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At least 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2011

Infrared Spectroscopy of Charge Transfer Complexes of Purines and Pyrimidines

The FTIR spectra of charge transfer complexes of purines and pyrimidines with organic acceptors such as TCNQ, TCNE, DDQ, chloranil and iodine are obtained and studied in the present work. Adenine, guanine, thymine, cytosine and uracil are the purines and pyrimidines which are found as constituent of DNA and RNA. Charge transfer induced hydrogen bonding is concluded on the basis of indirect transitions observed in the infrared range in these CTCs. Some CTCs show gaussian bands revealing delocalization of charge carriers. The CTCs show interband transition in three-dimensions rather than two-dimensions unlike CTCs of amino acids. There is no extended hydrogen bonded network spanning the whole crystal. This leads to indirect transition due to locally deformed lattice furnishing a phonon-assisted transition.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2012

Molecular interaction of the first 3 enzymes of the de novo pyrimidine biosynthetic pathway of Trypanosoma cruzi

Highlights: Black-Right-Pointing-Pointer An Escherichia coli strain co-expressing CPSII, ATC, and DHO of Trypanosoma cruzi was constructed. Black-Right-Pointing-Pointer Molecular interactions between CPSII, ATC, and DHO of T. cruzi were demonstrated. Black-Right-Pointing-Pointer CPSII bound with both ATC and DHO. Black-Right-Pointing-Pointer ATC bound with both CPSII and DHO. Black-Right-Pointing-Pointer A functional tri-enzyme complex might precede the establishment of the fused enzyme. -- Abstract: The first 3 reaction steps of the de novo pyrimidine biosynthetic pathway are catalyzed by carbamoyl-phosphate synthetase II (CPSII), aspartate transcarbamoylase (ATC), and dihydroorotase (DHO), respectively. In eukaryotes, these enzymes are structurally classified into 2 types: (1) a CPSII-DHO-ATC fusion enzyme (CAD) found in animals, fungi, and amoebozoa, and (2) stand-alone enzymes found in plants and the protist groups. In the present study, we demonstrate direct intermolecular interactions between CPSII, ATC, and DHO of the parasitic protist Trypanosoma cruzi, which is the causative agent of Chagas disease. The 3 enzymes were expressed in a bacterial expression system and their interactions were examined. Immunoprecipitation using an antibody specific for each enzyme coupled with Western blotting-based detection using antibodies for the counterpart enzymes showed co-precipitation of all 3 enzymes. From an evolutionary viewpoint, the formation of a functional tri-enzyme complex may have preceded-and led to-gene fusion to produce the CAD protein. This is the first report to demonstrate the structural basis of these 3 enzymes as a model of CAD. Moreover, in conjunction with the essentiality of de novo pyrimidine biosynthesis in the parasite, our findings provide a rationale for new strategies for developing drugs for Chagas disease, which target the intermolecular interactions of these 3 enzymes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2010

Preferential selection of isomer binding from chiral mixtures: alternate binding modes observed for the E and Z isomers of a series of 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines as ternary complexes with NADPH and human dihydrofolate reductase

The structures of six chirally mixed E/Z-isomers of 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines reveals only one isomer is bound in the active site of human DHFR. The configuration of all but one C9-analogue is observed as the E-isomer. The crystal structures of six human dihydrofolate reductase (hDHFR) ternary complexes with NADPH and a series of mixed E/Z isomers of 5-substituted 5-[2-(2-methoxyphenyl)-prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines substituted at the C9 position with propyl, isopropyl, cyclopropyl, butyl, isobutyl and sec-butyl (E2–E7, Z3) were determined and the results were compared with the resolved E and Z isomers of the C9-methyl parent compound. The configuration of all of the inhibitors, save one, was observed as the E isomer, in which the binding of the furopyrimidine ring is flipped such that the 4-amino group binds in the 4-oxo site of folate. The Z3 isomer of the C9-isopropyl analog has the normal 2,4-diaminopyrimidine ring binding geometry, with the furo oxygen near Glu30 and the 4-amino group interacting near the cofactor nicotinamide ring. Electron-density maps for these structures revealed the binding of only one isomer to hDHFR, despite the fact that chiral mixtures (E:Z ratios of 2:1, 3:1 and 3:2) of the inhibitors were incubated with hDHFR prior to crystallization. Superposition of the hDHFR complexes with E2 and Z3 shows that the 2′-methoxyphenyl ring of E2 is perpendicular to that of Z3. The most potent inhibitor in this series is the isopropyl analog Z3 and the least potent is the isobutyl analog E6, consistent with data that show that the Z isomer makes the most favorable interactions with the active-site residues. The isobutyl moiety of E6 is observed in two orientations and the resultant steric crowding of the E6 analog is consistent with its weaker activity. The alternative binding modes observed for the furopyrimidine ring in these E/Z isomers suggest that new templates can be designed to probe these binding regions of the DHFR active site.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2015

