Thymine Moieties Research Articles

Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties

Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties

A diaminotriazine-functionalized polydiacetylene for colorimetric sensing of thymine and oligothymidine

The development of analytical methods for qualitative and quantitative detection of DNA and its core bases has attracted great attention. In this study, a diaminotriazine (DAT)-containing polydiacetylene (PDA-DAT) colorimetric sensor was developed for selective detection of thymine and oligothymidine. PDA-DAT displayed a blue-to-purple color change in the presence of thymine with a detection limit of 12.6 nM. FTIR analysis demonstrated that the color change is associated with formation of multiple hydrogen bonds between the DAT and thymine moieties in a molecular recognition process. As a consequence of the hydrogen bonding interactions, a change in the conformation of the PDA conjugated backbone takes place, causing an absorption spectral shift and corresponding color change. The PDA-DAT sensor system also selectively detects oligothymidine (40 mer) with a detection limit of 14.6 nM. The results of this study should serve as a foundation for the design of colorimetric sensors for thymine and oligothymidine.

Modulation of flexo-rigid balance in photoresponsive thymine grafted copolymers towards designing smart healable coating.

Efficacy and durability of the photovoltaic device mandates its protection against hot, humid weather condition, high energy of UV light and unwanted scratches. Such challenges can be mitigated by smart polymeric coating with inherent properties e.g. hydrophobicity to prevent moisture, optimal viscocity for better processibility and crack-healing. The hydrophobic polymers TP1–TP4 containing pendant photo-crosslinkable thymine moieties are designed that undergo [2 + 2] photocycloaddition upon UVB irradiation and can be dynamically reverted back upon irradiation with UVC light. A judicious control of solvent environment, chain length, functionality% and concentration of the polymers regulate the aspects of photodimerization thereby, rendering intra or inter-chain collapse to form diverse nanostructures. Photodimerization of the thymine moieties renders coil to globule transformation in dilute condition whereas irradiation performed at high macromolecular concentration regime exhibits higher order nanostructures. The photoresponsive chain collapse leads to the formation of rigid crosslinked domains within flexible polymer chains akin to the hard–soft phases of thermoplastic elastomers. Such rigidification of the crosslinked segments endows a tool to photomodulate the glass transition temperature (Tg) that can dynamically revert back upon decrosslinking. Further, the structural modulation of the polymers is explored towards autonomic and nonautonomic self-healing behaviour at ambient conditions. Moreover, the self-healing efficacy can be tuned with the film thickness and it remains unaltered upon using solar simulator or direct sunlight. Overall, such hydrophobic low Tg polymers display photo-regulated self-healing mechanism consisting of both autonomic and non-autonomic self-healing and may find applications in designing smart protective coatings for photovoltaic devices.

Supramolecular Architecture through Self-Organization of Janus-Faced Homoazanucleosides.

Design of Janus-faced or double-headed homoazanucleosides with the possibility to undergo self-organization through base pairing has been conceptualized and accomplished. The synthetic strategy demonstrates the unique ability to introduce two similar or complementary nucleobases on opposite arms of a chiral polyhydroxypyrrolidine while also ensuring that their faces are anti to each other to allow only intermolecular interactions between the nucleobases, an essential requisite for self-assembly. Single-crystal X-ray structures were determined for all three types of homoazanucleosides, one possessing two adenine molecules, the other with two thymine moieties, and the third containing both adenine and thymine. The crystal structures of all three display noncovalent interactions, including Watson-Crick base pairing, Hoogsteen H-bonding, and π-π stacking, resulting in unusual supramolecular patterns. The most striking supramolecular motif among them, which emerged from the crystal structure of the homoazanucleoside containing both adenine and thymine, is a left-handed helix formed through Watson-Crick pairing between nucleobases. The present study thus forms a prelude to the design of Janus-faced building blocks to establish helical pillars as well as lateral branches that together define a three-dimensional (3D) lattice. The ready accessibility of these molecules is expected to spur the next generation of discoveries in the design of functional nanomaterials.

Programmed Recognition between Complementary Dinucleolipids To Control the Self-Assembly of Lipidic Amphiphiles.

