Thymine Derivatives Research Articles

Transient UV-vis absorption spectroscopic characterisation of 2'-methoxyacetophenone as a DNA photosensitiser.

2'-Methoxyacetophenone (2M) presents improved UVA absorption as compared with other acetophenone derivatives. On the basis of transient infrared spectroscopy it has been previously claimed that 2M is an interesting photosensitiser for cyclobutane pyrimidine dimers (CPDs) formation. In the present paper, a complete UV-Vis transient absorption spectroscopic characterisation of this compound is provided, including triplet-triplet spectra, triplet lifetimes and rate constants for quenching of 2M by a dimeric thymine derivative. Furthermore, generation of singlet oxygen has been proven by time-resolved near IR phosphorescence measurements. Overall, the obtained results confirm the potential of 2M as a DNA photosensitiser, not only for CPDs formation, but also for oxidative damage.

From Hydrogen Peroxide-Responsive Boronated Nucleosides Towards Antisense Therapeutics – A Computational Mechanistic Study

We used a combination of MD simulations and DFT calculations to reveal the precise chemical mechanism underlying the conversion of boronated nucleosides to natural nucleosides in the presence of hydrogen peroxide, which was recently experimentally demonstrated by Morihiro and Obika et al. (Chem. Sci. 2018, 9, 1112). Our results show that this process is initiated by the H2O2 deprotonation to a base concerted with the nucleophilic attack of the resulting OOH– anion onto the boron atom as the rate-limiting step of the overall transformation. This liberates a free base, followed by the 1,2-rearrangement to the C–OOH– adduct. Lastly, breaking of the O–O bond within the peroxide moiety cleaves the boron–carbon bond, giving boronic acid ester and the matching ketone as the final products. The obtained reaction profiles successfully interpret a much higher conversion rate of the thymine derivative over its guanine analogue, and rationalize why t-Bu-hydroperoxide is hindering the conversion, thus placing both aspects in firm agreement with experiments. The offered insight represents a promising tool for the future synthetic approaches of stimuli-responsive biomolecules, especially chemically caged prodrug-type nucleic acid therapeutics, bearing significant importance due to their application potential in diagnostics and therapy of various genetic disorders.

Evaluation of N-Hydroxy-, N-Metoxy-, and N-Acetoxybenzoyl-Substituted Derivatives of Thymine and Uracil as New Substances for Prevention and Treatment of Long-Term Complications of Diabetes Mellitus

New uracil and thymine derivatives, N1-,N3- and N1,N3-(RO-benzoyl)-(1H,3H)-pyrimidine- 2,4-diones, were synthesized (RO- is hydroxy, acetoxy- or methoxy-group). The compounds were studied in a complex of in vitro tests for the ability to inhibit the development of long-term complications of diabetes. Their ability to cleave cross-links of proteins has been evaluated. The most significant ways of pharmacological correction of thrombosis, angio-, nephro-, encephalo-, and cardiopathy, antiglycation, chelating, and antiplatelet activities, have been established. The most active compound in terms of antiplatelet action, N1- hydroxybenzoyluracil, exceeded acetylsalicylic acid by ~44%. In terms of their ability to chelate copper (II) cations, all compounds (with the exception of 1,3-bis(3-hydroxybenzoyl)-(1H,3H)-pyrimidine-2,4-dione that was not not studied in this test) showed the activity, whose IC50 fell in the range between that for pioglitazone (44.1 μM) and pyridoxamine (136.7 μM) comparison drugs. The best antiglycation effect at the 1 mM concentration was observed for N1,N3-bismethoxy- and N1,N3-bisacetoxybenzoyl derivatives of thymine. The maximum activity to cleave cross-links of proteins (C = 1 mM), comparable to that of alagebrium, was established for 1,3-bis(4-methoxybenzoyl)uracil, for which also high rates of other estimated activities were noted. Thus, the N1-,N3- and N1,N3-(RO-benzoyl) derivatives of uracil and thymine are promising basiсs for creating drugs that suppress the development of long-term complications of diabetes.

