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Worldwide, colorectal cancer (CRC) is the third most common type of cancer and the second most common cause of cancer-related deaths. Thymidylate synthase (TS) is a crucial component of DNA biosynthesis and has drawn interest as an essential target for cancer treatment. In the current work, we have designed and synthesized twenty-eight new diaryl-based pyrido[2,3-d]pyrimidine/alkyl-substituted pyrido[2,3-d]pyrimidine derivatives and evaluated their anticancer activity against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines cell lines. Additionally, we have carried out TS inhibitory activity and in silico studies for compounds 1n and 2j. All the synthesized compounds exhibited good anticancer activity, but among them, compounds 1n and 2j showed excellent anticancer activity, having IC50 values of 1.98 ± 0.69, 2.18 ± 0.93, 4.04 ± 1.06, and 4.18 ± 1.87 µM; and 1.48 ± 0.86, 3.18 ± 0.79, 3.44 ± 1.51, and 5.18 ± 1.85 µM, against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines respectively with control raltitrexed (IC50 1.07 ± 1.08, 1.98 ± 0.72, 1.34 ± 1.0, and 3.09 ± 0.96 µM, respectively) and hTS inhibitory activity with IC50 values of 20.47 ± 1.09 and 13.48 ± 0.96 nM with control raltitrexed (IC50 14.95 ± 1.01 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 1n and 2j to the catalytic site of TS with docking scores of -10.6 and − 9.5 kcal/mol, respectively, with reference raltitrexed (-9.4 kcal/mol). Additionally, the assessment of physicochemical, biochemical, structural, and toxicological characteristics were also in the acceptable range for these compounds. Based on the anticancer activity of compounds, SAR was also performed for lead optimization. [ABSTRACT FROM AUTHOR]

A gentisic acid based-Deep Eutectic Solvent (MTPPBr/GA-DES) was synthesized by mixing one mole of methyl triphenylphosphonium bromide (MTPPBr) and one mole of gentisic acid (GA: 2,5-dihydroxy-benzoic acid) based on the eutectic point phase diagram. Then, it was characterized by FT-IR, NMR, densitometer, and TGA/DTA techniques and used as a potent and novel catalyst for the fast and green synthesis of: (i) Five new 2(a-e) and five known 2(f-j) benzo[6,7]chromeno[2,3-d]pyrimidines and (ii) One new (3a) and eleven known 3(b-l) pyrano[2,3-d]pyrimidines, in solvent-free conditions, short reaction times, and high yields. It is important to mention that for the synthesis of 2(a-j), there is only one reference which states that the reaction times are extremely long (720–2400 min), while these times are reduced to approximately 35–50 min in our proposed strategy, indicatinging that the rate of reactions will be 20–48 times faster, which is the clear and most obvious advantage of our approach. [ABSTRACT FROM AUTHOR]

A new DES (MTPPBr-PHTH-DES) was prepared from a mixture of methyltriphenyl-phosphonium bromide (MTPPBr) and phthalic acid (PHTH). The eutectic point phase diagram showed that a one-to-one molar ratio of MTPPBr to PHTH is the optimal molar ratio for the synthesis of new DES. Then, it was characterized with various techniques such as FT-IR, TGA/DTA, densitometer, eutectic point, and NMR and used as a novel acid catalyst in the synthesis of pyrimido[4,5-d]pyrimidines and pyrano[3,2-c]chromes in solvent-free condition. Short reaction time, low temperature, high efficiency, green condition, and easy recycling and separation of the DES catalyst are among the most important features of the presented method. [ABSTRACT FROM AUTHOR]

No biomarker has yet been identified that allows accurate diagnosis and prognosis of oral cancers. In this study, we investigated the presence of key metabolites in oral cancer using proton nuclear magnetic resonance (NMR) spectroscopy to identify metabolic biomarkers of gingivobuccal oral squamous cell carcinoma (GB-OSCC). NMR spectroscopy revealed that uracil was expressed in 83.09% of tumor tissues and pyrimidine metabolism was active in GB-OSCC; these results correlated well with immunohistochemistry (IHC) and RNA sequencing data. Based on further gene and protein analyses, we proposed a pathway for the production of uracil in GB-OSCC tissues. Uridinetriphosphate (UTP) is hydrolyzed to uridine diphosphate (UDP) by CD39 in the tumor microenvironment (TME). We hypothesized that UDP enters the cell with the help of the UDP-specific P2Y6 receptor for further processing by ENTPD4/5 to produce uracil. As the ATP reserves diminish, the weakened immune cells in the TME utilize pyrimidine metabolism as fuel for antitumor activity, and the same mechanism is hijacked by the tumor cells to promote their survival. Correspondingly, the differential expression of ENTPD4 and ENTPD5 in immune and tumor cells, respectively, indicatedtheir involvement in disease progression. Furthermore, higher uracil levels were detected in patients with lymph node metastasis, indicating that metastatic potential is increased in the presence of uracil. The presence of uracil and/or expression patterns of intermediate molecules in purine and pyrimidine pathways, such asCD39, CD73, and P2Y6 receptors together with ENTPD4 and ENTPD5, hold promise as biomarker(s) for oral cancer diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