One of the major goals in systems chemistry is to create molecular assemblies with emergent properties that are characteristic of life. An interesting approach toward this goal is based on merging different biological building blocks into synthetic systems with properties arising from the combination of their molecular components. The covalent linkage of nucleic acids (or their constituents: nucleotides, nucleosides and nucleobases) with lipids in the same hybrid molecule leads, for example, to the so-called nucleolipids. Herein, we describe nucleolipids with a very short sequence of two nucleobases per lipid, which, in combination with hydrophobic effects promoted by the lipophilic chain, allow control of the self-assembly of lipidic amphiphiles to be achieved. The present work describes a spectroscopic and microscopy study of the structural features and dynamic self-assembly of dinucleolipids that contain adenine or thymine moieties, either pure or in mixtures. This approach leads to different self-assembled nanostructures, which include spherical, rectangular and fibrillar assemblies, as a function of the sequence of nucleobases and chiral effects of the nucleolipids involved. We also show evidence that the resulting architectures can encapsulate hydrophobic molecules, revealing their potential as drug delivery vehicles or as compartments to host interesting chemistries in their interior.

Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides.

Homonucleoside analogues cis-16 and trans-17 having a (5-methoxycarbonyl)isoxazolidine framework were synthesized via the 1,3-dipolar cycloaddition of nucleobase-derived nitrones with methyl acrylate. Hydrogenolysis of the isoxazolidines containing thymine, dihydrouracil, theophylline and adenine moieties efficiently led to the formation of the respective γ-lactam analogues. γ-Lactam analogues having 5-bromouracil and 5-chlorouracil fragments were synthesized by treatment of uracil-containing γ-lactams with NBS and NCS. Isoxazolidine and γ-lactam analogues of homonucleosides obtained herein were evaluated for activity against a broad range of DNA and RNA viruses. None of the compounds that were tested exhibited antiviral or cytotoxic activity at concentrations up to 100 µM. The cytostatic activities of all compounds toward nine cancerous cell lines was tested. γ-Lactams trans-15e (Cl-Ura) and cis-15h (Theo) appeared the most active toward pancreatic adenocarcinoma cells (Capan-1), showing IC50 values 21.5 and 18.2 µM, respectively. Isoxazolidine cis-15e (Cl-Ura) inhibited the proliferation of colorectal carcinoma (HCT-116).

The Photoaddition of a Psoralen to DNA Proceeds via the Triplet State.

Psoralens are natural compounds that serve in the light dependent treatment of certain skin diseases (PUVA therapy). They are DNA intercalators that upon photoexcitation form adducts with thymine bases. For one psoralen derivative, 4'-aminomethyl-4,5',8-trimethylpsoralen (AMT), the photoreactions are characterized here by nanosecond UV-vis and IR absorption spectroscopy. The triplet state of AMT is identified as the reactive one. On the 1-10 μs time scale this local triplet state transforms into a triplet biradical bearing one single bond between the addends. Within ∼50 μs this biradical forms the final adduct featuring a cyclobutane ring. This kinetic behavior is in stark contrast to the closely related photoaddition of two thymine moieties within the DNA. Origins of the differences are discussed.

TDG Gene Polymorphisms and Their Possible Association with Colorectal Cancer: A Case Control Study.

Genetic alterations that might lead to colorectal cancer involve essential genes including those involved in DNA repair, inclusive of base excision repair (BER). Thymine DNA glycosylase (TDG) is one of the most well characterized BER genes that catalyzes the removal of thymine moieties from G/T mismatches and is also involved in many cellular functions, such as the regulation of gene expression, transcriptional coactivation, and the control of epigenetic DNA modification. Mutation of the TDG gene is implicated in carcinogenesis. In the present study, we aimed to investigate the association between TDG gene polymorphisms and their involvement in colon cancer susceptibility. One hundred blood samples were obtained from colorectal cancer patients and healthy controls for the genotyping of seven SNPs in the TDG gene. DNA was extracted from the blood, and the polymorphic sites (SNPs) rs4135113, rs4135050, rs4135066, rs3751209, rs1866074, and rs1882018 were investigated using TaqMan genotyping. One of the six TDG SNPs was associated with an increased risk of colon cancer. The AA genotype of the TDG SNP rs4135113 increased the risk of colon cancer development by more than 3.6-fold, whereas the minor allele A increased the risk by 1.6-fold. It also showed a 5-fold higher risk in patients over the age of 57. SNP rs1866074 showed a significant protective association in CRC patients. The GA genotype of TDG rs3751209 was associated with a decreased risk in males. There is a significant relationship between TDG gene function and colorectal cancer progression.

The remarkable UV light invulnerability of thymine GNA dinucleotides.

