Nucleoside Pairs Research Articles

The marvelous dna macromolecule: computer modeling of dna 3d structure and diversity of watson-crick duplex conformations

The work reviews the development of ideas about the 3D structure of DNA and the mechanisms of its formation, from the discovery of the Double Helix to the present day. It tracks the methods of modeling the 3D structure at different stages of the study of the main molecule of life. The discussion underscores a marvelous expedient in DNA molecular structure and its adaptability to important biological functions based on the results of calculations of the intra- and intermolecular interactions of macromolecule subunits. The work presents new data about substantial contribution of chemically monotonous and conformationally flexible sugarphosphate backbone to the formation of sequence-dependent 3D structure of DNA. The diversity of the conformational possibilities of DNA is visible both in the formation of duplexes (as well as triplexes and quadruplexes) with different geometric parameters for base pairs and in the formation of duplexes with Watson-Crick nucleoside pairs containing local conformations corresponding to different regions of the torsion angles of the sugar-phosphate backbone (different conformational classes). Based on our calculations, these classes can be divided into two groups. The first group includes local conformations in which the torsion angles are close to one of energy minima of its isolated elemental repeating fragment, and the second group consists of conformations with one or more of these angles deviating from that of the nearest energy minimum by more than 30°. The regularities of the formation of the local 3D structure of these two groups differ significantly.

Noncanonical Isomers of Nucleoside Cation Radicals: An Ab Initio Study of the Dark Matter of DNA Ionization.

Cation radicals of DNA nucleosides, 2'-deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine, can exist in standard canonical forms or as noncanonical isomers in which the charge is introduced by protonation of the nucleobase, whereas the radical predominantly resides in the deoxyribose moiety. Density functional theory as well as correlated ab initio calculations with coupled clusters (CCSD(T)) that were extrapolated to the complete basis set limit showed that noncanonical nucleoside ion isomers were thermodynamically more stable than their canonical forms in both the gas phase and as water-solvated ions. This indicated the possibility of exothermic conversion of canonical to noncanonical forms. The noncanonical isomers were calculated to have very low adiabatic ion-electron recombination energies (REad) for the lowest-energy isomers 2'-deoxy-(N-3H)adenos-1'-yl (4.74 eV), 2'-deoxy-(N-7H)guanos-1'-yl (4.66 eV), 2'-deoxy-(N-3H)cytid-1'-yl (5.12 eV), and 2'-deoxy-5-methylene-(O-2H)uridine (5.24 eV). These were substantially lower than the REad value calculated for the canonical 2'-deoxyadenosine, 2'-deoxy guanosine, 2'-deoxy cytidine, and 2'-deoxy thymidine cation radicals, which were 7.82, 7.46, 8.14, and 8.20 eV, respectively, for the lowest-energy ion conformers of each type. Charge and spin distributions in noncovalent cation-radical dA⊂dT and dG⊂dC nucleoside pairs and dAT, dCT, dTC, and dGC dinucleotides were analyzed to elucidate the electronic structure of the cation radicals. Born-Oppenheimer molecular dynamics trajectory calculations of the dinucleotides and nucleoside pairs indicated rapid exothermic proton transfer from noncanonical T+· to A in both dAT+· and dA⊂dT+·, leading to charge and radical separation. Noncanonical T+· in dCT+· and dTC+· initiated rapid proton transfer to cytosine, whereas the canonical dCT+· dinucleotide ion retained the cation radical structure without isomerization. No spontaneous proton transfer was found in dGC+· and dG⊂dC+· containing canonical neutral and noncanonical ionized deoxycytidine.

How proton transfer affects the helical parameters in DNA:DNA microhelices

Proton transfer reactions are a widespread phenomenon in many areas of the life sciences and it is one of the origins of the spontaneous point mutations during DNA replication. Because of its importance, many studies have been reported on these reactions. However, the present work is the first one focused on the structural geometrical changes by double proton transfer (DPT). Thus, different Watson–Crick (WC) pairs were optimized first in a simple model with one nucleoside base pair, and in a microhelix form with three nucleoside base pairs. The canonical and few tautomeric forms were considered in DNA:DNA microhelices with A-type and B-type helical forms. The stability of these structures and how the DPT process affects the main geometrical parameters was analyzed, in particular the deformation of the helical parameters. The M06-2X DFT method was used for this purpose. The purine/pyrimidine ring in the keto form appears easier to be deformed than when it is in the enol form. The weaker WC base pair formed with mixed microhelices than with nucleobases alone and the significant deformation of the helical and backbone parameters with the DPT appears to complicate this process in microhelices. Communicated by Ramaswamy H. Sarma

