Nucleobases Thymine Research Articles

DNA Gene’s Basic Structure as a Nonperturbative Circuit Quantum Electrodynamics: Is RNA Polymerase II the Quantum Bus of Transcription?

Previously, we described that Adenine, Thymine, Cytosine, and Guanine nucleobases were superconductors in a quantum superposition of phases on each side of the central hydrogen bond acting as a Josephson Junction. Genomic DNA has two strands wrapped helically around one another, but during transcription, they are separated by the RNA polymerase II to form a molecular condensate called the transcription bubble. Successive steps involve the bubble translocation along the gene body. This work aims to modulate DNA as a combination of n-nonperturbative circuits quantum electrodynamics with nine Radio-Frequency Superconducting Quantum Interference Devices (SQUIDs) inside. A bus can be coupled capacitively to a single-mode microwave resonator. The cavity mode and the bus can mediate long-range, fast interaction between neighboring and distant DNA SQUID qubits. RNA polymerase II produces decoherence during transcription. This enzyme is a multifunctional biomolecular machine working like an artificially engineered device. Phosphorylation catalyzed by protein kinases constitutes the driving force. The coupling between n-phosphorylation pulses and any particular SQUID qubit can be obtained selectively via frequency matching.

The phosphodiester dissociative hydrolysis of a DNA model promoted by metal dications.

Phosphodiester bonds, which form the backbone of DNA, are highly stable in the absence of catalysts. This stability is crucial for maintaining the integrity of genetic information. However, when exposed to catalytic agents, these bonds become susceptible to cleavage. In this study, we investigated the role of different metal dications (Ca2⁺, Mg2⁺, Zn2⁺, Mn2⁺, and Cu2⁺) in promoting the hydrolysis of phosphodiester bonds. A minimal DNA model was constructed using two pyrimidine nucleobases (cytosine and thymine), two deoxyribose units, one phosphate group, and one metallic dication coordinated by six water molecules. The results highlight that Cu2⁺ is the most efficient in lowering the energy barrier for bond cleavage, with an energy barrier of 183kJ/mol, compared to higher barriers for metals like Zn2⁺ (202kJ/mol), Mn2⁺ (202kJ/mol), Mg2⁺ (210kJ/mol), and Ca2⁺ (223kJ/mol). Understanding the interaction between these metal ions and phosphodiester bonds offers insight into DNA stability and organic data storage systems. DFT calculations were employed using Gaussian 16 software, applying the B3LYP hybrid functional with def2-SVP basis sets and GD3BJ dispersion corrections. Full geometry optimizations were performed for the initial and transition states, followed by identifying energy barriers associated with phosphodiester bond cleavage. The optimization criteria included maximum force, root-mean-square force, displacement, and energy convergence thresholds.

Delayed fragmentation of isolated nucleobases induced by MeV ions.

We evaluated the dissociation of isolated gas-phase nucleobase molecules induced by mega electron volt (MeV)-energy ions to gain fundamental insights into the reactions of nucleobases upon fast ion irradiation. We studied five nucleobase molecules-adenine, guanine, cytosine, thymine, and uracil-as gas-phase targets. We compared the fragmentation patterns obtained from carbon ion impacts with those obtained from proton impacts to clarify the effect of heavy ion irradiation. We also compared the results with electron impact and photoionization results. In addition, we identified several delayed fragmentation pathways by analyzing the correlation between fragment pairs generated from singly and doubly charged intermediate ions. To determine the lifetimes of delayed fragmentation from singly charged intermediate ions, we evaluated the detection efficiencies of the microchannel plate detector for the neutral fragment HCN as a function of kinetic energy using a new methodology. As the first demonstration of this method, we estimated the lifetimes of C5H5N5+ generated by 1.2-MeV C+ and 0.5-MeV H+ collisions to be 0.87 ± 0.43 and 0.67 ± 0.09 µs, respectively. These lifetimes were approximately one order of magnitude longer than those of the doubly charged intermediate ion C5H5N52+.

