Uracil Units Research Articles

The solvatochromic effect of functionalized 6-aminoracil derivatives in light of DFT: FT-IR, TD-DFT, NBO, and FMO studies

Uracil-based compounds have increasing attention in material design for different applications as well as pharmaceutical purposes. Accordingly, the key electronic reasons underlying the solvatochromic effect and possible activity features by using quantum chemical computations should be explored in detail. This work focuses on the structural, electronic, and optical properties of the aminouracil derivatives to explore the key electronic-related properties that affect the solvatochromism features. The molecular geometries of the 1,3-dimethyl-5-(arylazo)-6-aminouracil derivatives were optimized using the DFT method at the B3LYP/6–31++G(d,p) basis set level. The solvent-phase simulations of the studied derivatives were utilized using the PCM (Polarized Continuum Model). The TD-DFT approach was employed to enlighten UV–visible characteristics such as possible electronic transitions, energies, and oscillator strengths. The NBO (Natural Bond Orbital) method was used to predict the possible intramolecular charge transfer and delocalization, as well as the interactions between donor-acceptor molecular orbitals. TD-DFT computations revealed that the bonded group within the arylazo ring would affect solvatochromic properties such as electronic excitation energies and transitions in the UV-Vis regions. The NBO analysis revealed that the electron movement from the lone pair of N atoms on the uracil unit to neighbor unfilled orbitals contributed to reducing the stabilization energy.

Evolution of uracil based thymidine phosphorylase inhibitors, SAR and electronic correlation: revisit

AbstractThymidine phosphorylase (TPase), a dimeric proteinaceous enzyme is responsible for elevation of drug resistance and cell apoptosis. Increased TPase levels lead to angiogenesis which is a major culprit for the metastasis and cancer in the body. Hence, an efficient approach for anticancer drug discovery is based up on inhibition of thymidine phosphorylase enzyme. Solving of the crystal structure of TPase made the drug discovery easier. Legion of drugs was designed and synthesized having a wide variety of structural moieties and different functionalities such as phosphonic acid, amines, arylamines, acetamides, benzoyl, esters, amides, and so forth. Among the structural designs and models engineered, uracil is one of the structural motifs utilized for drug design. In this review, uracil is chosen where in structural unit with its structural modifications were summarized. Uracil unit could be structurally modified at its N1, N3, C5, and C6 positions to afford innumerable uracil derivatives. In general consensus, N1‐ and N3‐substituted uracil derivatives resulted in diminished/lower inhibitory activities which might be attributed to reduced acidic character. Whereas, substitution at 5‐ and 6‐positions have yielded fruitful results and excellent thymidine phosphorylase inhibitors prevailed. Furthermore, uracil possessing nucleoside uridine/deoxyuridine was also derivatized to afford potential TPase inhibitors. 3′‐ & 5′‐Hydroxyl groups of uridine/deoxyuridine were also exploited for derivative preparation and some of them were found to be potent TPase inhibitors.

Design, Synthesis and Biological Activity of Dipeptide Derivatives Bearing Uracil Unit

Design, Synthesis and Biological Activity of Dipeptide Derivatives Bearing Uracil Unit

Synthesis mesomorphic and theoretical studies of some new unsymmetrical dimeric ethers of 6-amino-1,3-dimethyluracil and biphenyl cores

New sets of unsymmetric calamitic molecules with uracil unit at one end and biphenyl core at another end were synthesized. Liquid crystal property of these molecules was investigated by POM and DSC techniques. All compounds exhibit LC property depending on the spacer and terminal alkoxy chain of the molecules. First set shows smectic phase in lower members and nematic phase appeared in higher members. The second set favour nematic liquid crystalline phase with respect to spacer alkyl chain length. Molecules are escaped from the planarity as a result disturbing the layer stacking leads to nematic phase in higher analogues. Theoretical studies have been performed for all the compounds and are found to be in agreement with the results of the current studies.

