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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma

Highlights: • Multicomponent reaction (MCR) is a productive and economical method for the synthesis of antitumor compounds by connecting functional moieties. • A series of indole substituted dihydropyrido[2,3-d]pyrimidines were synthesized by MCR. • 4p exhibits antitumor activity both in vitro and in vivo via inhibiting AKT and ERK1/2 pathways on hepatocellular carcinoma. Development of an effective and safe anti-cancer drug is an urgent request for hepatocellular carcinoma (HCC). In this study, we synthesized a series of novel indole substituted dihydropyrido[2,3-d]pyrimidines through the multicomponent reactions to connect pyrido[2,3-d]pyrimidine and indole moities via an one-pot three-component reaction of 3-cyanoacetyl indoles 1, various aromatic aldehyde 2, and 2,6-diaminopyrimidin-4(3H)-one 3. Subsequently, we screened their cytotoxicity via CCK-8 assay in HepG2 cells, a human hepatoma cell line and chose compound 4p that showed the lowest dosage of IC50 to study the antitumor activities to HCC. Interestingly, 4p significantly induced the cell cycle arrest and apoptosis of HepG2 via targeting AKT and ERK1/2 signaling pathways in vitro. To improve the solubility of compound 4p, we hosted this compound into the substituted glucopyranose ring of (2-Hydroxypropyl)-β-cyclodextrin (HBC), a cosolvent approved by FDA with the help of ultrasonication and heating. Finally, we showed that oral administration of HBC-hosted 4p effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice in subcutaneously xenografted model. These results suggest that multicomponent reactions connecting pyrido[2,3-d]pyrimidine and indole moities is a productive and economical method for the synthesis of anticancer compound, and oral administration of HBC-hosted 4p is an effective and safe agents for treatment of HCC, whose clinical application potency warrant further studies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Computational Chemistry-Guided Design of Selective Chemoresponsive Liquid Crystals Using Pyridine and Pyrimidine Functional Groups

Computational chemistry-guided designs of chemoresponsive liquid crystals (LCs) with pyridine or pyrimidine groups that bind to metal-cation-functionalized surfaces to provide improved selective responses to targeted vapor species (dimethylmethylphosphonate (DMMP)) over nontargeted species (water) are reported. The LC designs against experiments are tested by synthesizing 4-(4-pentyl-phenyl)-pyridine and 5-(4-pentyl-phenyl)-pyrimidine and quantifying LC responses to DMMP and water. Consistent with the computations, pyridine-containing LCs bind to metal-cation-functionalized surfaces too strongly to permit a response to either DMMP or water whereas pyrimidine-containing LCs undergo a surface-driven orientational transition in response to DMMP without interference from water. The computation predictions are not strongly dependent on assumptions regarding the degree of coordination of the metal ions but are limited in their ability to predict LC responses when using cations with mostly empty d orbitals. Overall, this work identifies a promising new class of chemoresponsive LCs based on pyrimidine that exhibits enhanced tolerance to water, a result that is important because water is a ubiquitous and particularly challenging chemical interferent in chemical sensing strategies based on LCs. The work also provides further evidence of the transformative utility of computational chemistry methods to design LC materials that exhibit selective orientational responses in specific chemical environments.

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

Pyrimidine homeostasis is accomplished by directed overflow metabolism

Cellular metabolism converts available nutrients into usable energy and biomass precursors. The process is regulated to facilitate efficient nutrient use and metabolic homeostasis. Feedback inhibition of the first committed step of a pathway by its final product is a classical means of controlling biosynthesis. In a canonical example, the first committed enzyme in the pyrimidine pathway in Escherichia coli is allosterically inhibited by cytidine triphosphate. The physiological consequences of disrupting this regulation, however, have not been previously explored. Here we identify an alternative regulatory strategy that enables precise control of pyrimidine pathway end-product levels, even in the presence of dysregulated biosynthetic flux. The mechanism involves cooperative feedback regulation of the near-terminal pathway enzyme uridine monophosphate kinase. Such feedback leads to build-up of the pathway intermediate uridine monophosphate, which is in turn degraded by a conserved phosphatase, here termed UmpH, with previously unknown physiological function. Such directed overflow metabolism allows homeostasis of uridine triphosphate and cytidine triphosphate levels at the expense of uracil excretion and slower growth during energy limitation. Disruption of the directed overflow regulatory mechanism impairs growth in pyrimidine-rich environments. Thus, pyrimidine homeostasis involves dual regulatory strategies, with classical feedback inhibition enhancing metabolic efficiency and directed overflow metabolism ensuring end-product homeostasis.