Nature of TiO2–oligonucleotides interactions by atomistic molecular dynamics simulations

We used molecular dynamics simulations to investigate the adsorption behavior of single-stranded deoxyribonucleic acid (ssDNA) segments on the anatase (101) surface. Four different ssDNA oligonucleotides, each consisting of six/twelve adenine (A6 and A12), six guanine (G6), six cytosine (C6) or six/twelve thymine (T6 and T12) nucleobases, were considered. We observed that the initial interaction between the ssDNA and the surface occurs primarily through hydrogen bonding between the nucleobases and the surface, followed by strong chemical bonding between the terminal phosphate group and the anatase surface. The interactions between the nucleobases and the surface varied between the different ssDNA segments. Adenine showed the highest affinity for the surface, whereas thymine showed the lowest affinity. In addition, the purine bases interact more strongly when the surface is negatively charged (as it would be at physiological pH) than in neutral surface (slightly acidic conditions), in agreement with experimental data from fluorescence experiments and ATR-FTIR spectroscopy. Moreover, our study provides mechanistic insights into the dynamic behavior of ssDNA on the anatase surface and comparative analyses on how different conditions (pH, fragment length, composition, etc.) affect DNA/TiO2 interactions. Therefore, we expect that experimental scientists will benefit from our work in the design of optimal nanoconjugates for their specific final goals and applications.

Novel Coumarin-Nucleobase Hybrids with Potential Anticancer Activity: Synthesis, In Vitro Cell-Based Evaluation, and Molecular Docking.

A new series of compounds planned by molecular hybridization of the nucleobases uracil and thymine, or the xanthine theobromine, with coumarins, and linked through 1,2,3-triazole heterocycles were evaluated for their in vitro anticancer activity against the human tumor cell lines: colon carcinoma (HCT116), laryngeal tumor cells (Hep-2), and lung carcinoma cells (A549). The hybrid compound 9a exhibited better activity in the series, showing an IC50 of 24.19 ± 1.39 μM against the HCT116 cells, with a selectivity index (SI) of 6, when compared to the cytotoxicity against the non-tumor cell line HaCat. The in silico search for pharmacological targets was achieved through molecular docking studies on all active compounds, which suggested that the synthesized compounds possess a high affinity to the Topoisomerase 1-DNA complex, supporting their antitumor activity. The in silico toxicity prediction studies suggest that the compounds present a low risk of causing theoretical mutagenic and tumorigenic effects. These findings indicate that molecular hybridization from natural derivative molecules is an interesting approach to seek new antitumor candidates.

Development of 3'-Deoxy-3',4'-didehydro-nucleoside Prodrug Inhibitors of West Nile and Zika Viruses.

The antiviral enzyme viperin catalyzes the formation of 3'-deoxy-3',4'-didehydro-cytidine-5'-triphosphate (ddhCTP). ddhCTP is incorporated into viral genomes and terminates genomic replication to confer broad-spectrum antiviral effects. We have previously utilized phosphoramidate pronucleotide (ProTide) technology to enable metabolic production of ddhCTP in cells from an exogenously dosed 3'-deoxy-3',4'-didehydro-cytidine ProTide, which confers inhibitory activity against West Nile virus (WNV) and Zika virus (ZIKV). Herein, we synthesized 3'-deoxy-3',4'-didehydro-nucleosides containing all native nucleobases (thymine, uracil, adenine, guanine, and hypoxanthine), elaborated each to a ProTide, and measured their activity for controlling WNV and ZIKV infection. In comparison to the ddhC ProTide, we found that the ProTides of 3'-deoxy-3',4'-didehydro-guanosine and 3'-deoxy-3',4'-didehydro-adenosine possess 2- and 4-fold greater antiviral effects against ZIKV, respectively. Collectively, this work advances the development of 3'-deoxy-3',4'-didehydro nucleosides as promising compounds for further development into broad-spectrum antiviral agents.

Selective Tautomer Production and Cryogenic Ion Spectroscopy of Radical Cations: The Uracil and Thymine Cases.