Electron- and proton-induced ionization of pyrimidine

This present work describes a quantum-mechanically based model of the electron- and proton-induced ionization of isolated pyrimidine molecules. The impact energies range from the target ionization threshold up to ~1 keV for electrons and from 10 keV up to 10 MeV for protons. The cross-section calculations are performed within the 1st Born approximation in which the ejected electron is described by a Coulomb wave whereas the incident and the scattered projectiles are both described by plane waves. The pyrimidine target is described using the Gaussian 09 software package. Furthermore, our theoretical predictions obtained are in good agreement with experimental absolute total cross sections, while large discrepancies are observed between existing semi-empirical models and the present calculations.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS1978

Chemical evolution. XXIX - Pyrimidines from hydrogen cyanide

Compounds obtained by hydrolysis of HCN oligomers formed by allowing pH 9.2, 0.1 M cyanide to stand at room temperature for 4 to 12 months were analyzed. Hydrolysis of HCN oligomers yielded 4,5-dihydroxypyrimidine and 5-hydroxyuracil; orotic acid was detected after hydrolysis at pH 8.5. A unified pathway from diaminofumaronitrile to the pyrimidines observed is suggested. As purines, pyrimidines and amino acids are released by hydrolysis of HCN oligomers in either acidic or mildly basic aqueous solutions, they could have been formed on the primitive earth in spite of fluctuations in pH. 4,5-dihydroxypyrimidines appear to be likely candidates for incorporation into primitive nucleic acids, as they should undergo Watson-Crick hydrogen bonding with adenine.

Ferris, J. P.↗
NASA NTRS2003

Direct Isolation of Purines and Pyrimidines from Nucleic Acids Using Sublimation

A sublimation technique was developed to isolate purines and pyrimidines directly from lambda-deoxyribonucleic acid (lambda-DNA) and Escherichia coli cells. The sublimation of adenine, cytosine, guanine, and thymine from lambda-DNA was tested under reduced pressure (approx. 0.5 Torr) at temperatures of >150 C. With the exception of guanine, approximately 60 -75% of each base was sublimed directly from the lambda-DNA and recovered on a coldfinger of the sublimation apparatus after heating to 450 C. Several nucleobases including adenine, cytosine, thymine, and uracil were also recovered from E. coli bacteria after heating the cells to the same temperature, although some thermal decomposition of the bases also occurred. These results demonstrate the feasibility of using sublimation to isolate purines and pyrimidines from native E. coli DNA and RNA without any chemical treatment of the cells.

Glavin, Daniel P.↗
NASA NTRS2003

Isolation of Purines and Pyrimidines from the Murchison Meteorite

The origin of life on Earth, and possibly on other planets such as Mars, would have required the presence of liquid water and a continuous supply of prebiotic organic compounds. The delivery of organic matter by asteroids, comets, and carbonaceous meteorites could have contributed to the early Earth's prebiotic inventory by seeding the planet with biologically important organic compounds. A wide variety of prebiotic organic compounds have previously been detected in the Murchison CM type carbonaceous chondrite including amino acids, purines and pyrimidines'. These compounds play a major role in terrestrial biochemistry and are integral components of proteins, DNA and RNA. In this study we developed a new extraction technique using sublimation in order to isolate purines and pyrimidines from Murchison2, which is cleaner and more time efficient that traditional methods3. Several purines including adenine, guanine, hypoxanthine and xanthine were positively identified by high performance liquid chromatography and ultraviolet absorption detection in our Murchison extracts. The purines detected in Murchison do not correlate with the distribution of nucleobases found in geological environments on Earth4. Moreover, the abundance of extraterrestrial amino acids and the low level of terrestrial amino acid contaminants found in Murchison', support the idea that the purines in t h s meteorite are extraterrestrial in origin.

Glavin, D. P.↗
NASA NTRS2010

Formation of Nucleobases from the UV Irradiation of Pyrimidine in Interstellar Ice Analogs

Previous laboratory simulations showed that complex molecules, including prebiotic compounds/can be formed under interstellar conditions from the vacuum UV irradiation of interstellar ice analogs containing H2O, CO, NH3 etc. Although some complex prebiotic species have not been confirmed In the interstellar medium, they are known to be present in meteorites. Nucleobases, the building blocks of DNA and RNA, have also been detected in meteorites. Here, we present a study of the formation of pyrimidine-based compounds from the UV irradiation of pyrimidine in H2O- and/or NH3-ices at 20-30 K, Our results show that various derivatives, induding the nucleobases uracil and cytosine, are formed under these conditions.