The starting compound 3-amino-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,6(5H)-dione (1) is reacted with each of diketone and β-ketoester, forming pyridopyrazolo[1,5-a]pyrimidines 4a,b and 14a,b, respectively. The compounds 4 and 14 reacted with each of aromatic aldehyde and arenediazonium salt to give the respective arylidenes and arylhydrazo derivatives, respectively. The structure of the new products was established using spectroscopic techniques. The cytotoxic activity of selected targets was tested in vitro against three cancer cell lines MCF7, HepG2 and HCT116. The data obtained from enzymatic assays of TrKA indicated that compounds 7b and 16c have the strongest inhibitory effects on TrKA with IC50 = 0.064 ± 0.0037 μg/ml and IC50 = 0.047 ± 0.0027 μg/ml, respectively, compared to the standard drug Larotrectinib with IC50 = 0.034 ± 0.0021 μg/ml for the HepG2 cancer cell line. In cell cycle analysis, compounds 7b, 15b, 16a and 16c caused the greatest arrest in cell cycle at the G2/M phase. In addition, compound 15b has a higher apoptosis-inducing effect (36.72%) than compounds 7b (34.70%), 16a (21.14) and 16c (26.54%). Compounds 7b, 16a and 16c were shown fit tightly into the active site of the TrKA kinase crystal structure (PDB: 5H3Q). Also, ADME study was performed on some selected potent anticancer compounds described in this study. Highlights: A series of new pyrido[4ʹ,3ʹ:3,4]pyrazolo[1,5-a]pyrimidine derivatives were synthesized. The anticancer activity of the new compounds were tested in vitro. Compounds 7b and 16c showed broad spectrum potent anticancer activity. Compound 15b induced cell cycle arrest at G2/M phase in HepG-2 cell line. Compound 7c, the most promising agent, can be absorbed very easily by the gastrointestinal tract with potential BBB permeability. [ABSTRACT FROM AUTHOR]

The exponential development of resistance to conventional chemical insecticides adds another important motive for the creation of novel insecticidal active agents. One of the keys to meeting this challenge is the exploration of novel classes of insecticidal molecules with different modes of action. Herein, a novel series of spiro pyrimidine derivatives was prepared using some green synthetic methodologies such as microwave irradiation, and sonication under ultrasound waves. Spiro pyrimidine aminonitrile 1 is a key starting material for the synthesis of targets 2–9 by reaction with different carbon electrophiles and nitrogen nucleophiles. The structures of all the newly synthesized compounds were approved using spectral data. The toxicological efficiency and biological impacts of the synthesized spiro pyrimidine derivatives were assessed against Culex pipiens L. larvae. The toxicity of synthesized compounds showed remarkable variations against the C. pipiens larvae. Where, 3, 4 and 2 were the most efficient compounds with LC50 values of 12.43, 16.29 and 21.73 µg/mL, respectively. While 1 was the least potent compound with an LC50 value of 95.18 µg/mL. As well, other compounds were arranged according to LC50 values as follows 5 > 7 > 6 > 9 > 8. In addition, 3 and 4 exhibited significant prolongation of the developmental duration and greatly inhibited adult emergence. Moreover, many morphological deformities were observed in all developmental stages. Furthermore, cytotoxicity of the most effective compounds was assessed against the normal human cells (WI-38) as non-target organisms, where compounds 2, 4 and 3 showed weak to non-toxic effects. The study of binding affinity and correlation between chemical structure and reactivity was carried out using molecular docking study and DFT calculations to investigate their mode of action. This study shed light on promising compounds with larvicidal activity and biological impacts on the C. pipiens life cycle. [ABSTRACT FROM AUTHOR]

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 μM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 μM, 2.3 ± 5.91 μM and 5.65 ± 2.33 μM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted. [ABSTRACT FROM AUTHOR]

Utilizing the Knoevenagel–Michael tandem cyclocondensation reaction of barbituric acid/1,3-dimethylbarbituric acid, malononitrile, and aryl aldehydes, a sustainable methodology for the photosynthesis of pyrano[2,3-d]pyrimidine scaffolds has been devised. The present study expounds on the development of a green radical synthetic approach toward this class of compounds. In this study, a novel halogenated dicyanobenzene-based photosensitizer was utilized in an aqueous solution, exposed to air at room temperature, and activated by a blue LED as a renewable energy source for the purpose of generating energy. The primary aim of this endeavor is to employ a recently developed, easily obtainable, and affordably priced halogenated cyanoarene-based donor–acceptor (D–A). The 3DPAFIPN [2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile]} photocatalyst, as a thermally activated delayed fluorescence (TADF), is capable of inducing single electron transfer (SET) upon irradiation with visible light, thereby offering a facile and efficient approach with a high degree of effectiveness, energy efficiency, and eco-friendliness. The aforementioned phenomenon facilitates the exploration of the temporal changes that have occurred in the interactions between the surroundings and chemical constituents. The present study aimed to investigate the turnover number (TON) and turnover frequency (TOF) for pyrano[2,3-d]pyrimidine scaffolds. Additionally, it has been demonstrated that gram-scale cyclization is a viable method for utilization in industrial applications. [ABSTRACT FROM AUTHOR]

The current study involves the design and synthesis of a newly synthesized pyrrolo[2,3-d]pyrimidine derivatives to contain chlorine atoms in positions 4 and 6 and trichloromethyl group in position 2 using microwave technique as a new and robust approach for preparation of this type of pyrrolo[2,3-d]pyrimidine derivatives. The chemical structure of the synthesized pyrrolo[2,3-d]pyrimidine derivatives 3–19 was well-characterized using spectral and elemental analyses as well as single-crystal X-ray diffraction. All compounds were tested in vitro against seven selected human cancer cell lines, namely, MCF7, A549, HCT116, PC3, HePG2, PACA2 and BJ1 using MTT assay. It was found that compounds 14a, 16b and 18b were the most active toward MCF7 with IC50 (1.7, 5.7, and 3.4 μg/ml, respectively) relative to doxorubicin (Dox.) (26.1 μg/ml). Additionally, compound 17 exerted promising cytotoxic effects against HePG2 and PACA2 with IC50 (8.7 and 6.4 μg/ml, respectively) relative to Dox. (21.6 and 28.3 μg/ml, respectively). The molecular docking study confirmed our ELISA result which showed the promising binding affinities of compounds 14a and 17 against Bcl2 anti-apoptotic protein. At the gene expression level, P53, BAX, DR4 and DR5 were up-regulated, while Bcl2, Il-8, and CDK4 were down-regulated in 14a, 14b and 18b treated MCF7 cells. At the protein level, compound 14b increased the activity of Caspase 8 and BAX (18.263 and 14.25 pg/ml) relative to Dox. (3.99 and 4.92 pg/ml, respectively), while the activity of Bcl2 was greatly decreased in 14a treated MCF7 (2.4 pg/ml) compared with Dox. (14.37 pg/ml). Compounds 14a and 14b caused cell cycle arrest at the G1/S phase in MCF7. Compounds 16b and 18b induced the apoptotic death of MCF7 cells. In addition, the percentage of fragmented DNA was increased significantly in 14a treated MCF7 cells. [ABSTRACT FROM AUTHOR]