Methods for detection of cytosine and thymine modifications in DNA

Methylation of cytosine at the 5-position is a common epigenetic modification in mammalian DNA and plays an important role in regulating gene expression. Oxidized derivatives of 5-methylcytosine were discovered recently, and some of these oxidized derivatives, in addition to being intermediates in an active demethylation pathway, might also function as epigenetic modifications. Oxidized derivatives of thymine are known to be products of DNA damage, although evidence exists that the oxidized thymine derivative 5-hydroxymethyluracil might have an epigenetic role. There is a pressing need to learn more about these modifications, as epigenetic modifications have roles in development and in diseases, including cancer. This emerging area of research requires highly accurate and sequence-specific methods for the detection of cytosine and thymine modifications in DNA. In this Review, we introduce the biochemistry of cytosine and thymine modifications and discuss established detection methods, such as bisulfite sequencing and its modifications, as well as newer methods, which have been developed to overcome the substantial obstacles associated with studying these modifications in genomic DNA. The modification of DNA at cytosine and thymine, such as methylation, hydroxylation and formylation, might have epigenetic roles. In this Review, the authors discuss established and newer methods for the detection of these modifications in genomic DNA.

Reaction mechanism of the cation radicals of thymine and thymine derivatives in aqueous solution: A theoretical study

Mechanisms of decomposition reaction of thymine cation radicals (T[Formula: see text]), 1-methyl substituted T[Formula: see text] (1-MeT[Formula: see text]), and 1,3-dimethyl substituted T[Formula: see text] (1,3-Me2T[Formula: see text]) generated by ionizing radiation or one-electron oxidation to thymine, 1-methylthymine and 1,3-dimethylthymine in aqueous solution have been investigated by theoretical calculations. Seven reaction paths including H2O or OH[Formula: see text] addition, and deprotonation were considered. The most likely reaction for T[Formula: see text] decomposition is N1 deprotonation forming T(-N1H)[Formula: see text]. When N1 hydrogen is replaced by methyl, T[Formula: see text] would deprotonate from C5 methyl group generating 1-methyl substituted UCH[Formula: see text] in neutral solution, and reaction with OH[Formula: see text] producing 1-methyl substituted T6OH[Formula: see text] in basic solution. When N1 and N3 hydrogens are both replaced by methyl, T[Formula: see text] decomposition reaction is similar to 1-MeT[Formula: see text], indicating that N3 hydrogen barely influences the subsequent reaction of 1-MeT[Formula: see text]. These results can provide theoretical support for experimental observations.

Aldehyde-hydrate equilibrium in nucleobase 2-oxoethyl derivatives: An NMR, ESI-MS and theoretical study

N-2-oxoethyl derivatives of nucleobases are useful starting materials for the preparation of potentially active nucleoside analogues. The 1HNMR, 13CNMR, DEPT and ESI-MS spectra of adenine and thymine N-2-oxoethyl derivatives reveal that the different species in equilibrium exist mainly in two forms: aldehyde and hydrate. The NMR spectra show that the equilibrium is shifted towards the hydrate form in water-DMSO 2:1, giving equilibrium constants of 8.3 and 5.3 for adenine and thymine derivatives, respectively. ESI-MS experiments show the dependence of equilibrium shift on pH: in the case of the thymine derivative, the effect on the equilibrium is more important than in the case of the adenine derivative; this difference is explained considering different protonation sites in both structures. All assumptions are supported by theoretical calculations, which suggest the important role played by solvent in the stabilization of molecular structures and equilibrium shift. All aspects analyzed in this work are very important in order to understand the further reactivity of these nucleobase derivatives.

EBV感染症治療候補薬1-（2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル）チミン（S-FMAU）の製造法開発

(2-Deoxy-2-fluoro-4-thio-β-d-arabinofuranosyl)thymine (S-FMAU) was synthesized very efficiently from corresponding d-arabinofuranose derivative 16a which was available in bulk. Three important transforming methods were mainly described. One was the practical inversional bromination process for secondary alcohol generated by opening furanose ring. Another was the highly efficient thiofuranose synthesis via intramolecular carbonyl assisted SN2 reaction. And the last was the β-selective glycosylation process with thymine derivative. Applications of the thiofuranose synthesis using intramolecular carbonyl assist were also discussed.

The impact of an extended nucleobase-2′-deoxyribose linker in the biophysical and biological properties of oligonucleotides

The introduction of a novel thymine derivative at the 3′-end of the sense strand generates more potent and selective siRNAs.

