was manifested by alternate positive and negative residual density patterns observed for these atoms, which `disappear' at low temperature. It also occurred that the potassium cation, quite uniformly coordinated by seven O atoms from all molecular fragments of the UMPH- anion, including the O atom from the ribofuranose ring, can be treated as spherical in the charge density model which was supported by theoretical calculations. Apart from the predominant electrostatic interactions, four relatively strong hydrogen bond types further support the stability of the crystal structure. This results in a compact and quite uniform structure (in all directions) of the studied crystal, as opposed to similar cases with layered architecture reported in the literature.

The role of the environment in the ion induced fragmentation of uracil.

The fragmentation of uracil molecules and pure and nano-hydrated uracil clusters by (12)C(4+) ion impact is investigated. This work focuses on the fragmentation behavior of complex systems and the effect of the environment. On the one hand, it is found that the environment in the form of surrounding uracil or water molecules has a significant influence on the fragmentation dynamics, providing an overall 'protective' effect, while on the other hand we observe the opening of specific fragmentation channels. In particular, we report on the first observation of a series of hydrated fragments. This indicates a strong interaction between uracil and water molecules, holding the water clusters bound to the observed molecular fragments.

Supramolecular systems based on dicationic pyrimidine-containing surfactants and polyethyleneimine

Aggregates based on a novel pyrimidine-containing amphiphile containing three uracil fragments were quantitatively characterized. The critical micelle concentration (CMC) is 2 mmol L–1 and the degree of binding of counterions is β = 0.95, which is consistent with the low zeta potential of the micelles equal to +5 mV. Aggregates with a diameter of 45 nm are formed in the CMC region, and in the region of higher concentrations the aggregates are rearranged to micelle-like particles. In the presence of hydrophilic polymer polyethyleneimine, the CMC significantly decreases (to 0.2 mmol L–1), the degree of binding of counterions decreases, and the electrokinetic potential increases. The size of the aggregates in the binary system is 6—7 nm.

Fragmentation of uracil after electron capture by doubly charged ions

Single electron capture from molecular uracil (C4H4N2O2) by doubly-charged He2+, C2+, and O2+ atomic ions followed by the fragmentation of uracil ions has been studied using time-of-flight mass-spectrometry at the collision velocity range 0.13–0.65 a.u. The uracil ion fragmentation mechanism has been clarified by the arrival time correlation analysis for all ion-fragments produced in a single collision. Electron capture with ionization cross section has been determined from experiment. As shown, single electron capture in reaction of uracil with C2+ leads to high fragmentation probability of the resulting uracil ion. The role of electron core rearrangement in the C2+ and O2+ atomic ions is discussed.

Hybrid mesoporous silica nanoparticles with pH-operated and complementary H-bonding caps as an autonomous drug-delivery system.

Mesoporous silica nanoparticles (MSNPs) are functionalized with molecular-recognition sites by anchoring a triazine or uracil fragment on the surface. After loading these MSNPs with dyes (propidium iodide or rhodamine B) or with a drug (camptothecin, CPT) they are capped by the complementary fragments, uracil and adenine, respectively, linked to the bulky cyclodextrin ring. These MSNPs are pH-sensitive and indeed, the dye release was observed at acidic pH by continuously monitored fluorescence spectroscopy studies. On the other hand, no dye leakage occurred at neutral pH, hence meeting the non-premature requirement to minimize side effects. In vitro studies were performed and confocal microscopy images demonstrate the internalization of the MSNPs and also dye release in the cells. To investigate the drug-delivery performance, the cytotoxicity of CPT-loaded nanoparticles was tested and cell death was observed. A remarkably lower amount of loaded CPT in the MSNPs (more than 40 times less) proved to be as efficient as free CPT. These results not only demonstrate the drug release after pore opening under lysosomal pH, but they also show the potential use of these MSNPs to significantly decrease the amount of the administered drug.