Understanding the Origin of Structural Diversity of DNA Double Helix

Deciphering the contribution of DNA subunits to the variability of its 3D structure represents an important step toward the elucidation of DNA functions at the atomic level. In the pursuit of that goal, our previous studies revealed that the essential conformational characteristics of the most populated “canonic” BI and AI conformational families of Watson–Crick duplexes, including the sequence dependence of their 3D structure, preexist in the local energy minima of the elemental single-chain fragments, deoxydinucleoside monophosphates (dDMPs). Those computations have uncovered important sequence-dependent regularity in the superposition of neighbor bases. The present work expands our studies to new minimal fragments of DNA with Watson–Crick nucleoside pairs that differ from canonic families in the torsion angles of the sugar-phosphate backbone (SPB). To address this objective, computations have been performed on dDMPs, cdDMPs (complementary dDMPs), and minimal fragments of SPBs of respective systems by using methods of molecular and quantum mechanics. These computations reveal that the conformations of dDMPs and cdDMPs having torsion angles of SPB corresponding to the local energy minima of separate minimal units of SPB exhibit sequence-dependent characteristics representative of canonic families. In contrast, conformations of dDMP and cdDMP with SPB torsions being far from the local minima of separate SPB units exhibit more complex sequence dependence.

Flying DNA Cation Radicals in the Gas Phase: Generation and Action Spectroscopy of Canonical and Noncanonical Nucleobase Forms.

Gas-phase chemistry of cation radicals related to ionized nucleic acids has enjoyed significant recent progress thanks to the development of new methods for cation radical generation, ion spectroscopy, and reactivity studies. Oxidative methods based on intramolecular electron transfer in transition-metal complexes have been used to generate nucleobase and nucleoside cation radicals. Reductive methods relying on intermolecular electron transfer in gas-phase ion-ion reactions have been utilized to generate a number of di- and tetranucleotide cation radicals, as well as charge-tagged nucleoside radicals. The generated cation radicals have been studied by infrared and UV-visible action spectroscopy and ab initio and density functional theory calculations, providing optimized structures, harmonic frequencies, and excited-state analysis. This has led to the discovery of stable noncanonical nucleobase cation radicals of unusual electronic properties and extremely low ion-electron recombination energies. Intramolecular proton-transfer reactions in cation radical oligonucleotides and Watson-Crick nucleoside pairs have been studied experimentally, and their mechanisms have been elucidated by theory. Whereas the range of applications of the oxidative methods is currently limited to nucleobases and readily oxidizable guanosine, the reductive methods can be scaled up to generate large oligonucleotide cation radicals including double-strand DNA. Challenges in the experimental and computational approach to DNA cation radicals are discussed.

The Electronic Property Differences between dA::dG and dA::dGoxo. A Theoretical Approach.

The dA::dGoxo pair appearing in nucleic ds-DNA can lead to a mutation in the genetic information. Depending on the dGoxo source, an AT→GC and GC→AC transversion might be observed. As a result, glycosylases are developed during the evolution, i.e., OGG1 and MutY. While the former effectively removes Goxo from the genome, the second one removes adenine from the dA::dGoxo and dA:dG pair. However, dA::dGoxo is recognized by MutY as ~6–10 times faster than dA:dG. In this article, the structural and electronic properties of simple nucleoside pairs dA:dG, dC:::dGoxo, dC:::dG, dA::dGoxo in the aqueous phase have been taken into theoretical consideration. The influence of solvent relaxation on the above is also discussed. It can be concluded that the dA::dGoxo nucleoside pair shows a lower ionization potential and higher electron affinity than the dA:dG pair in both a vertical and adiabatic mode. Therefore, it could be predicted, under electronic properties, that the electron ejected, for instance by a MutY 4[Fe-S]2+ cluster, is predisposed to trapping by the ds-DNA part containing the dA::dGoxo pair rather than by dA::dG.