Milam, Stefanie N.↗
NASA NTRS2010

Formation of Nucleobases from the UV Photo-Irradiation of Pyrimidine in Astrophysical Ice Analogs

Astrochemistry laboratory simulations have shown that complex organic molecules including compounds of astrobiological interest can be formed under interstellarl/circumstellar conditions from the vacuum UV irradiation of astrophysical ice analogs containing H2O, CO, CO2, CH3OH, NH13, etc. Of all prebiotic compounds, the formation of amino acids under such experimental conditions has been the most extensively studied. Although the presence of amino acids in the interstellar medium (ISM) has yet to be confirmed, they have been detected in meteorites, indicating that biomolecules and/or their precursors can be formed under extraterrestrial, abiotic conditions. Nucleobases, the building blocks of DNA and RNA, as well as other 1V-heterocycles, have also been detected in meteorites, but like amino acids, they have yet to be observed in the ISM. In this work, we present an experimental study of the formation of pyrimidine-based compounds from the UV photo-irradiation of pyrimidine in ice mixtures containing H2O, NH3, and/or CH3OH at low temperature and pressure.

Milam, S. N.↗
DOE OSTI2019

Design, synthesis, and antihypertensive activity of new pyrimidine derivatives endowing new pharmacophores

A new series of achiral pyrimidine derivatives based on nifedipine-like structure was designed and synthesized. These pyrimidyl derivatives contained hydrazine, hydrazones, acetohydrazide, differently substituted benzylidene functionalities, benzosulfohydrazine, various heterocycles such as pyrazole, pyrazolidinedione, thiazoline, and thiazolidinone rings, and fused ring systems such as triazolopyrimidine and pyrimidotriazine rings. Compounds 5a, 5b, 11b, 8b, 9b–d, and 15b showed a decrease in mean arterial rabbit blood pressure (MABP) ranging from 51.4 to 78.2 mmHg in rabbits in comparison with nifedipine-treated rabbits. Among these derivatives, compounds 5a, 5b, 9b, and 9c were found to exhibit calcium channel blockade activity on preparations of rabbit aortae. They exhibited relaxation in the range of 89.2% to 74.4% in comparison to nifedipine (57.6%) as well as a decrease in heart rate. Histopathological effect of compounds 5a,b on the expression of endothelial nitric oxide synthase (eNOS) was also examined on rat aorta. An intense expression of eNOS immune staining in aortic endothelium was seen for compound 5b indicating that it lowered blood pressure via activation of eNOS expression in aorta.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Synthesis and characterization of new N-{4,6-bis[2-(het)arylvinyl]pyrimidin-2-yl}-substituted polycyclic aromatic imides

Two series of new N-{4,6-bis[2-(het)arylvinyl]pyrimidin-2-yl}-substituted aromatic polycyclic imides were synthesized. The synthesized chromophores were characterized by UV and fluorescence spectroscopy, cyclic voltammetry, and quantum chemical density functional theory calculations. A change in the nature of aryl (hetaryl) moieties was found to cause changes in the optical properties of both solutions of these compounds and thin films prepared from these compounds. The replacement of the phthalimide moiety by the 1,8-naphthalimide one has led to a significant increase in the lowest unoccupied molecular orbital energy.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1 R132H . Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure–activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood–brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.

2-HG↗
DOE OSTI2011

Pathways for Fluorescence Quenching in 2-Aminopurine π-Stacked with Pyrimidine Nucleobases

Fluorescent analogues of nucleobases are very useful as probes to study DNA dynamics, because natural DNA does not fluoresce significantly. In many of these analogues, such as 2-aminopurine (2AP), the fluorescence is quenched when incorporated into DNA through processes that are not well understood. This work uses theoretical studies to examine fluorescence quenching pathways in 2AP-containing dimers. The singlet excited states of π-stacked dimer systems containing 2AP and a pyrimidine base, thymine or cytosine, have been studied using ab initio computational methods. Computed relaxation pathways along the excited-state surfaces reveal novel mechanisms that can lead to fluorescence quenching in the π-stacked dimers. The placement of 2AP on the 5’ or 3’ terminus of the dimers has different effects on the excitation energies and the relaxation pathways on the S₁ excited state. Conical intersections between the ground and first excited states exist when 2AP is placed at the 3’ side, whereas the placement of 2AP at the 5’ side leads to the switching of a bright state to a dark state. Both of these processes can lead to fluorescence quenching and may contribute to the fluorescence quenching observed in 2AP when incorporated in DNA.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Absolute total and partial dissociative cross sections of pyrimidine at electron and proton intermediate impact velocities