Purine-containing nucleotide second messengers regulate diverse cellular activities. Cyclic di-pyrimidines mediate anti-phage functions in bacteria; however, the synthesis mechanism remains elusive. Here, we determine the high-resolution structures of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases (CD-NTases) in clade E (CdnE) in its apo, substrate-, and intermediate-bound states. A conserved (R/Q)xW motif controlling the pyrimidine specificity of donor nucleotide is identified. Mutation of Trp or Arg from the (R/Q)xW motif to Ala rewires its specificity to purine nucleotides, producing mixed purine-pyrimidine cyclic dinucleotides (CDNs). Preferential binding of uracil over cytosine bases explains the product specificity of cyclic di-pyrimidine-synthesizing CdnE to cyclic di-UMP (cUU). Based on the intermediate-bound structures, a synthetic pathway for cUU containing a unique 2'3'-phosphodiester linkage through intermediate pppU[3'−5']pU is deduced. Our results provide a framework for pyrimidine selection and establish the importance of conserved residues at the C-terminal loop for the specificity determination of CD-NTases. Here, the authors present structural and functional characterization of bacterial CD-NTases that synthesize cyclic dipyrimidines for phage resistance, revealing a (R/Q)xW motif dictating pyrimidine selection which suggests a sequential pathway for synthesizing 2'3'-cyclic di-UMP. [ABSTRACT FROM AUTHOR]

Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa. TP53 alteration and TMPRSS2-ERG fusion are often found together in prostate cancer. Here, the authors show that gain-of-function mutant p53 collaborates with ERG proto-oncogene to drive prostate cancer tumourigenesis by activating beta-catenin expression and afterwards pyrimidine synthesis. [ABSTRACT FROM AUTHOR]

Context: The design and synthesis of safe and highly active sulfonylurea herbicides is still a challenge. Therefore, following some principles of structure-activity relationship (SAR) of sulfonylurea herbicides, this work focuses on evaluating two sulfonylurea derivatives bearing electron-withdrawing substituents, namely, –(CO)OCH3 and –NO2 on the aryl group, on herbicidal activity. To understand the effects caused by the substituent groups, the molecular and electronic structures of the sulfonylureas were evaluated by density functional theory. Likewise, the crystalline supramolecular arrangements of both compounds were analyzed by Hirshfeld surface, QTAIM, and NBO, with the aim of verifying changes in intermolecular interactions caused by substituent groups. Finally, through a toxicophoric analysis, we were able to predict the interacting groups in their biological target, acetolactate synthase, and verify the interactions with the binding site. Methods: All theoretical calculations were conducted using the highly parameterized empirical exchange-correlation functional M06-2X accompanied by the diffuse and polarized basis set 6-311++G(d,p). The atomic coordinates were obtained directly from the crystalline structures, and from the energies of the frontier molecular orbitals (HOMO and LUMO), chemical descriptors were obtained that indicated the influence of the functional groups in the sulfonylureas on the reactivity of the molecules. The intermolecular interactions in the crystals were analyzed using the Hirshfeld, QTAIM, and NBO surfaces. Toxicophoric modeling was performed by the PharmaGist webserver and molecular docking calculations were performed by the GOLD 2022.1.0 software package so that the ligand was fitted to the binding site in a 10 Å sphere. For this, genetic algorithm parameters were used using the ChemPLP scoring function for docking and ASP for redocking. [ABSTRACT FROM AUTHOR]

A correction notice is presented related to the article "Vitamin E inhibits the UVAI induction of "light" and "dark" cyclobutane pyrimidine dimers, and oxidatively generated DNA damage, in keratinocytes" whichy was publihsed in the previous issue of the periodical.

The Knoevenagel-Michael cyclocondensation of barbituric acid/1,3-dimethylbarbituric acid, malononitrile, and arylaldehyde derivatives was used to construct a multicomponent green tandem method for the metal-free synthesis of pyrano[2,3-d]pyrimidine scaffolds. At room temperature in aqueous ethanol, photo-excited state functions generated from Na2 eosin Y were employed as direct hydrogen atom transfer (HAT) catalysts by visible light mediated in the air atmosphere. This research looks towards expanding the use of a non-metallic organic dye that is both affordable and readily available. Because of its good yields, energy-effectiveness, high atom economy, time-saving qualities of the reaction, and operational simplicity, Na2 eosin Y is photochemically produced with the least amount of a catalyst. As a result, various ecological and sustainable chemical properties are met. Surprisingly, such cyclization may be carried out on a gram scale, indicating the reaction's potential industrial application. [ABSTRACT FROM AUTHOR]

Understanding and characterizing the molecular background of the maintenance of genomic integrity might be a major factor in comprehending the exceptional ability of the malaria parasite, Plasmodium falciparum to adapt at a fast pace to antimalarials. A balanced nucleotide pool is an essential factor for high-fidelity replication. The lack of detailed studies on deoxynucleotide-triphosphate (dNTP) pools in various intraerythrocytic stages of Plasmodium falciparum motivated our present study. Here, we focused on the building blocks of DNA and utilized an EvaGreen-based dNTP incorporation assay to successfully measure the temporal dynamics of dNTPs in every intraerythrocytic stage and in drug-treated trophozoites. Our findings show that the ratio of dNTPs in the ring-stage parasites significantly differs from the more mature trophozoite and schizont stages. We were also able to detect dGTP levels that have never been shown before and found it to be the least abundant dNTP in all stages. Treatment with WR99210, a TS-DHFR inhibitor drug, affected not only dTTP, but also dGTP levels, despite its presumed selective action on pyrimidine biosynthesis. Results from our studies might assist in a better understanding of genome integrity mechanisms and may potentially lead to novel drug related aspects involving purine and pyrimidine metabolic targets. [ABSTRACT FROM AUTHOR]