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

The role of pyrimidine and water as underlying molecular constituents for describing radiation damage in living tissue: A comparative study

Water is often used as the medium for characterizing the effects of radiation on living tissue. However, in this study, charged-particle track simulations are employed to quantify the induced physicochemical and potential biological implications when a primary ionising particle with energy 10 keV strikes a medium made up entirely of water or pyrimidine. Note that pyrimidine was chosen as the DNA/RNA bases cytosine, thymine, and uracil can be considered pyrimidine derivatives. This study aims to assess the influence of the choice of medium on the charged-particle transport, and identify how appropriate it is to use water as the default medium to describe the effects of ionising radiation on living tissue. Based on the respective electron interaction cross sections, we provide a model, which allows the study of radiation effects not only in terms of energy deposition (absorbed dose and stopping power) but also in terms of the number of induced molecular processes. Results of these parameters for water and pyrimidine are presented and compared.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

The photochemistry of pyrimidine in realistic astrophysical ices and the production of nucleobases

Nucleobases, together with deoxyribose/ribose and phosphoric acid, are the building blocks of DNA and RNA for all known life. The presence of nucleobase-like compounds in carbonaceous chondrites delivered to the Earth raises the question of an extraterrestrial origin for the molecules that triggered life on our planet. Whether these molecules are formed in interstellar/protostellar environments, in small parent bodies in the solar system, or both, is currently unclear. Recent experiments show that the UV irradiation of pyrimidine (C{sub 4}H{sub 4}N{sub 2}) in H{sub 2}O-rich ice mixtures that contain NH{sub 3}, CH{sub 3}OH, or CH{sub 4} leads to the formation of the pyrimidine-based nucleobases uracil, cytosine, and thymine. In this work, we discuss the low-temperature UV irradiation of pyrimidine in realistic astrophysical ice mixtures containing H{sub 2}O, CH{sub 3}OH, and NH{sub 3}, with or without CH{sub 4}, to search for the production of nucleobases and other prebiotic compounds. These experiments show the presence of uracil, urea, glycerol, hexamethylenetetramine, small amino acids, and small carboxylic acids in all samples. Cytosine was only found in one sample produced from ices irradiated with a higher UV dose, while thymine was not found in any sample, even after irradiation with a higher UV dose. Results are discussed to evaluate the role of the photochemistry of pyrimidine in the inventory of organic molecules detected in meteorites and their astrophysical/astrobiological implications.

79 ASTRONOMY AND ASTROPHYSICS↗
NASA NTRS2012

Nucleobases and Prebiotic Molecules in Organic Residues Produced from the Ultraviolet Photo-Irradiation of Pyrimidine in NH3 and H2O+NH3 Ices

Although not yet identified in the interstellar medium (ISM), N-heterocycles including nucleobases the information subunits of DNA and RNA are present in carbonaceous chondrites, which indicates that molecules of biological interest can be formed in non-terrestrial environments via abiotic pathways. Recent laboratory experiments and ab-initio calculations have already shown that the irradiation of pyrimidine in pure H2O ices leads to the formation of a suite of oxidized pyrimidine derivatives, including the nucleobase uracil. In the present work, NH3:pyrimidine and H2O:NH3:pyrimidine ice mixtures with different relative proportions were irradiated with UV photons under astrophysically relevant conditions. Liquid- and gas-chromatography analysis of the resulting organic residues has led to the detection of the nucleobases uracil and cytosine, as well as other species of prebiotic interest such as urea and small amino acids. The presence of these molecules in organic residues formed under abiotic conditions supports scenarios in which extraterrestrial organics that formed in space and were subsequently delivered to telluric planets via comets and meteorites could have contributed to the inventory of molecules that triggered the first biological reactions on their surfaces.