The vibrational and electronic spectroscopy of the radical cations of two nucleobases (NB) (uracil and thymine) was studied by cryogenic ion photodissociation spectroscopy. The radical cations have been generated from the photodissociation of NB-Ag+ complexes. A charge transfer process from the NB to Ag+ governs the deactivation mechanism, leading to the formation of the radical cation without further tautomerization. Single- and double-resonance spectroscopy allows for structural assignments of both the silver complexes and the radical cations by comparison with DFT-based calculations. Interestingly, a tautomer-dependent fragmentation is observed in the thymine enol form that involves the loss of NCO, a fragment which was never reported before for this NB. This selective photodissociation of silver complexes containing aromatic chromophore greatly expands the current technique to produce isomer-selected radical cations in the gas phase providing benchmark experimental data to assess calculations of open-shell species.

Pharmacogenomic Studies of Antiviral Drug Favipiravir.

In this work, we conducted a study of the interaction between DNA and favipiravir (FAV). This chemotherapeutic compound is an antiviral drug for the treatment of COVID-19 and other infections caused by RNA viruses. This paper examines the electroanalytical characteristics of FAV. The determined concentrations correspond to therapeutically significant ones in the range of 50-500 µM (R2 = 0.943). We have shown that FAV can be electro-oxidized around the potential of +0.96 V ÷ +0.98 V (vs. Ag/AgCl). A mechanism for electrochemical oxidation of FAV was proposed. The effect of the drug on DNA was recorded as changes in the intensity of electrochemical oxidation of heterocyclic nucleobases (guanine, adenine and thymine) using screen-printed graphite electrodes modified with single-walled carbon nanotubes and titanium oxide nanoparticles. In this work, the binding constants (Kb) of FAV/dsDNA complexes for guanine, adenine and thymine were calculated. The values of the DNA-mediated electrochemical decline coefficient were calculated as the ratio of the intensity of signals for the electrochemical oxidation of guanine, adenine and thymine in the presence of FAV to the intensity of signals for the electro-oxidation of these bases without drug (S, %). Based on the analysis of electrochemical parameters, values of binding constants and spectral data, intercalation was proposed as the principal mechanism of the antiviral drug FAV interaction with DNA. The interaction with calf thymus DNA also confirmed the intercalation mechanism. However, an additional mode of interaction, such as a damage effect together with electrostatic interactions, was revealed in a prolonged exposure of DNA to FAV.

Adsorption and formation energies of nucleobase–Fullerene: A first-principles simulation

A computational study was conducted using the density functional theory (DFT) method to determine the energy stability of a system composed of deoxyribonucleic acid/ribonucleic acid (DNA/RNA) nucleobase molecules on Fullerene C[Formula: see text] as a potential gene delivery system. The feasibility of the system for gene delivery and nanomedicine applications was assessed by examining the strong geometric bonds formed between Adenine, Cytosine, Guanine, Thymine, and Uracil nucleobases and C[Formula: see text]Si molecules in close proximity to Fullerene. The bonding affinities of each nucleobase with Fullerene were observed to follow the order Uracil > Guanine > Cytosine > Thymine > Adenine. Furthermore, calculations of adsorption and formation energies were performed to determine the most stable configuration within the Fullerene structure. Guanine demonstrated the highest stability, indicating its potential as an efficient carrier for the delivery of guanine-based genetic material into cells. Additionally, the Fullerene surface exhibited a high propensity for Cytosine adherence, as evidenced by the lowest adsorption energy observed for the interaction between Cytosine and Fullerene. The potential application of Si-doped Fullerene C60 as a gene delivery system was highlighted, based on the strong interactions observed with DNA/RNA nucleobase molecules. These valuable insights will contribute to the development of efficient gene delivery strategies and offer promising prospects for advancing gene therapy and nanomedicine.

Molecular aggregation by hydrogen bonding in cold-crystallization behavior of mixed nucleobases analyzed by temperature-controlled infrared spectroscopy.

The cold-crystallization behaviors of dodecyl-substituted nucleobases (adenine, uracil, and thymine) were analyzed. The dodecyl derivative from uracil alone did not exhibit cold crystallization; however, a mixture of adenine and uracil derivatives at a molar ratio of 1 : 1 exhibited cold crystallization. These results are similar to the thermal behavior of dodecyl derivatives of adenine and thymine alone and in mixtures reported in a previous study. Temperature-controlled infrared spectroscopy was used to observe the molecular assembly states of the liquid, supercooled state, and cold-crystallized compounds. Hydrogen-bonded molecular pairs in the high-temperature liquid state, multiple hydrogen-bonded networks in the supercooled state, and reverse Hoogsteen-type complementary hydrogen bonds in cold-crystallized compounds were observed using infrared spectroscopy. The heterogeneity of the system, due to multiple types of hydrogen bonding, retarded the crystallization rate, resulting in supercooling and cold crystallization. Infrared spectroscopy, which can be used to measure the aggregation state of molecules, including the liquid and supercooled states, is an effective analytical method for clarifying the process of cold crystallization.