Pyrimidine compounds have proven to be effective and efficient additives capable of protecting mild steel in acidic media. This class of organic compounds often functions as adsorption-type inhibitors of corrosion by forming a protective layer on the metallic substrate. The present study reports a computational study of forty pyrimidine compounds that have been investigated as sustainable inhibitors of mild steel corrosion in molar HCl solution. Quantitative structure property relationship was conducted using linear (multiple linear regression) and nonlinear (artificial neural network) models. Standardization method was employed in variable selection yielding five top chemical descriptors utilized for model development along with the inhibitor concentration. Multiple linear regression model yielded a fair predictive model. Artificial neural network model developed using k-fold cross-validation method provided a comprehensive insight into the corrosion protection mechanism of studied pyrimidine-based corrosion inhibitors. Using a multilayer perceptron with Levenberg–Marquardt algorithm, the study obtained the optimal model having a MSE of 8.479, RMSE of 2.912, MAD of 1.791, and MAPE of 2.648. The optimal neural network model was further utilized to forecast the protection capacities of nine non-synthesized pyrimidine derivatives. The predicted inhibition efficiencies ranged from 89 to 98%, revealing the significance of the considered chemical descriptors, the predictive capacity of the developed model, and the potency of the theoretical inhibitors. [ABSTRACT FROM AUTHOR]

Eight push–pull systems involving containing four transition metals (iron, ruthenium, cobalt, and nickel), metallocenes as donor groups, cyanoacrylate as electron attractor group, and thiophene-N = N- pyrimidine derivatives as π-conjugated bridges were designed and studied using DFT and TD-DFT methods involving B3LYP and CAM-B3LYP functionals combined with the cc-pVDZ/LANL2DZ basis sets. The main purpose of this work is to determine the effect of metallocene in improving the photosensitization property of such chromophores. This was done by calculating their light-harvesting efficiency LHE as well as other properties employed for DSSC application. The considered dyes were first studied in the gas phase, then in the presence of TiO2 nanoparticles representing the semi-conductor, and finally in the presence of a specific implicit solvent. The presence of iron as metal involved in the metallocene group supplemented by extending the π-conjugated bridge by a cyanovinyl spacer was demonstrated so as to give the most optimal response taking into account the lower cost and toxicity as well as the friendliness to the environment of iron as metal. [ABSTRACT FROM AUTHOR]

The protein ATP-binding cassette subfamily G member 2 (ABCG2) is one of the major factors behind multidrug resistance (MDR) in breast cancer. We performed three-dimensional quantitative structure–activity relationship (3D-QSAR) modelling, docking, and molecular dynamics (MD) simulation to design pyrimidine-based ABCG2 antagonists. The developed QSAR model (r2 = 0.92, q2 = 0.82, and good cross-validated r2 = 0.73) dictate requirement of electrostatic, and hydrophobic fields for modulating bioactivity. Based on this rationale, we designed and screened 1010 new compounds, among them 2 (ND-510 and ND-500) exhibit excellent drug-like features. Comparative molecular docking, MM/GBSA and ADMET profiles were determined to understand the interactive poses, affinity, and drug-likeness of the designed compounds. Furthermore, MD simulations were performed with the ABCG2 receptor, and the results were compared with the two earlier synthesized active compounds. The outcomes of the study will help researchers to develop new antagonists for treatment of MDR breast cancer. [ABSTRACT FROM AUTHOR]

Antimalarial drug resistance is a major threat due to the emerging resistance to all the available drugs in the market. In an approach to develop alternative drugs, a novel class of Pf-DHFR inhibitors was developed using pyrimidine as the core nucleus and substituting the 4- and 6- positions with amines and 4-amino benzoic acid (PABA) to avoid the problem of drug resistance. The resultant compounds 3(a–j) after primary in silico screening and filtering were synthesized using microwave efficiently in high yield and reduced time period compared to conventional synthesis. The antimalarial assay was performed in vitro, against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum using chloroquine as a reference standard. The IC50 values were in the range of 5.26–106.76 µg/ml for 3D7 and in Dd2 the value ranges from 4.71 to 112.98 µg/ml. Compounds 3d, 3e, 3f and 3h showed significant antimalarial activity against both the strains of P. falciparum with no cytotoxicity against fibroblast cell line and 3f was found to be the most potent among them. The hemolysis assay of all the compounds in fresh erythrocytes showed insignificant hemolysis below 5% at a higher dose level. Hence, the present study suggests the possible utility of PABA-substituted pyrimidine scaffold for further development of new Pf-DHFR inhibitors. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is characterized by arrested differentiation making differentiation therapy a promising treatment strategy. Recent success of inhibitors of mutated isocitrate dehydrogenase (IDH) invigorated interest in differentiation therapy of AML so that several new drugs have been proposed, including inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis. Cytarabine, a backbone of standard AML therapy, is known to induce differentiation at low doses, but the mechanism is not completely elucidated. We have previously reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) and brequinar, a DHODH inhibitor, induced differentiation of myeloid leukemia by activating the ataxia telangiectasia and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) via pyrimidine depletion. In this study, using immunoblotting, flow cytometry analyses, pharmacologic inhibitors and genetic inactivation of Chk1 in myeloid leukemia cell lines, we show that low dose cytarabine induces differentiation by activating Chk1. In addition, cytarabine induces differentiation ex vivo in a subset of primary AML samples that are sensitive to AICAr and DHODH inhibitor. The results of our study suggest that leukemic cell differentiation stimulated by low doses of cytarabine depends on the activation of Chk1 and thus shares the same pathway as pyrimidine synthesis inhibitors. [ABSTRACT FROM AUTHOR]