Cationic surfactant with 1,2,4-triazole- and uracil moieties as amphiphilic building blocks for supramolecular nanocontainers

Novel dicationic surfactant consisting of uracil unit bridging with 1,2,4-triazole moieties has been synthesized. Its aggregation behavior in aqueous solutions and critical micelle concentration value has been characterized by various techniques. Size and charge of aggregates have been evaluated, with agreement between different methods observed. The onset of micellization is shown to occur beyond ca. 3mM, while further structural transition is observed close to ca. 10mM. The solubilization capacity toward hydrophobic dye and micellar rate effect upon hydrolysis of ecological organophosphorus toxicants have been shown, with high substrate specificity observed.

(E)-tert-Butyl 2-(5-{[4-(dimethylamino)phenyl]diazenyl}-2,6-dioxo-1H-pyrimid-in-3-yl)acetate dichloromethane monosolvate.

In the title compound, C18H23N5O4·CH2Cl2, the di­chloro­methane solvent mol­ecule is disordered over two sets of sites in a 0.630 (13):0.370 (13) ratio. The dihedral angle between the uracil and phenyl rings is 30.2 (1)°. In the crystal, the principal inter­actions are N—H⋯O hydrogen bonds, which link uracil units across centres of symmetry, forming eight-membered rings with an R 2 2(8) graph-set motif. The structure also displays C—H⋯O and C—H⋯Cl hydrogen bonds. Intra­molecular C—H⋯O short contacts are also observed.

Synthesis and 2D self-assembly at the liquid–solid interface of novel H-bonding linear π-conjugated oligomers terminated by uracil and melamine units

2D self-assembly of a novel π-conjugated oligomer terminated by two uracil units is solvent dependent and involves multiple intermolecular H-bonds.

Metal binding properties of pyrimidinophanes and their acyclic counterparts

A series of acyclic and macrocyclic nucleobase derivatives that contain uracil and 2-thiocytosine units linked by polymethylene spacers was prepared. The length of spacers as well as the oxidation number of sulfur atoms entering into the structure of the compounds was varied. The crystal structure of pyrimidinophane with hexa- and heptamethylene linkers was established by X-ray analysis. The metal ion-binding properties of pyrimidinophanes and their acyclic counterparts were investigated by liquid extraction and 1H NMR titration experiments. The compounds with 2-thiocytosine fragments revealed a high selectivity of extraction towards Ag+ ions. The stoichiometry of silver complexes and the binding constants have been determined. The antibacterial activity of these complexes was also discussed.

Bismuth oxybromide promoted detoxification of cylindrospermopsin under UV and visible light illumination

Bismuth oxybromide (BiOBr) was prepared and characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS) and UV–vis diffuse reflectance spectroscopy (DRS). The BiOBr promoted detoxification of cylindrospermopsin (CYN) under UV (λ<350nm) and visible light (λ>420nm) illumination was studied. The results revealed that the toxic uracil unit of CYN was removed, and the carboxylic group of the degraded product was also decomposed, to give the innoxious tricyclic guanidine product under the title conditions. In contrast, the traditional Fenton reagents (Fe2+ and H2O2) limited to remove the uracil moiety of CYN with the carboxylic group intact. Presumably, the decarboxylation ability of BiOBr was induced by Br 4p valence band hole (hBr4p+), and the degradation mechanism was also proposed based on the experimental results and theoretical calculation.

On the stability of [(uracil)2-Cu]2+ complexes in the gas phase. Different pathways for the formation of [(uracil-H)(uracil)-Cu]+ monocations