Discotic Star Mesogen with Thymine Nucleobases Exhibiting a Rare Gyroid Cubic Mesophase with 3D Conductivity.

A unique gyroid cubic phase has been discovered for a discotic star mesogen with three covalently attached DNA bases. In this cubic phase, the conjugated core of the mesogens and the thymine pseudo guests self-assemble in mirror image continuous networks, representing a semiconducting material with three-dimensional transport pathways. The hole carrier mobilities are found to be in the typical range of poly(phenylenevinylene) scaffolds. This structure is stabilized by a weak hydrogen bonding between the thymine bases and can be switched to a columnar liquid crystal - thermally and by the addition of complementary adenine guests.

6-Pyrazolylpurine and its deaza derivatives as nucleobases for silver(I)-mediated base pairing with pyrimidines

The artificial nucleobase 6-pyrazolylpurine (6PP) and its deaza derivatives 1-deaza-6-pyrazolylpurine (1D6PP), 7-deaza-6-pyrazolylpurine (7D6PP), and 1,7-dideaza-6-pyrazolylpurine (1,7D6PP) were investigated with respect to their ability to differentiate between the canonical nucleobases cytosine and thymine by means of silver(I)-mediated base pairing. As shown by temperature-dependent UV spectroscopy and by circular dichroism spectroscopy, 6PP and (to a lesser extent) 7D6PP form stable silver(I)-mediated base pairs with cytosine, but not with thymine. 1D6PP and 1,7D6PP do not engage in the formation of stabilizing silver(I)-mediated base pairs with cytosine or thymine. The different behavior of 1D6PP, 7D6PP, and 1,7D6PP indicates that silver(I) binding occurs via the N1 position of the purine derivative, i.e. via the Watson–Crick face. The data show that 6PP is capable of differentiating between cytosine and thymine, which is potentially relevant in the context of detecting single-nucleotide polymorphisms.Graphical abstract

Base pairs with 5-chloroorotic acid and comparison with the natural nucleobase. Structural and spectroscopic study, and three suggested antiviral modified nucleosides

A structural and spectroscopic study of 5-chloroorotic acid (5-ClOA) biomolecule was carried out by IR and FT-Raman and the results obtained were compared to those achieved in 5-fluoroorotic acid and 5-aminoorotic acid compounds. The structures of all possible tautomeric forms were determined using DFT and MP2 methods. To know the tautomer form present in the solid state, the crystal unit cell was optimized through dimer and tetramer forms in several tautomeric forms. The keto form was confirmed through an accurate assignment of all the bands. For this purpose, an additional improvement in the theoretical spectra was carried out using linear scaling equations (LSE) and polynomic equations (PSE) deduced from uracil molecule. Base pairs with uracil, thymine and cytosine nucleobases were optimized and compared to the natural Watson-Crick (WC) pairs. The counterpoise (CP) corrected interaction energies of the base pairs were also calculated. Three nucleosides were optimized based on 5-ClOA as nucleobase, and their corresponding WC pairs with adenosine. These modified nucleosides were inserted in DNA:DNA and RNA:RNA microhelices, which were optimized. The position of the -COOH group in the uracil ring of these microhelices interrupts the DNA/RNA helix formation. Because of the special characteristic of these molecules they can be used as antiviral drugs. Communicated by Ramaswamy H. Sarma

Association of intermediates of bioenergetic pathways and plasma metabolomics with colorectal cancer (CRC): Diagnosis, stage, and survival.