Absolute total non-dissociative and partial dissociative cross sections of pyrimidine were measured for electron impact energies ranging from 70 to 400 eV and for proton impact energies from 125 up to 2500 keV. MOs ionization induced by coulomb interaction were studied by measuring both ionization and partial dissociative cross sections through time of flight mass spectrometry and by obtaining the branching ratios for fragment formation via a model calculation based on the Born approximation. The partial yields and the absolute cross sections measured as a function of the energy combined with the model calculation proved to be a useful tool to determine the vacancy population of the valence MOs from which several sets of fragment ions are produced. It was also a key point to distinguish the dissociation regimes induced by both particles. A comparison with previous experimental results is also presented.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2015

Isomeric signatures in the fragmentation of pyridazine and pyrimidine induced by fast ion impact

We present fast proton impact induced fragmentations of pyrimidine and pyridazine as an experimental resource to investigate isomeric signatures. Major isomeric imprints are identified for few fragment ions and differences of more than an order of magnitude for the cross sections of fragments of the same mass were measured. The observation of the molecular structure of these isomers gives no apparent indication for the reasons for such substantial differences. It is verified that the simple displacement of the position of one nitrogen atom strongly inhibits or favors the production of some ionic fragment species. The dependency of the fragmentation cross sections on the proton impact energy, investigated by means of time of flight mass spectroscopy and of a model calculation based in first order perturbation theory, allows us to disentangle the complex collision dynamics of the ionic fragments. The proton-induced fragmentation discriminates rather directly the association between a molecular orbital ionization and the fragment-ions creation and abundance, as well as how the redistribution of the energy imparted to the molecules takes place, triggering not only single but also double vacancy and leads to specific fragmentation pathways.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2015

Low-energy positron scattering by pyrimidine

This work reports elastic integral and differential cross sections for positron collisions with pyrimidine, for energies up to 20 eV. The cross sections were computed with the Schwinger multichannel method in the static plus polarization approximation. We also employed the Born closure procedure to account for the long range potential due to the permanent dipole moment of the molecule. Our results are compared with the experimental total cross section of Zecca et al. [J. Phys. B 43, 215204 (2010)], the experimental grand-total, quasi-elastic integral and differential cross section of Palihawadana et al. [Phys. Rev. A 88, 12717 (2013)]. We also compare our results with theoretical integral and differential cross sections obtained by Sanz et al. [Phys. Rev. A 88, 62704 (2013)] with the R-matrix and the independent atom model with screening-corrected additivity rule methods, and with the results computed by Franz and Gianturco [Phys. Rev. A 88, 042711 (2013)] using model correlation-polarization potentials. The agreement between the theory and the experiment is encouraging.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2013

Intersubunit communication in the dihydroorotase-aspartate transcarbamoylase complex of Aquifex aeolicus : Intersubunit Communication in a Pyrimidine Biosynthetic Complex

Aspartate transcarbamoylase and dihydroorotase, enzymes that catalyze the second and third step in de novo pyrimidine biosynthesis, are associated in dodecameric complexes in Aquifex aeolicus and many other organisms. The architecture of the dodecamer is ideally suited to channel the intermediate, carbamoyl aspartate from its site of synthesis on the ATC subunit to the active site of DHO, which catalyzes the next step in the pathway, because both reactions occur within a large, internal solvent-filled cavity. Channeling usually requires that the reactions of the enzymes are coordinated so that the rate of synthesis of the intermediate matches its rate of utilization. The linkage between the ATC and DHO subunits was demonstrated by showing that the binding of the bisubstrate analog, N-phosphonacetyl-L-aspartate to the ATC subunit inhibits the activity of the distal DHO subunit. Structural studies identified a DHO loop, loop A, interdigitating between the ATC domains that would be expected to interfere with domain closure essential for ATC catalysis. Mutation of the DHO residues in loop A that penetrate deeply between the two ATC domains inhibits the ATC activity by interfering with the normal reciprocal linkage between the two enzymes. Moreover, a synthetic peptide that mimics that part of the DHO loop that binds between the two ATC domains was found to be an allosteric or noncompletive ATC inhibitor (K i = 22 μM). A model is proposed suggesting that loop A is an important component of the functional linkage between the enzymes.

Evans, Hedeel Guy↗