The association of uracil dimers and copper(II) has been studied through the use of B3LYP/6-311+G(3df,2p)//6-31+G(d,p) calculations. Although uracil-Cu(2+) complexes have never been experimentally detected, our results show that [(uracil)2-Cu](2+) is thermodynamically stable with regard to both the proton loss and the fragmentation into (uracil)2(+)˙ + Cu(+), although it is metastable with respect to the coulomb explosion yielding [uracil-Cu](+) + uracil(+)˙. Importantly, a proton transfer from [(uracil)2-Cu](2+) to a third neutral uracil molecule is very exothermic. This is consistent with the fact that when electrospray mass spectrometry techniques are used [(uracil-H)(uracil)-Cu](+) and uracil-H(+) monocations are detected, but not the [(uracil)2-Cu](2+) doubly charged species. In the most stable conformers of [(uracil)2-Cu](2+) the two uracil monomers are held together through the metal cation which forms a linear bridge between two carbonyl groups each belonging to a different monomer. This is at variance with what has been found for complexes involving alkaline-earth dications, such as (uracil)2Ca(2+), in which the metal dication association preserves the network of hydrogen bonds which stabilize the free (uracil)2 dimers. The formation of [(uracil-H)(uracil)-Cu](+) complexes is accompanied by the enolization of the uracil units. All possible mechanisms to reach the experimentally detected [(uracil-H)(uracil)-Cu](+) singly charged ions, either by direct association of Cu(2+) to uracil dimers and posterior deprotonation of the formed complex or through the interaction of Cu(2+) with uracil followed by its deprotonation and subsequent association with a second uracil molecule, have been investigated.

6-(3,5-Dimethyl-benz-yl)-5-ethyl-1-[(2-phenyl-eth-oxy)meth-yl]pyrimidine-2,4(1H,3H)dione.

In the title pyrimidine derivative, C24H28N2O3, the uracil unit is essentially planar with an r.m.s. deviation of 0.0054 (1) Å for the eight non-H atoms. The pyrimidine ring is tilted by a dihedral angle of 77.08 (7)° with respect to the aromatic ring of the 3,5-dimethyl­benzyl substituent, whereas it is nearly parallel to the benzene ring of the pheneth­oxy­methyl unit, with a dihedral angle of 8.17 (8)°. An intra­molecular C—H⋯O hydrogen bond generates an S(6) ring motif. In the crystal, mol­ecules are linked by a pair of amide–uracil N—H⋯O hydrogen bonds into an inversion R 2 2(8) dimer. These dimers are stacked along the b axis through π–π inter­actions with a centroid–centroid distance of 3.9517 (8) Å. Weak C—H⋯π inter­actions are also present.

Facile Aza-Michael Additions of Uracil Derivatives to Acrylates

24 Aza-Michael adducts were synthesised in moderate to excellent yields by the addition of 5-substituted uracils to acrylates with ethylamine as a catalyst. Many of the adducts were obtained in almost quantitive yield without column chromatography. The procedure provideded an efficient approach to the synthesis of N-1 uracil adducts using acrylates as acceptors. The structures of the compounds were determined by 1H NMR, 13C NMR, mass spectra and X-ray crystallography analyses. The uracil unit is present in DNA and related natural products and has a broad spectrum of biological activity.

Oligonucleotide Analogues with Integrated Bases and Backbone. Part 28

AbstractThe protected hydrazide‐linked uracil‐ and adenine‐derived tetranucleoside analogues 17, 19, and 21 were synthesized in solution by coupling the dimeric hydrazines 6 and 10 with the carboxylic acids 7, 11, and 16. These hydrazines and acids were obtained by partially deprotecting the hydrazines 5, 9, and 15, and these were prepared by coupling the hydrazines 3 and 14 with the carboxylic acids 4 and 8. The crystal structure analysis of the fully protected UU dimer 5 showed the formation of an antiparallel cyclic duplex with the uracil units H‐bonded via HN(3) and OC(2). Stacking interactions were observed between the uracil units with a buckle twist of 30.9°, and between the uracil unit II and the fluoren‐9‐yl group of Fmoc (=9H‐fluoren‐9‐yl)methoxycarbonyl). The hydrazide HN(3′) and the CO group of Fmoc form an intramolecular H‐bond. The uracil‐ and adenine‐derived, water‐soluble hydrazide‐linked self‐complementary octamers 23–32 and the non‐self‐complementary uracil derived decamer 33 were obtained by coupling the carboxylic acids 4 and 8 on a solid support. 1H‐NMR Analysis in CDCl3, mixtures of CDCl3 and (D6)DMSO, and (D8)THF showed that the partially deprotected dimers 5, 6, 12, and 13 form weakly associated linear duplexes. The partially deprotected tetramers 17 and 18 do not associate. The hydrazide‐linked octamers 23–32 do not stack in aqueous solution, and the non‐self‐complementary decamer 33 does not stack with the complementary strands of DNA 43 and RNA 42. The Cbz‐protected amide‐linked octamers 51–56 derived from uracil, adenine, cytosine, and guanine were obtained as the main products by solid‐phase synthesis from the carboxylic acids 46–49. The fully deprotected amide‐linked octamers proved insoluble, and could neither be purified nor analysed.