Electric-Field-Driven Molecular Recognition Reactions of Guanine with 1,2-Dipalmitoyl-sn-glycero-3-cytidine Monolayers Deposited on Gold Electrodes

Monolayers of 1,2-dipalmitoyl-sn-glycero-3-cytidine were incubated with guanine in a 0.1 M NaF electrolyte at the surface of a Langmuir trough and transferred to gold (111) electrodes using the Langmuir-Schaefer technique. Chronocoulometry and photon polarization modulation infrared reflection absorption spectroscopy were employed to investigate the influence of the static electric field on the orientation and conformation of the cytidine nucleolipid molecules on the metal surface in the presence of guanine and to monitor the molecular recognition of guanine with the cytosine moiety. When the monolayer is exposed to guanine solutions, the cytosine moiety binds to the guanine residue in either a Watson-Crick complex at positively charged electrode surfaces or a noncomplexed state at negative surface charges. The positive electrostatic field causes the cytosine moiety and the cytosine-guanine complex to adopt a nearly parallel orientation with respect to the plane of the monolayer with a measured tilt angle of ∼10°. The parallel orientation is stabilized by the interactions between the permanent dipole of the cytosine moiety or the Watson-Crick complex and the static electric field. At negative charge densities, the tilt of the cytosine moiety increases by ∼15-20°, destabilizing the complex. Our results demonstrate that the static electric field has an influence on the molecular recognition reactions between nucleoside base pairs at the metal-solution interface and can be controlled by altering the surface charge at the metal.

Novel entry to the synthesis of (S)- and (R)-5-methoxycarbonylhydroxymethyluridines - a diastereomeric pair of wobble tRNA nucleosides.

Two novel methods for the preparation of the virtually equimolar mixtures of (S)- and (R)-diastereomers of 5-methoxycarbonylhydroxymethyluridine (mchm5U) have been developed. The first method involved α-hydroxylation of a 5-malonate ester derivative of uridine (5) with SeO2, followed by transformation to (S)- and (R)-5-carboxymethyluridines (cm5U, 8) and, finally, into the corresponding methyl esters. In the second approach, (S)- and (R)-mchm5-uridines were obtained starting from 5-formyluridine derivative (9) by hydrolysis of the imidate salt (11) prepared in the acid catalyzed reaction of 5-cyanohydrin-containing uridine (10b) with methyl alcohol. In both methods, the (S)- and (R) diastereomers of mchm5U were effectively separated by preparative C18 RP HPLC.

Correction to Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment.

ADVERTISEMENT RETURN TO ISSUEPREVErratumNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with ExperimentReid F. BrownReid F. BrownMore by Reid F. Brown, Casey T. AndrewsCasey T. AndrewsMore by Casey T. Andrews, and Adrian H. Elcock*Adrian H. ElcockMore by Adrian H. Elcockhttp://orcid.org/0000-0003-2820-1376Cite this: J. Chem. Theory Comput. 2018, 14, 12, 6742–6743Publication Date (Web):November 14, 2018Publication History Published online14 November 2018Published inissue 11 December 2018https://doi.org/10.1021/acs.jctc.8b00594Copyright © 2018 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1039Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (203 KB) Get e-Alerts Get e-Alerts

Phosphorus availability regulates intracellular nucleotides in marine eukaryotic phytoplankton

AbstractMarine eukaryotic phytoplankton adapt to low phosphorus (P) in the oceans through a variety of step‐wise mechanisms including lipid substitution and decreased nucleic acid content. Here, we examined the impact of low P concentrations on intracellular metabolites whose abundances can be quickly adjusted by cellular regulation within laboratory cultures of three model phytoplankton and in field samples from the Atlantic and Pacific Oceans. We quantified the relative abundances of monophosphate nucleotides and their corresponding nucleosides, using a combination of targeted and untargeted metabolomics methods. Under P‐deficient conditions, we observed a marked decrease in adenosine 5′‐monophosphate (AMP) with a concomitant increase in adenosine. This shift occurred within all detected pairs of monophosphate nucleotides and nucleosides, and was consistent with previous work showing transcriptional changes in nucleotide synthesis and salvage under P‐deficient conditions for model eukaryotes. In the field, we observed AMP‐to‐adenosine ratios that were similar to those in laboratory culture under P‐deficient conditions.

Analysis of Configuration and Conformation of Furanose Ring in Carbohydrate and Nucleoside by Vibrational Circular Dichroism.