Novel therapies are urgently needed for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy. In addition, therapies that target unique vulnerabilities in the tumor microenvironment (TME) of EOC have largely been unrealized. One strategy to achieve selective drug delivery for EOC therapy involves use of targeted antifolates via their uptake by folate receptor (FR) proteins, resulting in inhibition of essential one-carbon (C1) metabolic pathways. FRα is highly expressed in EOCs, along with the proton-coupled folate transporter (PCFT); FRβ is expressed on activated macrophages, a major infiltrating immune population in EOC. Thus, there is great potential for targeting both the tumor and the TME with agents delivered via selective transport by FRs and PCFT. In this report, we investigated the therapeutic potential of a novel cytosolic C1 6-substituted pyrrolo[2,3-d]pyrimidine inhibitor AGF94, with selectivity for uptake by FRs and PCFT and inhibition of de novo purine nucleotide biosynthesis, against a syngeneic model of ovarian cancer (BR-Luc) which recapitulates high-grade serous ovarian cancer in patients. In vitro activity of AGF94 was extended in vivo against orthotopic BR-Luc tumors. With late-stage subcutaneous BR-Luc xenografts, AGF94 treatment resulted in substantial anti-tumor efficacy, accompanied by significantly decreased M2-like FRβ-expressing macrophages and increased CD3+ T cells, whereas CD4+ and CD8+ T cells were unaffected. Our studies demonstrate potent anti-tumor efficacy of AGF94 in the therapy of EOC in the context of an intact immune system, and provide a framework for targeting the immunosuppressive TME as an essential component of therapy. [ABSTRACT FROM AUTHOR]

Heteroatom-participated lignin depolymerization for heterocyclic aromatic compounds production is of great importance to expanding the product portfolio and meeting value-added biorefinery demand, but it is also particularly challenging. In this work, the synthesis of pyrimidines from lignin β-O-4 model compounds, the most abundant segment in lignin, mediated by NaOH through a one-pot multi-component cascade reaction is reported. Mechanism study suggests that the transformation starts by NaOH-induced deprotonation of Cα-H bond in β-O-4 model compounds, and involves highly coupled sequential cleavage of C-O bonds, alcohol dehydrogenation, aldol condensation, and dehydrogenative aromatization. This strategy features transition-metal free catalysis, a sustainable universal approach, no need of external oxidant/reductant, and an efficient one-pot process, thus providing an unprecedented opportunity for N-containing aromatic heterocyclic compounds synthesis from biorenewable feedstock. With this protocol, an important marine alkaloid meridianin derivative can be synthesized, emphasizing the application feasibility in pharmaceutical synthesis. Lignin depolymerization to make heterocyclic aromatic compounds is of great importance to expanding the product portfolio derived from biomass, but it is also particularly challenging. In this work, the authors report pyrimidine synthesis from lignin β-O-4 model compounds via a one-pot multicomponent cascade reaction. [ABSTRACT FROM AUTHOR]

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. All DNA/RNA nucleobases were identified in carbonaceous meteorites. Having been provided to the early Earth as a component in carbonaceous meteorites, these molecules might have played a role for the emergence of genetic functions in early life. [ABSTRACT FROM AUTHOR]

Background: Continuing our interest in preparing of new heterocyclic compounds and examining their various biological activities, this work was designed to prepare new condensed and non-condensed heterocyclic compounds 9a-c, 10a-c, 11a-c, 13a-c and 14a-c were synthesized starting with pyrimidine-2-thiones 4a-c. Results: Thiazolo[3,2-a]pyrimidines 9a-c were synthesized by S-alkylation of pyrimidine-2-thiones,4a-c, internal cyclization in alkaline medium with ammonia, condensation with benzaldehyde and finally reaction with hydroxylamine hydrochloride.[1,2,4]thiadiazolo[4,5-a]pyrimidines 11a-c were formed by heating of the 4a-c with benzoylcholride to afford 10a-c followed by reaction with sodium hypochlorite, ammonia and sodium hydroxide. Cyclocondensation of 4a-c with ethyl acetoacetate or formic acid yielded pyrazol-3-ones 13a-c or [1,2,4] triazolo[4,3-a]pyrimidines 14a-c, respectively Elements analysis, IR, 1H-NMR, 13C-NMR and mass spectra were used to validate the structures of newly synthesized heterocycles. Screening of the selected compounds 4a, 6a, 7a, 9a, 10a, 13a and 14a against colon carcinoma cell lines (HCT-116) and hepatocellular carcinoma cell lines (HepG-2). Conclusions: Elements analysis, IR, 1H-NMR, 13C-NMR and mass spectra were used to validate the structures of newly synthesized heterocycles. Screening of the selected compounds 4a, 6a, 7a, 9a, 10a, 13a and 14a against colon carcinoma cell lines (HCT-116) and hepatocellular carcinoma cell lines (HepG-2) showed that compound 10a exhibited the most cytotoxic, while compounds 4a, 6a and 14a exhibited considerable cytotoxic activity. [ABSTRACT FROM AUTHOR]