1-(2-Bromo-2-deoxy-β-D-xylofuranosyl)uracil

In the title compound, C9H11BrN2O5, the ribofuran­ose ring has a C2-exo, C3-endo twist configuration and is attached to the uracil unit via a β-N1-glycosidic bond. The crystal structure is stabilized by two inter­molecular O—H⋯O inter­actions and one inter­molecular N—H⋯O inter­action.

Synthesis and structure of pyrimidinophanes with a sulfur atom in the spacer

The cyclization of 1,3-bis(ω-bromoalkyl)uracils with sodium sulfide led to pyrimidinophanes, containing one uracil unit and an S atom in the spacer, macrocyclic structure was confirmed by X-ray data; the S atom in bridge can be oxidized into sulfoxide or sulfone or converted into sulfonium ion.

6,6′-Diamino-1,1′,3,3′-tetramethyl-5,5′-(4-chlorobenzylidene)bis[pyrimidine-2,4(1H,3H)-dione

The title compound, C19H21ClN6O4, is a 1:2 adduct of p-chloro­benzaldehyde and uracil. It crystallizes with two mol­ecules in the asymmetric unit. The two uracil units in the same mol­ecule are connected by a pair of strong N—H⋯O hydrogen bonds. The packing is stabilized by N—H⋯O, C—H⋯O and C—H⋯N inter­actions.

Synthesis and antimicrobial activity of pyrimidinophanes with two uracil units and bridging nitrogen atoms

A series of pyrimidinophanes containing two uracil units and nitrogen atoms in bridging polymethylene chains –(CH2) n N(Et)(CH2) m – (n, m = 5, 6) have been synthesized. The uracil moieties are represented by 6-methyl-, 5-decyl-6-methyl-, and 5-fluorouracils. Quaternization of the bridging N atom with ethylbromide or n-decylbromide yielded amphiphilic pyrimidinophanes, which were evaluated for their antibacterial and antifungal activity in terms of minimal inhibiting concentration (MIC) against Gram-positive and Gram-negative bacteria and fungi. It has been found that MICs of the amphiphilic pyrimidinophanes decrease with increasing lipophilicity of the alkyl substituents at the bridging N atoms and with increasing polymethylene N(pyr)–N chain length (in some cases MIC against Staphylococcus aureus is below 1 ig/mL). The MICs increase dramatically upon introduction of lipophilic n-decyl substituents at C(5) atoms of the uracil moiety. The results can be used in the search for new highly effective antimicrobial agents.

Synthesis, characterization and antiproliferative activity of metal complexes with the Schiff base derived from the condensation 1:2 of 2,6-diformyl-4-methylphenol and 5,6-diamino-1,3-dimethyluracil