Nuevo, Michel↗
NASA NTRS2014

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

Nucleobases are the informational subunits of DNA and RNA. They consist of Nheterocycles that belong to either the pyrimidine-base group (uracil, cytosine, and thymine) or the purinebase group (adenine and guanine). Several nucleobases, mostly purine bases, have been detected in meteorites [1-3], with isotopic signatures consistent with an extraterrestrial origin [4]. Uracil is the only pyrimidine-base compound formally reported in meteorites [2], though the presence of cytosine cannot be ruled out [5,6]. However, the actual process by which the uracil was made and the reasons for the non-detection of thymine in meteorites have yet to be fully explained. Although no N-heterocycles have ever been observed in the ISM [7,8], the positions of the 6.2-μm interstellar emission features suggest a population of such molecules is likely to be present [9]. In this work we study the formation of pyrimidine-based molecules, including the three nucleobases uracil, cytosine, and thymine from the ultraviolet (UV) irradiation of pyrimidine in ices consisting of several combinations of H(sub2)O, NH(sub3), CH(sub3)OH, and CH(sub4) at low temperature, in order to simulate the astrophysical conditions under which prebiotic species may be formed in the interstellar medium, in the protosolar nebula, and on icy bodies of the Solar System.

UV Irradiation↗
DOE OSTI2015

Intermediate energy cross sections for electron-impact vibrational-excitation of pyrimidine

We report differential cross sections (DCSs) and integral cross sections (ICSs) for electron-impact vibrational-excitation of pyrimidine, at incident electron energies in the range 15–50 eV. The scattered electron angular range for the DCS measurements was 15°–90°. The measurements at the DCS-level are the first to be reported for vibrational-excitation in pyrimidine via electron impact, while for the ICS we extend the results from the only previous condensed-phase study [P. L. Levesque, M. Michaud, and L. Sanche, J. Chem. Phys. 122, 094701 (2005)], for electron energies ⩽12 eV, to higher energies. Interestingly, the trend in the magnitude of the lower energy condensed-phase ICSs is much smaller when compared to the corresponding gas phase results. As there is no evidence for the existence of any shape-resonances, in the available pyrimidine total cross sections [Baek et al., Phys. Rev. A 88, 032702 (2013); Fuss et al., ibid. 88, 042702 (2013)], between 10 and 20 eV, this mismatch in absolute magnitude between the condensed-phase and gas-phase ICSs might be indicative for collective-behaviour effects in the condensed-phase results.

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

Absolute cross sections for electronic excitation of pyrimidine by electron impact

We measured differential cross sections for electron-impact electronic excitation of pyrimidine, both as a function of electron energy up to 18 eV, and of scattering angle up to 180°. The emphasis of the present work is on recording detailed excitation functions revealing resonances in the excitation process. The differential cross sections were summed to obtain integral cross sections. These are compared to results of R-matrix calculations, which successfully reproduce both the magnitude of the cross section and the major resonant features. Comparison of the experiment to the calculated contributions of different symmetries to the integral cross section permitted assignment of several features to specific core-excited resonances. Comparison of the resonant structure of pyrimidine with that of benzene revealed pronounced similarities and thus a dominant role of π–π{sup ∗} excited states and resonances. Electron energy loss spectra were measured as a preparation for the cross section measurements and vibrational structure was observed for some of the triplet states. A detailed analysis of the electronic excited states of pyrimidine is also presented.

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

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach-Part 2

Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Molecular structure determination: Equilibrium structure of pyrimidine (m-C 4 H 4 N 2 ) from rotational spectroscopy (reSE) and high-level ab initio calculation (re) agree within the uncertainty of experimental measurement

The pure rotational spectrum of pyrimidine (m-C 4 H 4 N 2 ), the meta-substituted dinitrogen analog of benzene, has been studied in the millimeter-wave region from 235 GHz to 360 GHz. The rotational spectrum of the ground vibrational state has been assigned and fit to yield accurate rotational and distortion constants. Over 1700 distinct transitions were identified for the normal isotopologue in its ground vibrational state and least-squares fit to a partial sextic S-reduced Hamiltonian. Transitions for all four singly substituted 13 C and 15 N isotopologues were observed at natural abundance and were likewise fit. Deuterium-enriched samples of pyrimidine were synthesized, giving access to all eleven possible deuterium-substituted isotopologues, ten of which were previously unreported. Experimental values of rotational constants and computed values of vibration–rotation interaction constants and electron-mass corrections were used to determine semi-experimental equilibrium structures (r e SE ) of pyrimidine. The r e SE structure obtained using coupled-cluster with single, double, and perturbative triple excitations [CCSD(T)] corrections shows exceptional agreement with the re structure computed at the CCSD(T)/cc-pCV5Z level (≤0.0002 Å in bond distance and ≤0.03° in bond angle). Of the various computational methods examined, CCSD(T)/cc-pCV5Z is the only method for which the computed value of each geometric parameter lies within the statistical experimental uncertainty (2σ) of the corresponding semi-experimental coordinate. The exceptionally high accuracy and precision of the structure determination is a consequence of the large number of isotopologues measured, the precision and extent of the experimental frequency measurements, and the sophisticated theoretical treatment of the effects of vibration–rotation coupling and electron mass. Taken together, these demanding experimental and computational studies establish the capabilities of modern structural analysis for a prototypical monocyclic aromatic compound.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS2004