e15575 Background: Metabolomics is an evolving technique that can offer a non-invasive method for comprehensive identification of metabolic biomarkers. We evaluated the feasibility of measuring plasma metabolites in a longitudinal, observational cohort of patients (pts) with stage I-IV CRC for association with disease characteristics and overall survival (OS). Methods: In this retrospective analysis of prospectively collected blood samples from a single-institute cohort of pts with stage I-IV CRC, up to 150 metabolites of central carbon metabolism were analyzed by mass spectrometry and high-performance liquid chromatography. All blood samples were collected at pre-chemotherapy baseline. Analytes were compared by relative area under the curve (AUC) and differences evaluated by ANOVA. Blood samples were collected from two non-CRC pts to serve as healthy controls. Comparison of plasma metabolite levels were stratified by diagnosis of CRC vs. healthy control, non-metastatic CRC (stage I-III) vs. metastatic CRC (stage IV), and short OS vs. long OS (defined by the median threshold OS of 24.8 months in the cohort). Results: Plasma metabolomics was performed on a total of 32 pts with CRC. The median age of the cohort was 65 years (range 20-90) with the majority being female (53%) and having stage IV disease (78%). Of 25 pts with stage IV CRC, 88% had pre-chemotherapy blood samples collected in the first-line setting and 44% were KRAS mutant compared to 37% KRAS WT and 19% unknown KRAS status. Compared to healthy controls, CRC pts had higher levels of glutamate, nucleotides UMP and CMP, and nucleosides hypoxanthine and inosine (all p < 0.05). When stratified by stage, stage I-III CRC pts had higher levels of the non-essential amino acid (AA) serine and essential AAs threonine and methionine, while stage IV had higher levels of the aldopentose ribose (all p < 0.05) Those with short OS had increased levels in intermediates of glycolysis (lactate, UDP-Glc), glutamine metabolism (GlcNAc), MTA cycle (SAM, 5-Methioadenosine), and pentose phosphate pathway (R5P) as well as increased levels of proline (non-essential AA), phenylalanine (essential AA), thymine (nucleobase), and UDP (nucleotide) compared to pts with long OS (all p < 0.05). Notably, both stage IV and short OS pts had trends in increased intermediates of glutamine metabolism (glutamate, a-KG, UDP-GlcNAc) that did not reach significance. Conclusions: We show that pts with CRC compared to healthy controls and those with stage IV and short OS appear to be enriched in intermediates of multiple bioenergetic pathways including AA synthesis, nucleotide synthesis, glycolysis, methyl donor biology, and glutamine signaling. These findings are hypothesis-generating and can inform more focused evaluation of potential biomarkers and therapeutic targets in CRC.

Reactive oxygen species-responsive thymine-conjugated chitosan: Synthesis and evaluation as cryogel

Chitosan (CS) is a biodegradable, biocompatible cationic polysaccharide based natural polymer with antibacterial and anti-inflammatory properties. Hydrogels made from CS have found their applications in wound healing, tissue regeneration and drug delivery. Although, mucoadhesive properties are resulted from the polycationic nature of CS, in hydrogel form amines are engaged in interactions with water leading to decrease in mucoadhesive properties. In case of injury, presence of elevated level of reactive oxygen species (ROS) has inspired many drug delivery platforms to conjugate ROS responsive linkers for on demand drug delivery. In this report we have conjugated a reactive oxygen species (ROS) responsive thioketal (Tk) linker and nucleobase thymine (Thy) with CS. Cryogel from this doubly functionalized polymer CS-Thy-Tk was prepared through crosslinking with sodium alginate. Inosine was loaded on the scaffold and studied for its release under oxidative condition. We anticipated that the presence of thymine shall retain the mucoadhesive nature of the CS-Thy-Tk polymer in hydrogel form and when placed at the site of injury, due to the presence of excessive ROS at inflammatory condition, loaded drug shall release due to degradation of the linker. Porous cryogel scaffold was prepared via chemical crosslinking of amine functional group of chitosan with carboxylic acid containing polysaccharide sodium alginate. The cryogel was evaluated for porosity (FE-SEM), rheology, swelling, degradation, mucoadhesive properties and biocompatibility. Resulted scaffold was found to be porous with average pore size of 107 ± 23 μm, biocompatible, hemocompatible and possesses improved mucoadhesive property (mucin binding efficiency of 19.54 %) which was found to be 4 times better as compared to chitosan (4.53 %). The cumulative drug release found to be better in the presence of H2O2 (∼90 %) when compared to that of PBS alone (∼60–70 %). Therefore, the modified CS-Thy-TK polymer may hold potential as interesting scaffold in case of conditions associated with elevated ROS level such as injury and tumor.