We herein demonstrate the UV resistance of glycol nucleic acid (GNA) dinucleotides. This resistance sustains the hypothesis of GNA as a nucleic acid prebiotic ancestor on early Earth, a time of intense solar UV light. Such photorobustness, due to the absence of intrastrand base stacking, could offer an opportunity for nanodevice development requiring challenging UV conditions.

Helical supramolecular self-assembly by prolamide thymidine/uridine analogues

ABSTRACTThis report describes the syntheses of rationally designed non-sugar nucleoside as prolamide nucleosides which contain prolyl ring and pyrimidine nucleobases (uracil/thymine) via acetamide bonds. These nucleosides have propensity to form distinctive self-assembly supramolecular helical structures ubiquitously through Watson-Crick/reverse type of hydrogen bonding with nucleobases. Moreover, the prolyl acetamide backbone groups- carbonyl (-C = O) and hydroxyl (-OH) group, are also involved in strengthening of self-assembled helical structures. Importantly, both prolamide thymidine and prolamide uridine have shown two distinctive helical structural patterns, in spite of containing the same backbone. Hence thymine and uracil moieties of prolamide nucleosides are responsible for unique supramolecular helical structural architectures.

Pyrene-nucleobase conjugates: synthesis, oligonucleotide binding and confocal bioimaging studies.

Fluorescent pyrene–linker–nucleobase (nucleobase = thymine, adenine) conjugates with carbonyl and hydroxy functionalities in the linker were synthesized and characterized. X-ray single-crystal structure analysis performed for the pyrene–C(O)CH2CH2–thymine (2) conjugate reveals dimers of molecules 2 stabilized by hydrogen bonds between the thymine moieties. The photochemical characterization showed structure-dependent fluorescence properties of the investigated compounds. The conjugates bearing a carbonyl function represent weak emitters as compared to compounds with a hydroxy function in the linker. The self-assembly properties of pyrene nucleobases were investigated in respect to their binding to single and double strand oligonucleotides in water and in buffer solution. In respect to the complementary oligothymidine T10 template in water, compounds 3 and 5 both show a self-assembling behavior according to canonical base–base pairing. However, in buffer solution, derivative 5 was much more effective than 3 in binding to the T10 template. Furthermore the adenine derivative 5 binds to the double-stranded (dA)10–T10 template with a self-assembly ratio of 112%. Such a high value of a self-assembly ratio can be rationalized by a triple-helix-like binding, intercalation, or a mixture of both. Remarkably, compound 5 also shows dual staining pattern in living HeLa cells. Confocal microscopy confirmed that 5 predominantly stains mitochondria but it also accumulates in the nucleoli of the cells.

Selective adsorption of modified nucleoside cancer biomarkers by hybrid molecularly imprinted adsorbents.

Modified adenosine nucleosides have been proposed to be potential DNA-based biomarkers for early diagnosis of tumor and a promising tool for the development of noninvasive prediction systems. However, the low concentration of modified adenosine nucleosides in physiological fluids makes them challenging for both quantitative and qualitative determination. Therefore, materials, which are potentially useful for selective adsorption of nucleobase-containing compounds, were obtained. To obtain the adsorbents, the silica gel particles were coated layer-by-layer with films of the polymers with different combinations of polymers containing thymine groups. Next, the microspheres were irradiated with UV light in the presence of 2'-deoxyadenosine or 5'-deoxy-5'-(methylthio)adenosine, as template molecules, which resulted in the photodimerization of thymine moieties and molecular imprinting of adsorbed modified adenosine compounds. The selectivity of the adsorption was significantly enhanced by the photoimprinting process. Eventually, the imprinted particles have shown an improved ability to recognize mainly 2'-deoxyadenosine and 5'-deoxy-5'-(methylthio)adenosine molecules. The best performing adsorbent was obtained using modified natural polysaccharides. The studied materials could serve as promising adsorbents of biomarkers for tumor diagnostics.

Pressure-sensitive adhesive utilizing molecular interactions between thymine and adenine

A simple pressure-sensitive adhesion (PSA) system incorporating noncovalent interaction between thymine and adenine is presented. A copolymer having thymine moieties is combined with a low-molecular-weight bifunctional adenine cross-linker. Molecular interactions caused by multiple hydrogen bonds between the thymine and adenine units are evaluated by FT-IR spectral measurement. Mechanical properties of the PSA are examined by stress–strain curves and dynamic mechanical analysis. As the number of adenine cross-linkers increases, Young's modulus increases from 0.24 to 3.0 MPa, and the glass transition temperature increases. Furthermore, it is found that the PSAs have adequate adhesive property from their shear strength test. Heat treatment at 80 °C is effective for reinforcement because of interchange of the hydrogen bonds. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015