Rational Design of a Solvatochromic Fluorescent Uracil Analogue with a Dual‐Band Ratiometric Response Based on 3‐Hydroxychromone

Fluorescent nucleoside analogues with strong and informative responses to their local environment are in urgent need for DNA research. In this work, the design, synthesis and investigation of a new solvatochromic ratiometric fluorophore compiled from 3-hydroxychromones (3HCs) and uracil fragments are reported. 3HC dyes are a class of multi-parametric, environment-sensitive fluorophores providing a ratiometric response due to the presence of two well-resolved bands in their emission spectra. The synthesized conjugate demonstrates not only the preservation but also the improvement of these properties. The absorption and fluorescence spectra are shifted to longer wavelengths together with an increase of brightness. Moreover, the two fluorescence bands are better resolved and provide ratiometric responses across a broader range of solvent polarities. To understand the photophysical properties of this new fluorophore, a series of model compounds were synthesized and comparatively investigated. The obtained data indicate that uracil and 3HC fragments of this derivative are coupled into an electronic conjugated system, which on excitation attains strong charge-transfer character. The developed fluorophore is a prospective label for nucleic acids. Abstract in Ukrainian: .

Multi-photon ionization and fragmentation of uracil: Neutral excited-state ring opening and hydration effects

Multi-photon ionization (MPI) of the RNA base uracil has been studied in the wavelength range 220-270 nm, coinciding with excitation to the S2(ππ*) state. A fragment ion at m/z = 84 was produced by 2-photon absorption at wavelengths ≤232 nm and assigned to C3H4N2O(+) following CO abstraction. This ion has not been observed in alternative dissociative ionization processes (notably electron impact) and its threshold is close to recent calculations of the minimum activation energy for a ring opening conical intersection to a σ(n-π)π* closed shell state. Moreover, the predicted ring opening transition leaves a CO group at one end of the isomer, apparently vulnerable to abstraction. An MPI mass spectrum of uracil-water clusters is presented for the first time and compared with an equivalent dry measurement. Hydration enhances certain fragment ion pathways (particularly C3H3NO(+)) but represses C3H4N2O(+) production. This indicates that hydrogen bonding to water stabilizes uracil with respect to neutral excited-state ring opening.

Trimerization of nitriles in the synthesis of multipyrimidinophanes

Multimacrocycles, i.e., compounds in which several macrorings are covalently linked by intermolecular bridges, are promising subjects for studies due to their potential unique aggregation and complexing properties. Multicalixarenes [1], multicyclodextrins [2, 3], multiporphyrins [4–6], and combinations of different covalently linked macrocycles [7, 8] have been synthesized and are extensively studied. In the present communication we describe the synthesis of macrocyclic compounds containing uracil fragments, pyrimidinophanes, and a new method for their covalent binding with each other to obtain a multimacroring, multipyrimidinophane. At present, multipyrimidinophanes are known, in which two “monomeric” pyrimidinophane units are linked through intermolecular paraand meta-phenylenedimaleimide [9], 4,4′-diphenol [10], and methylene [11] bridges. We now report on the synthesis of multipyrimidinophane consisting of three macrocyclic units attached to the carbon atoms of 1,3,5-triazine ring via trimerization of CN groups to 1,3,5-triazine structure. Successful cyclotrimerization of nitriles to 1,3,5-triazines requires quite severe conditions (high temperature and pressure) [12]. Cyanamide derivatives undergo cyclotrimerization more readily than nitriles [13–15]. For example, dialkylcyanamides react with trifluoromethanesulfonic anhydride under mild conditions to give the corresponding 1,3,5-triazines in almost quantitative yield [16, 17]. Both sterically hindered cyanamides and those containing various heteroatoms (N, O, S) in the substituents can be involved in this reaction. By reaction of 1,3-bis(5-bromopentyl)-6-methyluracil (I) with disodium cyanamide in acetonitrile we obtained 22% of pyrimidinophane II containing a cyanamide fragment in the decamethylene linker (Scheme 1). The H NMR spectrum of II was typical of other pyrimidinophanes consisting of one uracil fragment and 10 methylene group in the bridge; namely, protons in the methylene groups on the uracil nitrogen atoms (CH2 and CH2) were magnetically nonequivalent [18], and they resonated as four multiplets in the region δ 4.45–3.62 ppm. Pyrimidinophane II was treated with trifluoromethanesulfonic anhydride in methylene chloride. The reaction was accompanied by heat evolution, and the product was assigned the structure of multipyrimidinophane III formed as a result of trimerization of the ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 7, pp. 1096–1098. © Pleiades Publishing, Ltd., 2013. Original Russian Text © A.E. Nikolaev, V.E. Semenov, I.V. Galyametdinova, L.F. Saifina, D.R. Sharafutdinova, V.S. Reznik, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 7, pp. 1110–1112.