Solid-State Photochemical Reaction of Multisubstituted Thymine Derivatives

Solid-state photochemical reactions in crystals, known as topochemical reactions, are solvent-free green chemical reactions that produce stereospecific molecules. The photoreaction of thymine is interesting because the dimeric photoproduct can form four types of stereoisomers and when the dimer is formed in DNA helices it can cause skin cancers. We investigated the photoreaction of five multisubstituted thymine derivatives in the solid-state, which were designed with crystal engineering concepts to promote π–π stacking of benzene rings in the crystal. Powder X-ray diffraction analysis revealed that a para-substituted bis-thymine derivative was aligned along the c axis in the crystal and was susceptible to topochemical reaction to form a polymer, as previously reported. Ortho- and meta-substituted bis-thymine derivatives and a tetrakis-substituted derivative were found to be topochemically unreactive using both gel permeation chromatography (GPC) and X-ray crystal structural analysis. The tris-substituted ...

Anti-mycobacterial activity of thymine derivatives bearing boron clusters

A series of novel thymine derivatives bearing lipophilic, electron-neutral 1,2-dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane or hydrophilic 7,8-dicarba-nido-undecaborate anions were synthesized. Synthesis was performed via copper(I)-catalysed Huisgen-Meldal-Sharpless 1,3-dipolar cycloaddition of N1-propargylthymine or N1,N3-bispropargylthymine to 1-(3-azidopropyl)-1,2-dicarba-closo-dodecaborane. The obtained compounds were tested in vitro against Mycobacterium tuberculosis thymidylate kinase (TMPKmt) and as inhibitors of mycobacteria growth in culture using both saprophytic Mycobacterium smegmatis (M. smegmatis) and pathogenic Mycobacterium tuberculosis (M. tuberculosis) strains. The most potent TMPKmt inhibitor in the series contained two negatively charged 7,8-dicarba-nido-undecaborate modifications at positions 1 and 3 of thymine (9) and exhibited a Ki value of 1.5 μM. The most potent inhibitors of mycobacteria growth was compound 5 with one electron-neutral 1,2-dicarba-closo-dodecaborane modification at position 1 of thymine, and compound 8 with two modifications, at position 1 and 3. Both compounds completely inhibited M. smegmatis proliferation at a concentration of 100 μg/mL (0.25 mM and 0.15 mM, respectively).

Interactions of Some Divalent Metal Ions with Thymine and Uracil Thiosemicarbazide Derivatives

ABSTRACTThe study of interactions between metal ions and nucleobases, nucleosides, nucleotides, or nucleic acids has become an active research area in chemical, biological, and therapeutic fields. In this respect, the coordination behavior of nucleobase derivatives to transition metals was studied in order to get a better understanding about DNA-metal interactions in in vitro and in vivo systems. Two nucleobase derivatives, 3-benzoyl-1-[3-(thymine-1-yl)propamido]thiourea and 3-benzoyl-1-[3-(uracil-1-yl)propamido]thiourea, were synthesized and their dissociation constants were determined at different temperatures and 0.3 ionic strength. Potentiometric studies were carried out on the interaction of the derivatives towards some divalent metals in 50% v/v ethanol-water containing 0.3 mol.dm−3 KCl, at five different temperatures. The formation constants of the metal complexes for both ligands follow the order: Cu2+ > Ni2+ > Co2+ > Zn2+ > Pb2+ > Cd2+ > Mn2+. The thermodynamic parameters were estimated; the complexation process has been found to be spontaneous, exothermic, and entropically favorable.

Novel carbocyclic nucleoside analogs suppress glomerular mesangial cells proliferation and matrix protein accumulation through ROS-dependent mechanism in the diabetic milieu. II. Acylhydrazone-functionalized pyrimidines.

We report herein the synthesis of a novel series of carbocyclic acylhydrazone derivatives of uracil, thymine and cytosine from the corresponding nucleic bases and their biological activity to treat diabetic nephropathy. Intriguingly, five derivatives significantly reduced high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. The anti-oxidative effects displayed by these molecules suggest that their activity might involve a ROS-dependent mechanism.