Isolation of Purines and Pyrimidines from the Murchison Meteorite Using Sublimation

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 exogenous 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 dominate terrestrial biochemistry and are integral components of proteins, DNA and RNA. Several purines including adenine, guanine, hypoxanthine, and xanthine, as well as the pyrimidine uracil, have previously been detected in water or formic acid extracts of Murchison using ion-exclusion chromatography and ultraviolet spectroscopy. However, even after purification of these extracts, the accurate identification and quantification of nucleobases is difficult due to interfering UV absorbing compounds. In order to reduce these effects, we have developed an extraction technique using sublimation to isolate purines and pyrimidines from other non-volatile organic compounds in Murchison acid extracts.

Glavin, D. P.↗
NASA NTRS2012

Nucleobases and Other Prebiotic Species from the UV Irradiation of Pyrimidine in Astrophysical Ices

Nucleobases are aromatic N-heterocycles that constitute the informational subunits of DNA and RNA and are divided into two families: pyrimidine bases (uracil, cytosine, and thymine) and purine bases (adenine and guanine). Nucleobases have been detected in meteorites and their extraterrestrial origin confirmed by isotope measurement. Although no N-heterocycles have been individually identified in the ISM, the 6.2-micron interstellar emission feature seen towards many astronomical objects suggests a population of such molecules is likely present. We report on a study of the formation of pyrimidine-based molecules, including nucleobases and other species of prebiotic interest, from the ultraviolet (UV) irradiation of pyrimidine in low temperature ices containing H2O, NH3, C3OH, and CH4, to simulate the astrophysical conditions under which prebiotic species may be formed in the Solar System.

Sandford, Scott↗
NASA NTRS2022

Identifying the Wide Diversity of Extraterrestrial Purine and Pyrimidine Nucleobases in Carbonaceous Meteorites

The lack of pyrimidine diversity in meteorites remains a mystery since prebiotic chemical models and laboratory experiments have predicted that these compounds can also be produced from chemical precursors found in meteorites. Here we report the detection of nucleobases in three carbonaceous meteorites using state-of-the-art analytical techniques optimized for small-scale quantification of nucleobases down to the range of parts per trillion (ppt). In addition to previously detected purine nucleobases in meteorites such as guanine and adenine, we identify various pyrimidine nucleobases such as cytosine, uracil, and thymine, and their structural isomers such as isocytosine, imidazole-4-carboxylic acid, and 6-methyluracil, respectively. Given the similarity in the molecular distribution of pyrimidines in meteorites and those in photon-processed interstellar ice analogues, some of these derivatives could have been generated by photochemical reactions prevailing in the interstellar medium and later incorporated into asteroids during solar system formation. This study demonstrates that a diversity of meteoritic nucleobases could serve as building blocks of DNA and RNA on the early Earth.

Yasuhiro Oba↗
DOE OSTI2019

Synthesis and anticancer activity evaluation of novel oxacalix[2]arene[2]pyrimidine derivatives

A series of novel oxacalix[2]arene[2]pyrimidine derivatives were synthesized, and their antitumor activities against HeLa, MCF7, HepG2, and A549 human cancer cell lines were evaluated using an MTT assay. Some of the synthesized compounds exhibited considerable anti-proliferative activity against the human cancer cell lines. Compound 5l, which contains an ethanolamine moiety, exhibited the strongest inhibitory activity against HepG2 with an IC{sub 50} value of 12.37 μM. Moreover, a cell apoptosis assay indicated that the anti-proliferative activity of 5l might be attributed to its induction of apoptosis. Our report highlights the potential anticancer efficacy of novel oxacalix[2]arene[2]pyrimidines.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Green synthesis and 3D pharmacophore study of pyrimidine and glucoside derivatives with in vitro potential anticancer and antioxidant activities