A reliable and convenient method for determining the configuration and conformation of the furanose ring in carbohydrates and nucleosides by vibrational circular dichroism (VCD) spectroscopy is described. Diastereomeric pairs of several furanose monosaccharides and nucleosides were prepared, and their VCD spectra were analyzed. The results revealed that VCD spectroscopy elucidates the equibrated state of the furanose ring puckers, which is often difficult to study by other techniques.

Molecular recognition of a lipophilic guanosine derivative in Langmuir films at the air-water interface

Molecular recognition of a lipophilic deoxyguanosine derivative at the air-water interface was investigated by film balance experiments and Brewster Angle Microscopy. Results showed that guanosine, despite strong tendency towards self-assembly, interacts with both complementary and noncomplementary liponucleosides (lipophilic derivatives of deoxycytidine and deoxythymidine). At surface pressures below 17mN/m, attractive and repulsive interactions were present in case of both mixed monolayers and were the strongest at guanosine molar fractions of 0.5 and 0.75. At higher values of surface pressure, deoxyguanosine-deoxycytidine interactions were strictly attractive and were present only for monolayers with guanosine molar fraction of 0.75. On the contrary, attractive and repulsive interactions remained present in case of deoxyguanosine-deoxythymidine mixed monolayers. This indicates that interactions between guanosine and cytidine are much stronger than guanosine-thymidine interactions. Interactions for none of the nucleoside pairs, however, are specific and π–stacking interactions between the aromatic planes of liponucleoside derivatives probably dominate over hydrogen bonding interactions. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.

Excess Electron Attachment to the Nucleoside Pair 2'-Deoxyadenosine (dA)-2'-Deoxythymidine (dT).

The 2'-deoxyadenosine···2'-deoxythymidine (dAdT(•-)) radical anion nucleoside pair has been investigated both experimentally and theoretically in the gas phase. The vertical detachment energy (VDE) and adiabatic electron affinity (AEA) were determined by anion photoelectron spectroscopy (PES). The measured photoelectron spectrum features a broad band having an onset at ∼1.1 eV and a maximum at the electron binding energy (EBE) ranging from 1.7 to 1.9 eV. Calculations performed at the M06-2X/6-31++G** level reveal that the observed PES signal is probably due to a dAdT(•-) complex in which the thymine of the dT nucleoside forms hydrogen bonds that engage its O7 and O8 atoms as well as the 3'- and 5'-hydroxyl groups of 2'-deoxyadenosine (dA), while dT's 3'-hydroxyl group interacts with the N1 of dA. In this heterodimer, the excess electron is entirely located on thymine. The biologically relevant Watson-Crick arrangement of the dAdT(•-) dimer was found to be substantially less stable (by ∼19 kcal mol(-1) in Gibbs free energy scale) than the above-mentioned configuration; hence, it is not populated in the gas phase.

Longitudinal analysis of the associations between antiretroviral therapy, viraemia and immunosuppression with lipid levels: the D:A:D study.

Antiretroviral (ART) drugs have been associated with higher triglycerides (TG), higher total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-C) levels. Associations between lipid levels with HIV viraemia and immunosuppression in the presence of ART remain unclear. Participants from the D:A:D study with at least one TG/TC/HDL-C measurement were included. Linear mixed effect models were used to determine the association of ART, viral load (VL), nadir and current CD4+ T-cell count and previous AIDS diagnosis with lipids. Of 49,717 participants, 90%, 92% and 80% contributed at least one TG/TC/HDL-C measurement (median follow-up 6.8, 6.8 and 5.0 years, respectively). Predicted mean (95% CI) baseline levels for TG, TC and HDL-C (mmol/l), were 2.10 (2.05, 2.14), 4.94 (4.91, 4.98) and 1.08 (1.07, 1.10), respectively. Lopinavir was associated with the worst TG profile, (27.2% higher levels compared to atazanavir; 95% CI 25.2%, 29.2%), and darunavir had a similar profile as atazanavir. The nucleoside pair lamivudine/tenofovir was associated with the most favourable TG profile (-2.8%; -3.5%, -2.0%) compared with emtricitabine/tenofovir, whereas lamivudine/abacavir (+10.2%; +9.3%, +11.2%) and lamivudine/stavudine (+8.0%; +6.9%, +9.0%), were associated with the worst. Raltegravir was associated with lower TG (-5.2%; -6.4%, -3.9%), and nevirapine had a more favourable HDL-C profile (+11.3%; +10.8%, +11.7%) than efavirenz (+5.3%; 5.0%, 5.7%), compared to atazanavir. Higher VLs were associated with lower TG/TC/HDL-C, whereas higher CD4+ T-cell counts were associated with higher TG/TC/HDL-C. TG, TC and HDL-C levels, which generally improved over time, are dependent on ART, viraemia and, to a lesser extent, immunosuppression.