Cytosinium orotate dihydrate

The title compound, C4H6N3O+·C5H3N2O4 −·2H2O or Cyt+·Or−·2H2O, was synthesized by a reaction between cytosine (4-amino-2-hy­droxy­pyrimidine, Cyt) and orotic acid (2,4-dihy­droxy-6-carb­oxy­pyrimidine, Or) in aqueous solution. The two ions are joined by two N+—H⋯O− (±)-(CAHB) hydrogen bonds, forming a dimer with graph-set motif R 2 2(8). In the crystal, the ion pairs of the asymmetric unit are joined by four N—H⋯O inter­actions to adjacent dimers, forming hydrogen-bonded rings with R 2 2(8) graph-set motif in a two-dimensional network. The formation of the three-dimensional array is facilitated by water mol­ecules, which act as bridges between structural sub-units linked in R 3 2(8) and R 3 2(7) hydrogen-bonded rings. The orotate anion is essentially planar, as the dihedral angle between the planes defined by the carboxylate group and the uracil fragment is 4.0 (4)°.

Ultrafast non-adiabatic fragmentation dynamics of doubly charged uracil in gas and liquid phase

We have studied the fragmentation of uracil in both gas phase and water environments. We have applied a combination of time-dependent density functional theory and Born-Oppenheimer molecular dynamics methods to investigate fragmentation of doubly-charged uracil. We also present the results of new ion/ion coincidence measurements in which uracil fragments are produced in collisions with 100 keV protons. Breaking of the molecule in more than two fragments mainly arises from inner shell two-electron vacancies. Orbitals of similar energy and/or localized in similar bonds can lead to very different fragmentation patterns, thus showing the importance of the intramolecular chemical environment. Simulations performed in a liquid environment predict the formation of very different fragments.

Electron transfer-induced fragmentation of thymine and uracil in atom–molecule collisions

Ion-pair formation has been studied in hyperthermal (30-100 eV) neutral potassium collisions with gas phase thymine (C(5)H(6)N(2)O(2)) and uracil (C(4)H(4)N(2)O(2)). Negative ions formed by electron transfer from the alkali atom to the target molecule were analysed by time-of-flight (TOF) mass spectrometry. The most abundant product anions are assigned to CNO(-) and (U-H)(-)/(T-H)(-) and the associated electron transfer mechanisms are discussed. Special emphasis is given to the enhancement of ring breaking pathways in the present experiments, notably CNO(-) formation, compared with free electron attachment measurements.

Intra- and intermolecular interactions in the series of acyclic and macrocyclic compounds containing nucleotide bases and their derivatives

Intra-and intermolecular interactions in acyclic compounds containing nucleotide base (uracil and thymine) derivatives and their macrocyclic analogs (pyrimidinophanes) were studied by IR, UV, luminescence, and NMR spectroscopy. Molecules of these compounds include one or two N3-methylsubstituted or N3-unsubstituted uracil fragment or two adenine fragments linked through a hexamethylene spacer to an uracil, 5,5′-methylenediuracil or diphenylmethane fragment. The examined compounds almost all are characterized by π-π interactions and intramolecular hydrogen bonding between the terminal uracil or adenine fragments. Intramolecular association constants were determined and factors affecting them were discussed. Complex formation of acyclic and macrocyclic ligands with adenine and thymine derivatives was studied. The low values of the association constants were interpreted in terms of a competition between intra-and intermolecular bonding and very labile ligand structure.