A series of mononuclear complexes with Co(II), Ni(II), Cu(II), Zn(II), Hg(II), Mo(VI) and Pd(II) containing the ligand derived from the 1:2 condensation of 2,6-diformyl-4-methylphenol and 5,6-diamino-1,3-dimethyluracil (hereafter denoted as BDFDAAU) were synthesized. The complexes were characterized by elemental analysis, thermogravimetry (TG) and differential scanning calorimetry (DSC), IR, 1H, 13C and 15N NMR, UV–visible–near IR (UV–VIS–NIR), EPR and magnetic measurements. The deprotonated ligand in the phenolic oxygen shows a symmetric tridentate coordination mode through the two azomethine nitrogen atoms and the phenolic oxygen atom whereas the coordination of the neutral ligand takes place through the phenolic oxygen atom and one azomethine nitrogen atom. In the Mo(VI) complex, the ligand is bideprotonated in the phenolic oxygen and an amino group from one uracil unit; so, the coordination mode changes again into an asymmetric way: phenolic oxygen atom, one azomethine nitrogen atom and the nitrogen atom from the deprotonated amino group. The antiproliferative behaviour against the five human tumor cell lines (human neuroblastoma NB69, human breast cancer MCF-7 and EVSA-T, human glioma H4 and human bladder carcinoma cell line ECV) suggested a modulator behaviour, according to the concentration, of cell growth due to their estrogen-like characteristics.

Triuracils – 1,3‐Bis[ω‐(N‐methyluracil‐1‐yl)alkyl]thymines and Their 5,5′‐Cyclic Counterparts

AbstractA series of acyclic compounds with two 3,6‐dimethyluracil or 3‐methyluracil units attached to a a thymine or isocyanurate fragment by polymethylene or xylylene spacers are investigated. Ring‐closure reactions with paraformaldehyde in aqueous HCl in the presence of copper(I) chloride afforded pyrimidinophanes which can be considered macrocyclic counterparts of the acyclic triuracils. By X‐ray diffraction data the structures of the macrocycles in the solid state are characterised by a close arrangement of the uracil units, but there are no π‐π contacts between them. On the contrary, significant hypochromism of the macrocyclic triuracils compared with their acyclic counterparts indicates stacking between the thymine and 3,6‐dimethyluracil units in chloroform and H2O solutions. The conformational behaviour of the acyclic and macrocyclic compounds in solution has been determined by NMR, UV and computational methods. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2007)

Effects of Microsolvation on the Adenine−Uracil Base Pair and Its Radical Anion: Adenine−Uracil Mono- and Dihydrates

Microhydration effects upon the adenine-uracil (AU) base pair and its radical anion have been investigated by explicitly considering various structures of their mono- and dihydrates at the B3LYP/DZP++ level of theory. For the neutral AU base pair, 5 structures were found for the monohydrate and 14 structures for the dihydrate. In the lowest-energy structures of the neutral mono- and dihydrates, one and two water molecules bind to the AU base pair through a cyclic hydrogen bond via the N(9)-H and N(3) atoms of the adenine moiety, while the lowest-lying anionic mono- and dihydrates have a water molecule which is involved in noncyclic hydrogen bonding via the O4 atom of the uracil unit. Both the vertical detachment energy (VDE) and adiabatic electron affinity (AEA) of the AU base pair are predicted to increase upon hydration. While the VDE and AEA of the unhydrated AU pair are 0.96 and 0.40 eV, respectively, the corresponding predictions for the lowest-lying anionic dihydrates are 1.36 and 0.75 eV, respectively. Because uracil has a greater electron affinity than adenine, an excess electron attached to the AU base pair occupies the pi* orbital of the uracil moiety. When the uracil moiety participates in hydrogen bonding as a hydrogen bond acceptor (e.g., the N(6)-H(6a)...O(4) hydrogen bond between the adenine and uracil bases and the O(w)-H(w)...N and O(w)-H(w)...O hydrogen bonds between the AU pair and the water molecules), the transfer of the negative charge density from the uracil moiety to either the adenine or water molecules efficiently stabilizes the system. In addition, anionic structures which have C-H...O(w) contacts are energetically more favorable than those with N-H...O(w) hydrogen bonds, because the C-H...O(w) contacts do not allow the unfavorable electron density donation from the water to the uracil moiety. This delocalization effect makes the energetic ordering for the anionic hydrates very different from that for the corresponding neutrals.