Base-Pairing Energies of Protonated Nucleoside Base Pairs of dCyd and m(5)dCyd: Implications for the Stability of DNA i-Motif Conformations.

Hypermethylation of cytosine in expanded (CCG)n•(CGG)n trinucleotide repeats results in Fragile X syndrome, the most common cause of inherited mental retardation. The (CCG)n•(CGG)n repeats adopt i-motif conformations that are preferentially stabilized by base-pairing interactions of protonated base pairs of cytosine. Here we investigate the effects of 5-methylation and the sugar moiety on the base-pairing energies (BPEs) of protonated cytosine base pairs by examining protonated nucleoside base pairs of 2'-deoxycytidine (dCyd) and 5-methyl-2'-deoxycytidine (m(5)dCyd) using threshold collision-induced dissociation techniques. 5-Methylation of a single or both cytosine residues leads to very small change in the BPE. However, the accumulated effect may be dramatic in diseased state trinucleotide repeats where many methylated base pairs may be present. The BPEs of the protonated nucleoside base pairs examined here significantly exceed those of Watson-Crick dGuo•dCyd and neutral dCyd•dCyd base pairs, such that these base-pairing interactions provide the major forces responsible for stabilization of DNA i-motif conformations. Compared with isolated protonated nucleobase pairs of cytosine and 1-methylcytosine, the 2'-deoxyribose sugar produces an effect similar to the 1-methyl substituent, and leads to a slight decrease in the BPE. These results suggest that the base-pairing interactions may be slightly weaker in nucleic acids, but that the extended backbone is likely to exert a relatively small effect on the total BPE. The proton affinity (PA) of m(5)dCyd is also determined by competitive analysis of the primary dissociation pathways that occur in parallel for the protonated (m(5)dCyd)H(+)(dCyd) nucleoside base pair and the absolute PA of dCyd previously reported.

Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment.

We report the results of a series of 1-μs-long explicit-solvent molecular dynamics (MD) simulations performed to compare the free energies of stacking (ΔGstack) of all possible combinations of DNA and RNA nucleoside (NS) pairs and dinucleoside-monophosphates (DNMPs). For both NS pairs and DNMPs, we show that the computed stacking free energies are in reasonable qualitative agreement with experimental measurements and appear to provide the closest correspondence with experimental data yet found among computational studies; in all cases, however, the computed stacking free energies are too favorable relative to experimental data. Comparisons of NS-pair systems indicate that stacking interactions are very similar in RNA and DNA systems except when a thymine or uracil base is involved: the presence of a thymine base favors stacking by ∼0.3 kcal/mol relative to a uracil base. One exception is found in the self-stacking of cytidines, which are found to be significantly more favorable for the DNA form; an analysis of the rotational orientations sampled during stacking events suggests that this is likely to be due to more favorable sugar-sugar interactions in stacked complexes of deoxycytidines. Comparisons of the DNMP systems indicate that stacking interactions are more favorable in RNA than in DNA except, again, when thymine or uracil bases are involved. Finally, additional simulations performed using a previous generation of the AMBER force field-in which the description of glycosidic bond rotations was less than optimal-produce computed stacking free energies that are in poorer agreement with experimental data. Overall, the simulations provide a comprehensive view of stacking thermodynamics in NS pairs and in DNMPs as predicted by a state-of-the-art MD force field.

An observational comparison of first-line combination antiretroviral treatment (cART) with 2NRTI and ATV/r or DRV/r in HIV-infected patients in Italy.