In recent times, fused azaheterocycles emerged as impressive therapeutic agents. Binding studies of such azaheterocycles with biomolecules is an important subject for pharmaceutical and biochemical studies aiming at the design and development of new drugs. Fused heterocyclic scaffolds, such as thiazolopyrmidines have long been used in the pharmaceutical industry for the treatment of various diseases. In this study, we have accomplished a regioselective synthesis of 2-aroyl-3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidines by the reaction of tetrahydropyrimidine-2(H)-thione with α-bromo-1,3-diketones, generated in situ from 1,3-diketones and NBS, using visible light as an inexpensive, green and renewable energy source under mild reaction conditions with wide-ranging substrate scope. The regioisomer was characterized unambiguously by 2D-NMR [1H-13C] HMBC and [1H-13C] HMQC spectroscopy. In silico toxicity data analysis showed the low toxicity risks of the synthesized compounds. Computational molecular docking studies were carried out to examine the interaction of thiazolo[3,2-a]pyrimidines with calf-thymus DNA (ct-DNA) and Bovine Serum Albumin (BSA). Moreover, different spectroscopic approaches viz. steady-state fluorescence, competitive displacement assay, UV–visible and circular dichroism (CD) along with viscosity measurements were employed to investigate the binding mechanisms of thiazolo[3,2-a]pyrimidines with DNA and BSA. The results thus obtained revealed that thiazolo[3,2-a]pyrimidines offer groove bindings with DNA and showed moderate bindings with BSA. [ABSTRACT FROM AUTHOR]

The evolution of microorganisms often involves changes of unclear relevance, such as transient phenotypes and sequential development of multiple adaptive mutations in hotspot genes. Previously, we showed that ageing colonies of an E. coli mutant unable to produce cAMP when grown on maltose, accumulated mutations in the crp gene (encoding a global transcription factor) and in genes involved in pyrimidine metabolism such as cmk; combined mutations in both crp and cmk enabled fermentation of maltose (which usually requires cAMP-mediated Crp activation for catabolic pathway expression). Here, we study the sequential generation of hotspot mutations in those genes, and uncover a regulatory role of pyrimidine nucleosides in carbon catabolism. Cytidine binds to the cytidine regulator CytR, modifies the expression of sigma factor 32 (RpoH), and thereby impacts global gene expression. In addition, cytidine binds and activates a Crp mutant directly, thus modulating catabolic pathway expression, and could be the catabolite modulating factor whose existence was suggested by Jacques Monod and colleagues in 1976. Therefore, transcription factor Crp appears to work in concert with CytR and RpoH, serving a dual role in sensing both carbon availability and metabolic flux towards DNA and RNA. Our findings show how certain alterations in metabolite concentrations (associated with colony ageing and/or due to mutations in metabolic or regulatory genes) can drive the evolution in non-growing cells. Microbial evolution often involves transient phenotypes and sequential development of multiple mutations of unclear relevance. Here, the authors show that the evolution of non-growing E. coli cells can be driven by alterations in pyrimidine nucleoside levels associated with colony ageing and/or due to mutations in metabolic or regulatory genes. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Antioxidative effects of polypyrimidine tract-binding protein-associated splicing factor against pathological retinal angiogenesis through promotion of mitochondrial function" published in the Journal of Molecular Medicine. The authors apologize for mistakenly confusing the results of different stressors in their experiment and provide corrected figures. They also acknowledge an error in the labeling of the Y axis in one of the figures. The publisher, Springer Nature, remains neutral and does not endorse any jurisdictional claims or institutional affiliations. [Extracted from the article]

Colorectal cancer (CRC) is the fourth most lethal disease worldwide. Despite an urgent need for therapeutic advance, selective target identification in a preclinical phase is hampered by molecular and metabolic variations between cellular models. To foster optimal model selection from a translational perspective, we performed untargeted ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry-based polar metabolomics and lipidomics to non-transformed (CCD841-CON and FHC) and transformed (HCT116, HT29, Caco2, SW480 and SW948) colon cell lines as well as tissue samples from ten colorectal cancer patients. This unveiled metabolic signatures discriminating the transformed from the non-transformed state. Metabolites involved in glutaminolysis, tryptophan catabolism, pyrimidine, lipid and carnitine synthesis were elevated in transformed cells and cancerous tissue, whereas those involved in the glycerol-3-phosphate shuttle, urea cycle and redox reactions were lowered. The degree of glutaminolysis and lipid synthesis was specific to the colon cancer cell line at hand. Thus, our study exposed pathways that are specifically associated with the transformation state and revealed differences between colon cancer cell lines that should be considered when targeting cancer-associated pathways. [ABSTRACT FROM AUTHOR]

P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure–activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition. [ABSTRACT FROM AUTHOR]

Corneal innervation plays a major role in the pathobiology of diabetic corneal disease. However, innervation impact has mainly been investigated in the context of diabetic epitheliopathy and wound healing. Further studies are warranted in the corneal stroma-nerve interactions. This study unravels the nerve influence on corneal stroma metabolism. Corneal stromal cells were isolated from healthy (HCFs) and diabetes mellitus (Type1DM and Type2 DM) donors. Cells were cultured on polycarbonate membranes, stimulated by stable Vitamin C, and stroma-only and stroma-nerve co-cultures were investigated for metabolic alterations. Innervated compared to stroma-only constructs exhibited significant alterations in pyrimidine, glycerol phosphate shuttle, electron transport chain and glycolysis. The most highly altered metabolites between healthy and T1DMs innervated were phosphatidylethanolamine biosynthesis, and pyrimidine, methionine, aspartate metabolism. Healthy and T2DMs main pathways included aspartate, glycerol phosphate shuttle, electron transport chain, and gluconeogenesis. The metabolic impact on T1DMs and T2DMs was pyrimidine, purine, aspartate, and methionine. Interestingly, the glucose-6-phosphate and oxaloacetate was higher in T2DMs compared to T1DMs. Our in vitro co-culture model allows the examination of key metabolic pathways corresponding to corneal innervation in the diabetic stroma. These novel findings can pave the way for future studies to fully understand the metabolic distinctions in the diabetic cornea. [ABSTRACT FROM AUTHOR]

In an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results. [ABSTRACT FROM AUTHOR]