A high-level quantum chemical study of the thermodynamics associated with chlorine transfer between N-chlorinated nucleobases

The relative free energies of the isomers formed upon N-chlorination of each nitrogen atom within the DNA nucleobases (adenine, guanine, and thymine) have been obtained using the high-level G4(MP2) composite ab initio method (the free energies of the N-chlorinated isomers of cytosine have been reported at the same level of theory previously). Having identified the lowest energy N-chlorinated derivatives for each nucleobase, we have computed the free energies associated with chlorine transfer from N-chlorinated nucleobases to other unsubstituted bases. Our results provide quantitative support pertaining to the results of previous experimental studies, which demonstrated that rapid chlorine transfer occurs from N-chlorothymidine to cytidine or adenosine. The results of our calculations in the gas-phase reveal that chlorine transfer from N-chlorothymine to either cytosine, adenine, or guanine proceed via exergonic processes with ΔG o values of −50.3 (cytosine), −28.0 (guanine), and −6.7 (adenine) kJ mol–1. Additionally, we consider the effect of aqueous solvation by augmenting our gas-phase G4(MP2) energies with solvation corrections obtained using the conductor-like polarizable continuum model. In aqueous solution, we obtain the following G4(MP2) free energies associated with chlorine transfer from N-chlorothymine to the three other nucleobases: −58.4 (cytosine), −26.4 (adenine), and −18.7 (guanine) kJ mol–1. Therefore, our calculations, whether in the gas phase or in aqueous solution, clearly indicate that chlorine transfer from any of the N-chlorinated nucleobases to cytosine provides a thermodynamic sink for the active chlorine. This thermodynamic preference for chlorine transfer to cytidine may be particularly deleterious since previous experimental studies have shown that nitrogen-centered radical formation (via N–Cl bond homolysis) is more easily achieved in N-chlorinated cytidine than in other N-chlorinated nucleosides.

Communication: Non-adiabatic derivative coupling elements for the coupled cluster singles and doubles model.

We present an efficient implementation of analytical non-adiabatic derivative coupling elements for the coupled cluster singles and doubles model. The derivative coupling elements are evaluated in a biorthonormal formulation in which the nuclear derivative acts on the right electronic state, where this state is biorthonormal with respect to the set of left states. This stands in contrast to earlier implementations based on normalized states and a gradient formula for the derivative coupling. As an illustration of the implementation, we determine a minimum energy conical intersection between the nπ* and ππ* states in the nucleobase thymine.

The application of TMAH thermochemolysis on the detection of nucleotides: applications for the SAM and MOMA space experiments

The Sample Analysis at Mars (SAM) instrument onboard the Curiosity rover and Mars Organic Molecule Analyzer (MOMA) instrument onboard the ExoMars rover are two of the most important instruments used for the in-situ search for biosignatures of life on Mars. Tetramethylammonium hydroxide (TMAH) thermochemolysis combined with pyrolysis-gas chromatography and mass spectrometry (Py-GC/MS) has been one of the main techniques utilized by SAM and will be utilized by MOMA. They are both capable of detecting molecular fragments and patterns indicative of life in the Martian near-surface. This study identifies the TMAH thermochemolysis products of targeted nucleotides using flash pyrolysis and SAM-like ramp pyrolysis experiments. Additionally, the optimal TMAH thermochemolysis temperature was determined. Results indicate that the methylated nucleosides can be detected at low abundances when exposed to TMAH thermochemolysis flash pyrolysis at 200 °C. Notably, higher pyrolysis temperatures led to the degradation of nucleosides. Furfuryl methyl ether, one of the degradation products of these nucleosides, was also identified from 200 to 600°C in this study. 300 °C is the optimal temperature for the detection of methylated phosphate under flash pyrolysis of the tested nucleotides with TMAH thermochemolysis. Methylated nucleobases, methyl furfuryl and methyl phosphate are the main products of the tested nucleotides under SAM-like ramp thermochemolysis. Ramped thermochemolysis also resulted in improved performance over flash pyrolysis in the detection of characteristic nucleotide compounds. Uracil and thymine can be detected by both SAM and MOMA if there are nucleotides on Mars; additionally, MOMA will be able to detect adenine. Therefore, methyl furfuryl, methylated phosphate, and the methylated nucleobases uracil, thymine, and adenine are the organic compounds that should be within the SAM and MOMA detection windows if there is DNA/RNA conserved in Martian soil. These experiments will provide a reference for the data collected in-situ by the Curiosity rover and the future ExoMars rover.