A facile and an efficient one-pot green synthesis of pyrimidine derivatives using the environmentally friendly Cerium(IV) ammonium nitrate (CAN) as catalyst and water as a solvent has been described. Some of the synthesized pyrimidines react with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in ethanol containing potassium hydroxide to give S-glucoside derivatives. The structures of the newly synthesized compounds were elucidated on the basis of their spectral and elemental analyses. In addition, selected derivatives of the products were screened for their anticancer activities against four tumor cell lines using MTT assay and the results showed that some of these compounds have potent cytotoxic effect, as concluded from their IC{sub 50} values. Molecular modeling studies including generation of a 3D pharmacophore model were carried out. The study showed high correlation with the experimental results. Antioxidant activity of the synthesized products was also investigated and most of them showed potent activity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Azomethines, isoxazole, N-substituted pyrazoles and pyrimidine containing curcumin derivatives: Urease inhibition and molecular modeling studies

Curcumin has shown large number of pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its various derivatives for diverse biological functions. In this study, curcumin derived azomethine, isoxazole, pyrimidines and N-substituted pyrazoles were synthesized to investigate their urease enzyme inhibition. The structures of newly synthesized compounds were described by IR, MS, {sup 1}H NMR and {sup 13}C NMR spectral data. Urease enzyme inhibition was evaluated through in vitro assays in which compound 8b was found to be the most potent (IC{sub 50} = 2.44 ± 0.07 μM) among the tested compounds. The compounds with diazine ring system except the 4d showed better urease inhibition (IC{sub 50} = 11.43 ± 0.21–19.63 ± 0.28 μM) than the standard urease inhibitor thiourea (IC{sub 50} = 22.61 ± 0.23 μM). Similarly enzyme kinetics data revealed that compounds 3c-3e and 8b were competitive inhibitors with Ki values of 20.0, 19.87, 20.23 and 19.11 μM respectively while the compounds 4b, 4c and 4e were mixed type of inhibitors with Ki values 6.72, 19.69 and 6.72 μM respectively. Molecular docking studies were also performed to identify the plausible binding modes of the most active compounds. - Highlights: • Azomethines, Isoxazole, N-substituted pyrazoles and pyrimidine with curcumin scaffold were synthesized. • Anti-urease studies of target compounds were performed. • Molecular modeling of most active compounds at active site of urease. • Thiourea conjugated with curcumin showed excellent urease inhibition with IC{sub 50} = 2.44 ± 0.07 μM.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Fully functional global genome repair of (6-4) photoproducts and compromised transcription-coupled repair of cyclobutane pyrimidine dimers in condensed mitotic chromatin

During mitosis, chromatin is highly condensed, and activities such as transcription and semiconservative replication do not occur. Consequently, the condensed condition of mitotic chromatin is assumed to inhibit DNA metabolism by impeding the access of DNA-transacting proteins. However, about 40 years ago, several researchers observed unscheduled DNA synthesis in UV-irradiated mitotic chromosomes, suggesting the presence of excision repair. We re-examined this subject by directly measuring the removal of UV-induced DNA lesions by an ELISA and by a Southern-based technique in HeLa cells arrested at mitosis. We observed that the removal of (6-4) photoproducts from the overall genome in mitotic cells was as efficient as in interphase cells. This suggests that global genome repair of (6-4) photoproducts is fully functional during mitosis, and that the DNA in mitotic chromatin is accessible to proteins involved in this mode of DNA repair. Nevertheless, not all modes of DNA repair seem fully functional during mitosis. We also observed that the removal of cyclobutane pyrimidine dimers from the dihydrofolate reductase and c-MYC genes in mitotic cells was very slow. This suggests that transcription-coupled repair of cyclobutane pyrimidine dimers is compromised or non-functional during mitosis, which is probably the consequence of mitotic transcriptional repression. -- Highlights: Black-Right-Pointing-Pointer Global genome repair of (6-4) photoproducts is fully active in mitotic cells. Black-Right-Pointing-Pointer DNA in condensed mitotic chromatin does not seem inaccessible or inert. Black-Right-Pointing-Pointer Mitotic transcriptional repression may impair transcription-coupled repair.

60 APPLIED LIFE SCIENCES↗