Biofilms are multicellular communities of microorganisms that generally attach to surfaces in a self-produced matrix. Unlike planktonic cells, biofilms can withstand conventional antibiotics, causing significant challenges in the healthcare system. Currently, new chemical entities are urgently needed to develop novel anti-biofilm agents. In this study, we designed and synthesized a set of 2,4,5,6-tetrasubstituted pyrimidines and assessed their antibacterial activity against planktonic cells and biofilms formed by Staphylococcus aureus. Compounds 9e, 10d, and 10e displayed potent activity for inhibiting the onset of biofilm formation as well as for killing pre-formed biofilms of S. aureus ATCC 25923 and Newman strains, with half-maximal inhibitory concentration (IC50) values ranging from 11.6 to 62.0 µM. These pyrimidines, at 100 µM, not only decreased the number of viable bacteria within the pre-formed biofilm by 2–3 log10 but also reduced the amount of total biomass by 30–50%. Furthermore, these compounds were effective against planktonic cells with minimum inhibitory concentration (MIC) values lower than 60 µM for both staphylococcal strains. Compound 10d inhibited the growth of S. aureus ATCC 25923 in a concentration-dependent manner and displayed a bactericidal anti-staphylococcal activity. Taken together, our study highlights the value of multisubstituted pyrimidines to develop novel anti-biofilm agents. [ABSTRACT FROM AUTHOR]

A one-pot three component reaction of benzaldehydes, 1H-tetrazole-5-amine, and 3-cyanoacetyl indole in the presence of a new hexamethylenetetramine-based ionic liquid/MIL-101(Cr) metal–organic framework as a recyclable catalyst was explored. This novel catalyst, which was fully characterized by XRD, FE-SEM, EDX, FT-IR, TGA, BET, and TEM exhibited outstanding catalytic activity for the preparation of a range of pharmaceutically important tetrazolo[1,5-a]pyrimidine-6-carbonitriles with good to excellent yields in short reaction time. [ABSTRACT FROM AUTHOR]

Despite the widespread applications of C–H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing groups (DGs) served as ancillary ligands to ensure ortho-, meta- and para-C–H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C–H functionalization: introduction of DG prior to C–H activation and removal of DG post-functionalization. Here we report a temporary directing group (TDG) for meta-C–H functionalization via reversible imine formation. By overruling facile ortho-C–H bond activation by imine-N atom, a suitably designed pyrimidine-based TDG successfully delivered selective meta-C–C bond formation. Application of this temporary directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the meta position has been explored. Site-selective C–H functionalization still faces some challenges, such as the introduction and removal of an appropriate directing group. Here, the authors introduce a temporary directing group for selective meta-C–H functionalization of 2-arylbenzaldehydes via reversible imine formation. [ABSTRACT FROM AUTHOR]

Enterovirus A71 (EV-A71) is one of the aetiological agents for the hand, foot and mouth disease (HFMD) in young children and a potential cause of neurological complications in afflicted patients. Since its discovery in 1969, there remains no approved antiviral for EV-A71 and other HFMD-causing enteroviruses. We set out to address the lack of therapeutics against EV-A71 by screening an FDA-approved drug library and found an enrichment of hits including pyrimidine antimetabolite, gemcitabine which showed 90.2% of inhibition on EV-A71 infection. Gemcitabine and other nucleoside analogs, LY2334737 and sofosbuvir inhibition of EV-A71 infection were disclosed using molecular and proteomic quantification, and in vitro and in vivo efficacy evaluation. Gemcitabine displayed a significant reduction of infectious EV-A71 titres by 2.5 logs PFU/mL and was shown to target the early stage of EV-A71 viral RNA and viral protein synthesis process especially via inhibition of the RNA dependent RNA polymerase. In addition, the drug combination study of gemcitabine's synergistic effects with interferon-β at 1:1 and 1:2 ratio enhanced inhibition against EV-A71 replication. Since gemcitabine is known to metabolize rapidly in vivo, other nucleoside analogs, LY2334737 and sofosbuvir conferred protection in mice against lethal EV-A71 challenge by potentially reducing the death rate, viral titers as well on virus-induced pathology in the limb muscle tissue of mice. Additionally, we found that gemcitabine is competent to inhibit other positive-sense RNA viruses of the Flaviviridae and Togaviridae family. Overall, these drugs provide new insights into targeting viral factors as a broad-spectrum antiviral strategy with potential therapeutic value for future development and are worthy of potential clinical application. [ABSTRACT FROM AUTHOR]

The biological functions of nitric oxide (NO) depend on its concentration, and excessive levels of NO induce various harmful situations known as nitrosative stress. Therefore, organisms possess many kinds of strategies to regulate the intracellular NO concentration and/or to detoxify excess NO. Here, we used genetic screening to identify a novel nitrosative stress tolerance gene, RIB1, encoding GTP cyclohydrolase II (GTPCH2), which catalyzes the first step in riboflavin biosynthesis. Our further analyses demonstrated that the GTPCH2 enzymatic activity of Rib1 is essential for RIB1-dependent nitrosative stress tolerance, but that riboflavin itself is not required for this tolerance. Furthermore, the reaction mixture of a recombinant purified Rib1 was shown to quench NO or its derivatives, even though formate or pyrophosphate, which are byproducts of the Rib1 reaction, did not, suggesting that the reaction product of Rib1, 2,5-diamino-6-(5-phospo-d-ribosylamino)-pyrimidin-4(3 H)-one (DARP), scavenges NO or its derivatives. Finally, it was revealed that 2,4,5-triamino-1H-pyrimidin-6-one, which is identical to a pyrimidine moiety of DARP, scavenged NO or its derivatives, suggesting that DARP reacts with N2O3 generated via its pyrimidine moiety. [ABSTRACT FROM AUTHOR]