The influence of the phosphorothioate diester bond on the DNA oxidation process

Abstract This study describes the influence of the phosphorothioate internucleotide bond on the deoxyribonucleic acid (DNA) oxidation process. The interaction of an ultraviolet radiation (UVA) with a targeted double-stranded (ds) oligonucleotide, in which one strand contains an antraquinone (AQ) moiety on the 5’-end, may lead to a hole migration process through the double helix. In the end, the migration of theformed radical cation terminates in a suitable place. Usually, this is a guanine-rich sequence. In another experiment, phosphorothioate internucleotide bonds were detected in the bacterial genome as a natural modification. In this study, a polyacrylamide gel electrophoresis (PAGE) autoradiogram analysis of irradiated ds-DNA showed that the oxidation reaction was not inhibited by an isolated guanine. Instead, irrespective of the absence or presence of a phosphorothioate bond, the termination of the ds-DNA oxidation process was predominantly observed on the thymine moieties. Based on the obtained results, it can be concluded that in the discussed case, a hole migration by a hopping mechanism is in competition with an oxidation reaction with a superoxide radical anion. Alternatively, the radical cation migration process is sequence-dependent due to its different ionization potentials. Therefore, the presence of a phosphorothioate internucleotide bond did not change the stability of ds-DNA under UVA irradiation conditions.

Progress, perspective, and commercialization of heavy metal ion detection technology into China

Heavy metals contamination resulting from fossil fuel combustion among other sources has been become a focus of the community of nations. New detection methods can help to manage this growing concern. In 2008, Dr. Zang and his colleagues succeeded in building a fluorescent sensor based on a perylene modification with two thymine moieties to successfully detect mercury in water. Through the sub-national EcoPartnership program sponsored by the U.S. and China, the development of this technology has been advanced and is now ready for demonstration as a real time, in situ testing procedure. The Utah-Qinghai EcoPartnership is also helping to facilitate commercialization of new technologies through the coordination of government entities, local universities, and commercial partners. Adapting new technology for deployment in China depends on understanding the specific roles of all these partners. Dr. Dingman offers an instructive insight on new technology implementation based on his years of involvement with Chinese government agencies and research institutions. Finally, new advances in intellectual property (IP) protection are enabling the successful deployment of useful technologies into China.

A highly sensitive and reversible chemosensor for Hg(2+) detection based on porphyrin-thymine conjugates.

In this study, we demonstrated a highly sensitive, selective, and reversible chemosensor for Hg(2+) determination. This chemosensor was synthesized by direct condensation of thymin-1-ylacetic acid with zinc tetraaminoporphyrin, which has a porphyrin core as the fluorophore and four thymine (T) moieties as the specific interaction sites for Hg(2+) . The probe (4T-ZnP) exhibited split Soret bands with a small peak at 408 nm and a strong band at 429 nm in a dimethylformamide/H2 O (7/3, v/v) mixed solvent as well as a strong emission band at 614 nm. Upon the addition of Hg(2+) , the probe displayed strong fluorescence quenching due to the formation of T-Hg(2+) -T complexes. With the aid of the fluorescence spectrometer, the chemosensor in the dimethylformamide/H2 O (7/3, v/v) mixed solvent (0.3 μM) exhibited a detection limit of 6.7 nM. Interferences from other common cations, such as Co(2+) , K(+) , Sn(2+) , Zn(2+) , Cu(2+) , Ni(2+) , Mn(2+) , Na(+) , Ca(2+) , Mg(2+) , Pb(2+) , and Cd(2+) , associated with Hg(2+) analysis were effectively inhibited.

Synthesis, physicochemical characteristics, and biocompatibility of self-assemble polymers bearing guanine, cytosine, uracil, and thymine moieties

We synthesized chemically well-defined brush (i.e., comb-like) polymers bearing guanine, cytosine, uracil, or thymine moieties at the bristle ends. The polymers were stable up to 220 °C and were readily solution-processable, yielding high-quality films. Interestingly, the brush polymers favorably self-assembled to form molecular multibilayer structures stabilized by hydrogen bonding interactions among the nucleobase moieties at the bristle ends, which provided nucleobase-rich surfaces. The multibilayer-structured polymer films showed high water affinity. They also displayed selective protein adsorption, suppressed bacterial adherence, facilitated cell adhesion, and exhibited good biocompatibility in mice. The brush polymer DNA-mimicking comb-like polymers are suitable as biomaterials and in protein separation applications. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 1151–1160