Self-assembly of thyminyl l-tryptophanamide (TrpT) building blocks for the potential development of drug delivery nanosystems

The design, synthesis and characterization of a novel nucleoamino acid derivative based on an l-tryptophanamide functionalised with a thymine nucleobase (named TrpT) is here described. The novel construct’s tendency to self-assemble into supramolecular networks in aqueous solution was demonstrated by dynamic light scattering (DLS), circular dichroism (CD), fluorescence and UV spectroscopic measurements. TrpT nanoaggregates showed good stability (up to 5 h) at 140 µM and proved to comprise species of mean hydrodynamic diameter 330 nm and a homogeneous size distribution; scanning electron microscopy (SEM) analysis further revealed these to be spherical-shaped assemblies. The ability of TrpT nanoaggregates to bind curcumin, selected as a model anticancer drug, was also evaluated and its release was monitored over time by confocal microscopy. Molecular docking studies were performed on both TrpT self-assembly and curcumin-loaded nanoaggregates suggesting that the phytomolecule can be accommodated in the interior of the supramolecular network via hydrophobic (π−π and π-alkyl) interactions; the formation of TrpT-curcumin adducts may improve the polarity of the highly-hydrophobic curcumin with a resulting logP closer to the optimal values expected for a good drug bioavailability, as estimated by the ADMETlab software. Finally, the high stability of TrpT nanoassembly in human serum, and the absence of significant toxic effects on human model cells in a cell viability assay, were also demonstrated. Despite its thymine-based scaffold, TrpT was shown not to bind adenine-bearing nucleic acids, suggesting that this interaction is hindered by its intrinsic propensity to self-assemble in preference to forming A-T base pairings. Instead, TrpT was able to interact with a serum protein such as bovine serum albumin (BSA), known to improve the bloodstream transportation and bioavailability of its cargo. Collectively, our findings support the potential use of TrpT for the development of new drug delivery systems.Graphical abstract

Meteorites and the RNA World: Synthesis of Nucleobases in Carbonaceous Planetesimals and the Role of Initial Volatile Content

Prebiotic molecules, fundamental building blocks for the origin of life, have been found in carbonaceous chondrites. The exogenous delivery of these organic molecules onto the Hadean Earth could have sparked the polymerization of the first RNA molecules in Darwinian ponds during wet-dry cycles. Here, we investigate the formation of the RNA and DNA nucleobases adenine, uracil, cytosine, guanine, and thymine inside parent body planetesimals of carbonaceous chondrites. An up-to-date thermochemical equilibrium model coupled with a 1D thermodynamic planetesimal model is used to calculate the nucleobase concentrations. Different from previous studies, we assume the initial volatile concentrations more appropriate for the formation zone of carbonaceous chondrite parent bodies. This represents more accurately cosmochemical findings that these bodies have formed inside the inner, ∼2–5 au, warm region of the solar system. Due to these improvements, our model represents the concentrations of adenine and guanine measured in carbonaceous chondrites. Our model did not reproduce per se the measurements of uracil, cytosine, and thymine in these meteorites. This can be explained by transformation reactions between nucleobases and the potential decomposition of thymine. The synthesis of prebiotic organic matter in carbonaceous asteroids could be well explained by a combination of (i) radiogenic heating, (ii) aqueous chemistry involving a few key processes at a specific range of radii inside planetesimals where water can exist in the liquid phase, and (iii) a reduced initial volatile content (H2, CO, , and CH2O) of the protoplanetary disk material in the parent body region compared to the outer region of comets.