Selective Transport of Mercury(II) Ions across Supported Liquid Membrane with Thymine Derivative as Carrier

Abstract We describe a new highly selective supported liquid membrane (SLM) system made of a polypropylene flat sheet with a thymine derivative in kerosene as the carrier, for the selective transport of mercury ion. When the carrier existed in the membrane, only mercury ions were selectively transported. This SLM selectively separated mercury ions from a mixed solution of mercury and heavy metal ions. The hydrogen ion concentration in the receiving phase is a dominant factor in the mercury ion transport across the SLM.

Synthesis and anticancer activity studies of ferrocenyl-thymine-3,6-dihydro-2H-thiopyranes – A new class of metallocene-nucleobase derivatives

A convenient synthesis of ferrocenyl-4-thiothymine-3,6-dihydro-2H-thiopyrane (3) and ferrocenyl-thymine-3,6-dihydro-2H-thiopyrane (4) by a hetero-Diels-Alder cycloaddition reaction is reported. These complexes represent new class of ferrocenyl nucleobase derivatives. The 2H-thiopyrane ring mimics the sugar subunit present in natural nucleosides and nucleotides. The X-ray crystal structure analysis of the precursor thioketone (1) showed that individual molecules of 1 form H-bonded dimers in the solid state. Compounds 3 and 4 were tested in vitro for their antiproliferative activity against human colon carcinoma HT-29, estrogen receptor-responsive human breast adenocarcinoma MCF-7, estrogen-negative human breast adenocarcinoma MDA-MB-231, human promyelocytic leukemia HL-60 and human monocytic MonoMac6 cancer cells. Ferrocenyl-4-thiothymine-3,6-dihydro-2H-thiopyrane 3 showed a cytostatic effect on MonoMac6, MCF-7 and HL-60 cell lines, but was devoid of activity on MDA-MB-231 and HT-29 cells. In contrast, all cell lines tested were sensitive toward thymine derivative 4. Proapoptic activity of 3 and 4 was confirmed by means of acridine orange/ethidium bromide (AO/EB) double-staining assay.

Gold nanoparticle-based colorimetric detection of mercury ion via coordination chemistry

A simple, fast, and convenient colorimetric detection of Hg2+ in aqueous media was presented based on the selective binding capability of thymine derivative (N-T) toward Hg2+. N-T decorated AuNPs solution was stable in red color, while the presence of Hg2+ induces significant aggregation of AuNPs along with red-to-blue color changes. Therefore, Hg2+ content in real water samples can be qualitatively detected by our naked eyes; meanwhile, good linear relationship of Hg2+ along with A650nm/520nm values could be obtained for its quantitative determination. Furthermore, our system shows excellent selectivity to mercury ions against any other tested metal ions and anions, and good sensitivity with LOD of 0.8nM in real water samples.

From nucleobases to nucleolipids: an ITC approach on the thermodynamics of their interactions in aqueous solutions.

Hybrid constructions based on nucleosides and lipophilic components, known as nucleolipids, have become an extremely interesting class of molecules, especially for their potential biomedical applications. In this matter, it seemed important to define the nature and estimate the strength of their interaction with polynucleotides by different ways. We report in this work a systematic investigation through isothermal titration calorimetry of the thermodynamics of the association and dissociation of adenine and thymine derivatives, not previously performed. Then we use the results obtained on these simple systems as a basis for comparison with the binding of phospholipids functionalized with adenosine and thymidine to polyadenylic or polyuridylic acids applying the same experimental technique.

Mild steel corrosion inhibition in HCl by di-alkyl and di-1,2,3-triazole derivatives of uracil and thymine

The corrosion inhibition efficiency (IE) of four di-alkyl derivatives of uracil and thymine and six 1,2,3-triazole benzyl derivatives of uracil and thymine compounds was measured in the system: pipeline steel grade API 5L X52/1 M HCl using electrochemical impedance spectroscopy (EIS). The influence of the inhibitor concentration, 5–200 ppm, on the IE of all these compounds was determined. The results obtained showed that in all cases, the IE increased with increasing inhibitor concentration, and that, except for one of the di-alkyl derivatives of uracil, that was capable of attaining solely an IE of 84% at 200 ppm, the remainder displayed IEs greater that 90% at rather low concentrations, namely around 20 ppm. In this sense, the most remarkable inhibitor was one of the 1,2,3-triazole benzyl derivative of uracil, which gave 96% IE with merely 5 ppm. For all cases, it was found that these inhibitors follow a physisorption mechanism, which can be adequately described by the Langmuir isotherm. Moreover, it is shown that these compounds can affect both the anodic and cathodic processes, thus it can be classified as a mixed-type inhibitor capable of blocking both anodic and cathodic sites on the API 5L X52 steel surface immersed in HCl. The influence of the steel immersion time on their IE was also assessed in the corroding media for the two most efficient inhibitors. It is shown that even when the IE of both inhibitors diminished practically linearly as a function of time, both can provide adequate protection (IE > 88%) to the steel substrate even after 350 exposure hours to this highly corrosive media.