A dual crosslinked self-healing system: Supramolecular and covalent network formation of four-arm star polymers

Restoration of large volume damage together with mechanical stability of self-healing polymers requires fast and efficient reversible crosslinking processes together with the presence of a static network. We investigate four-arm star polymers as a dual self-healing material, equipped with hydrogen bonding moieties and azide endgroups applicable for crosslinking based on “click” cycloaddition reaction (CuAAC). The concepts takes advantage of additional supramolecular network formation due to supramolecular cluster formation. To this effect four-arm star poly(isobutylene)s were prepared via living carbocationic polymerization (LCCP) in combination with simple endgroup transformation steps and microwave-assisted click-chemistry to introduce thymine moieties as supramolecular tie points. Four-arm star thymine-telechelic PIB was obtained as a tough rubbery material as proven via melt-rheology and SAXS measurements with clusters of ≈10 hydrogen bonding moieties resulting in a self-healing response at room temperature. To enable the design of a doubly crosslinked self-healing system, four-arm star PIBs bearing an average of 1.7 azide groups and 2.3 thymine endgroups/polymer were crosslinked with a three-arm star alkyne-telechelic PIB. A weakly crosslinked covalent network reinforced by supramolecular hydrogen bonding interactions was obtained in which “click”-crosslinking reduces the number of clustered hydrogen bonds from ≈10 to ≈8. Macroscopic self-healing studies of the double covalent and supramolecular network structure revealed fast and multiple self-healing at 20 °C within 24 h. The now designable four-arm star polymers enabled the design of a highly efficient self-healing system based on double network formation due to “click”-crosslinking and supramolecular cluster formation.

Polymeric/silicagel hybrid molecularly photoimprinted adsorbents for adenosine and its derivatives

The adsorbents of adenosine, a potential cancer biomarker present in physiological fluids, urine in particular, were obtained and studied. The adsorbents were fabricated by coating submicron-sized silica gel particles with ultrathin layers of polymers containing thymine moieties. The thymine groups selectively adsorbed compounds containing adenine, a nucleobase complementary to thymine, via the formation of hydrogen bonds. Irradiation of the adsorbents with light selectively absorbed by thymine chromophores in the presence of adenine as a template molecule resulted in the photochemical molecular imprinting of adenine. The non-imprinted adsorbent showed preferential adenosine adsorption from a solution containing a mixture of nucleosides. The adenine-imprinted materials showed considerably higher than non-imprinted adsorbents selectivity of adenosine adsorption versus other nucleosides.

Free energy landscapes of the encapsulation mechanism of DNA nucleobases onto carbon nanotubes

The confinement mechanism of DNA nucleobases onto single-walled carbon nanotubes is probed at physiological temperature (310 K) using classical molecular dynamics and fully atomistic molecular potentials. The corresponding free energy landscapes are constructed in terms of two order parameters, ξ1 and ξ2, for both purine (adenine) and pyrimidine (thymine) moieties, by a metadynamics scheme. Two zig-zag topologies, (16, 0) and (23, 0), are employed as solid models with limiting skeletal diameters, D = 1.25 nm and D = 1.8 nm, respectively, considering hydrophobic and electrically charged nanopores, q = +0.05 e−/C. The uncharged nanotubes always exhibit a single free energy minimum located close to the pore center, regardless of individual diameter, whereas the charged nanotubes either inhibit encapsulation or exhibit two energetically distinct confining regions, at the center and close to the pore termini. Very interestingly, the purely hydrophobic solids exhibit a quasi-isotropic free-energy landscape around the nanopore center, F (ξ1, ξ2). Independent umbrella sampling calculations show that for the (23, 0) electrically charged nanotubes, the probability maximum at a distance of Ω = 0.54 nm from the pore center is the global one for adenine. These subtle differences are quantified by decomposing the interaction energy between a nucleobase and the solid into its dispersive and electrostatic contributions, and a critical comparison with DFT and experimental data for graphite is discussed. Purine and pyrimidine show similar interaction energies within the hydrophobic nanopores, however, adenine confinement results in slightly more stable hybrids by 0.9–1.4 kJ mol−1; binding affinity increases with the nanotube curvature as a result of enhanced dispersive energy. The detailed thermodynamical analysis reported herein is of paramount importance to study the sequence specific properties of DNA/carbon nanotube hybrids.