IntroductionIn a recent clinical trial (ACTG 5257), no difference in viral failure (VF) of a first-line cART containing atazanavir/r (ATV/r) or darunavir/r (DRV/r) was found [1]. For the endpoint of discontinuation due to intolerance, the regimen with DRV/r was superior to that of ATV/r (49% of the stops of ATV/r were attributed to jaundice or hyperbilirubinemia). These and other intolerances to ATV/r remain a concern for clinicians.MethodsParticipants in the ICONA Foundation Study who started cART with 2NRTI+ ATV/r or DRV/r while ART-naïve were included. Several endpoints were evaluated: confirmed VF>200 copies/mL after six months of therapy, discontinuation of DRV/r or ATV/r for any reasons or because of intolerance/toxicity (as reported by the treating physician) and the combined endpoint of VF or stop. Survival analysis with Kaplan–Meier curves and Cox regression model stratified by clinical site was used. Patients' follow-up accrued from cART initiation to the date of the event or to the date of last available visit/viral load.Results894 patients starting 2NRTI+ATV/r and 686 2NRTI+DRV/r when ART-naïve on average in 2011 (IQR: 2010–2012) were studied. Most common NRTIs used were FTC/TDF (84%) and ABC/3TC (12%). Median age was 40 years, 22% females, 44% heterosexuals. Patients starting ATV/r were more likely to be hepatitis B/C infected (2% and 14% vs 1% and 9%, p=0.001), they started one year earlier (2011 vs 2012, p=0.001), were more likely to be enrolled in sites located in the north of Italy (63% vs 54%, p=0.04), started cART less promptly after HIV diagnosis (5 vs 2 months, p=0.02) and less likely to have started TDF/FTC (83% vs 85%, p=0.02). By two years of cART, 9.8% (95% CI 7.6–12.0) of those starting ATV/r experienced discontinuation due to intolerance/toxicity vs 6.5% in DRV/r group (95% CI 4.2–8.8, p=0.04). After controlling for several potential confounders (age, gender, nation of birth, mode of HIV transmission, hepatitis co-infection status, AIDS diagnosis, nucleoside pair started, baseline CD4 count and viral load and year of starting cART) the relative hazard (RH) for ATV/r vs DRV/r was 2.01 (95% CI 1.23, 3.28, p=0.005). There were no statistical differences detected for any of the other outcomes. ConclusionsAlthough unmeasured confounding cannot be ruled out, our results seem to be consistent with those of the ACTG 5257. When all cause discontinuations were considered, or the composite endpoint of treatment failure, there was no difference between ATV/r- and DRV/r-based regimens.

Synthesis and X-Ray Structure of New Anticancer Nucleosides Based on 1-((2-Hydroxyethoxy)methyl)-5-(phenylthio)-1H-1,2,4-triazole-3-carboxamide

A pair of new anticancer nucleosides based on 1,2,4-triazole nucleosides and 1-((2-hydroxyethoxy) methyl)-5-(phenylthio)-1H-1,2,4-triazole-3-carboxamide have been synthesized, and have given the corresponding products in excellent yields. Its structures and conformations were confirmed by single crystal X-ray diffraction.

Dual door entry to exciplex emission in a chimeric DNA duplex containing non-nucleoside–nucleoside pair

Dual door entry to exciplex formation was established in a chimeric DNA duplex wherein a fluorescent non-nucleosidic base surrogate () is paired against a fluorescent nucleosidic base surrogate (). Packing of the nucleobases via intercalative stacking interactions led to an exciplex emission either via FRET from the donor or direct excitation of the FRET acceptor .

Novel computational study on π-stacking to understand mechanistic interactions of Tryptanthrin analogues with DNA

Based on recently published initial experimental results on the intercalation of a class of broad spectrum antiparasitic compounds, we present a purely theoretical approach for determining if these compounds may preferentially intercalate with guanosine/cytosine (GC)-rich or adenosine/thymidine (TA)-rich regions of DNA. The predictive model presented herein is based upon utilization of density functional theory (DFT) to determine a priori how the best intercalator may energetically and sterically interact with each of the nucleoside base pairs. A potential new method using electrostatic potential maps (EPMs) to visually select the best poses is introduced and compared to the existing brute-force center of mass (COM) approach. The EPM and COM predictions are in agreement with each other, but the EPM method is potentially much more efficient. We report that 4-azatryptantrin, the best intercalator, is predicted to favor π-stacking with GC over that of TA by approximately 2–4 kcal/mol. This represents a significant difference if one takes into account the Boltzmann distribution at physiological temperature. This theoretical method will be utilized to guide future experimental studies on the elucidation of possible mechanism(s) for the action of these antiparasitic compounds at the molecular level.