Side-Chain Supramolecular Polymers Employing Conformer Independent Triple Hydrogen Bonding Arrays

Derivatives of thymine have been extensively used to promote supramolecular materials assembly. Such derivatives can be synthetically challenging to access and may be susceptible to degradation. The current article uses a conformer-independent acceptor–donor–acceptor array (ureidopyrimidine) which forms moderate affinity interactions with diamidopyridine derivatives to effect supramolecular blend formation between polystyrene and poly(methyl methacrylate) polymers obtained by RAFT which have been functionalized with the hydrogen bonding motifs.

MLR-Based QSAR Models for Predicting Inhibitory Activity of Reverse Transcriptase by HEPT Derivatives using GETAWAY Descriptors

In this study, quantitative structure-activity relationship (QSAR) models for non-nucleoside reverse transcriptase inhibitors based on 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) derivatives were generated. The structures of the compounds and their activities were obtained from the literature. The data set were divided into two sets: training set (N=91) and validating set (N=10). All 3-D structures of these inhibitors were optimized by semi-empirical method, AM1 prior to calculations of 3-D molecular descriptors, GETAWAY. Multiple linear regression (MLR) using stepwise method was applied to determined significant descriptors. Out of 197 GETAWAY descriptors, 4-14 molecular descriptors have significant relationships with the activities (expressed as log (1/EC50)) of HEPT. The MLR method generated 14 models. The predictive power of these models were evaluated internally by applying the following statistical parameters for the training set and test set: root-mean-square error for prediction (RMSE), correlation coefficient (R), squared correlation coefficient (R2), adjusted squared correlation coefficient (R2adj), difference between R2 and R2adj (R2 – R2adj), squared cross-validation correlation coefficient (Q2). External validation was performed by employing Golbraikh and Tropsha criteria. Moreover, residual analysis was performed. Internal validation of Model XX (N = 91) revealed that it has the highest predictive power (RMSE = 0.4288, R = 0.9393, R2 = 0.882, R2adj = 0.8620, R2 - R2adj = 0.0203, Q2 = 0.8317). However, external validation (using the validating set, N=10) showed that Model XII has the highest predictive power (R2 = 0.961, R20 = 0.9565, k = 0.8648, k’ = 0.9800, [R2 - R20] = 0.0066, [R2 - R20] /R2 = 0.0069, R2pred = 0.9481) based on Golbraikh and Tropsha criteria. Residual analysis confirmed that both models are valid.

SYNTHESIS OF 3-O-ARYL ESTERS OF ( R , S )-9-(2,3-DIHYDROXYPROPYL)ADENINE AND ITS PYRIMIDINE ANALOGS AS NEW POTENTIAL INHIBITORS OF S -ADENOSYL- L -HOMOCYSTEINE HYDROLASE

With the aim of searching for new antiviral agents of the acyclonucleoside type, 3-O-aryl esters of (R,S)-9-(2,3-dihydroxypropyl)adenine and its pyrimidine analogs have been synthesized. Alkylation of adenine and cytosine by aryl glycidyl ethers in the presence of potassium carbonate affords 46-76% yields of the corresponding N9- and N1-substituted derivatives. The interaction of aryl glycidyl ethers with trimethylsilyl derivatives of uracil and thymine also results in 41-57% yields of N1-monosubstituted products with identical acyclic chain structure. Authors: A. A. Ozerov, M. S. Novikov, and A. K. Brel’. English Translation in Chemistry of Heterocyclic Compounds , 1999, 35 (1), pp 78-83 http://link.springer.com/article/10.1007/BF02251667