Partition coefficients describe the equilibrium partitioning of a single, defined charge state of a solute between two liquid phases in contact, typically a neutral solute. Octanol–water partition coefficients ( K ow ), or their logarithms (log P), are frequently used as a measure of lipophilicity in drug discovery. The partition coefficient is a physicochemical property that captures the thermodynamics of relative solvation between aqueous and nonpolar phases, and therefore provides an excellent test for physics-based computational models that predict properties of pharmaceutical relevance such as protein-ligand binding affinities or hydration/solvation free energies. The SAMPL6 Part II octanol–water partition coefficient prediction challenge used a subset of kinase inhibitor fragment-like compounds from the SAMPL6 p K a prediction challenge in a blind experimental benchmark. Following experimental data collection, the partition coefficient dataset was kept blinded until all predictions were collected from participating computational chemistry groups. A total of 91 submissions were received from 27 participating research groups. This paper presents the octanol–water log P dataset for this SAMPL6 Part II partition coefficient challenge, which consisted of 11 compounds (six 4-aminoquinazolines, two benzimidazole, one pyrazolo[3,4-d]pyrimidine, one pyridine, one 2-oxoquinoline substructure containing compounds) with log P values in the range of 1.95–4.09. We describe the potentiometric log P measurement protocol used to collect this dataset using a Sirius T3, discuss the limitations of this experimental approach, and share suggestions for future log P data collection efforts for the evaluation of computational methods. [ABSTRACT FROM AUTHOR]

Ultraviolet (UV) radiation could induce pyrimidine-related dimeric lesions in genomic DNA. Though the cyclobutane pyrimidine dimers (CPDs) are the most abundant UV-induced lesions, the pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) may have more serious, potentially lethal, and mutagenic effects. It is important to have 6-4PP-containing oligodeoxynucleotides to be prepared for studying their adverse biological effects. Here, we developed a UV-irradiated water droplet method for the preparation of a biotinylated, 6-4PP-containing 10-mer oligodeoxynucleotide. By the use of HPLC purification and enrichment twice, the final yield is estimated to be about 8.1%. In contrast, without applying droplet technique, the direct UV irradiation against oligonucleotide-containing aqueous solution, the product yield is very low. The enzymatic hydrolyzation of the obtained product shows a 6-4PP characteristic ion transition of 545.12 → 432.13 in negative ion mode UHPLC-Q-TOF/MS. The established procedure for the preparation of 6-4PP-containing oligonucleotides is convenient with an improved yield. [ABSTRACT FROM AUTHOR]

A number of di-, tri-, and tetraazido-substituted azines as potential energetic dispersing agents of solid propellants for ramjet engines have been studied. The enthalpy of combustion and the enthalpy of formation of several azides (2,4,6-triazidopyrimidine, 2,4,6-triazidopyridine, 3,4,5-triazidopyridine-2,6-dicarbonitrile, and 3,4,5,6-tetraazidopyridine-2-carbonitrile) were experimentally determined. Eleven azides were compared with HMX in terms of the enthalpy of combustion in oxygen to CO2 and water (in the case of the presence of hydrogen in the component), as well as in terms of the temperature of the products of adiabatic conversion of the investigated components due to the high enthalpy of formation in the absence of an external oxidizer and the amount of gases released in this process. The enthalpy of combustion of all the investigated azides burned in air was found to be significantly higher than that of HMX, and for seven of the azides studied, the combustion temperature is significantly higher. As regards the gas release volume (24–31 mol/kg), the azides are inferior to HMX (41.9 mol/kg). Based on the combination of properties, the investigated azides can be considered as promising dispersing agents of solid propellants for ramjet engines. [ABSTRACT FROM AUTHOR]

References 1 Dong L, Lin T, Li W. Correction to: Antioxidative effects of polypyrimidine tract-binding protein-associated splicing factor against pathological retinal angiogenesis through promotion of mitochondrial function. Authors Lijie Dong, Tingting Lin, Wenbo Li, Yaru Hong, YiFeng Ke and Xiaoring Li agree with this retraction. [Extracted from the article]

The adsorption of pyrimidine mononucleotides from aqueous solutions on the surface of nanocrystalline titanium dioxide is studied. The interaction of the nucleotides with hydroxyl groups of titanium dioxide is interpreted in terms of the surface complexation theory. The results of an experimental study of the dependence of adsorption on the pH and ionic strength of solutions are used to calculate the stability constants of the outer-sphere adsorption complexes, which result from the electrostatic interaction of protonated groups with anionic forms of nucleotides. [ABSTRACT FROM AUTHOR]

Objectives: To predict the amino acid residues playing important roles in acetyl-CoA and substrate binding and to study the acetyl group transfer mechanism of Chryseobacterium sp. 5-3B N-acetyltransferase (5-3B NatA). Results: A 3-dimensional homology model of 5-3B NatA was constructed to compare the theoretical structure of this compound with the structures of previously reported proteins belonging to the bacterial GCN5 N-acetyltransferase family. Homology modeling of the 5-3B NatA structure and a characterization of the enzyme's kinetic parameters identified the essential amino acid residues involved in binding and acetyl-group transfer. Leu, Leu, and Lys were implicated in the binding of phosphopantothenic acid, and Tyr and Lys in that of adenosyl biphosphate. The data supported the participation of Glu and Tyr in catalyzing acetyl-group transfer to l-2-phenylglycine. Conclusions: 5-3B NatA catalyzes the enantioselective N-acetylation of l-2-phenylglycine via a ternary complex comprising the enzyme, acetyl-CoA, and the substrate. [ABSTRACT FROM AUTHOR]

The study deals with the development of a method for the determination of ametoctradin by HPLC with UV detection. Samples were extracted with aqueous acetone and then purified by distribution between immiscible solvents and also on solid-phase extraction cartridges. The procedure was tested in the determination of ametoctradin in water in the range 0.001-0.01 mg/L, in soil, potato vine and potato tubers, salad, onion, cucumber, tomatoes, carrots, grapes, and grape juice in the range from 0.005 to 0.1 mg/kg, depending on the matrix. The average recoveries were 78−92% with RSD < 0.08%. The proposed procedure is applicable to the determination of ametoctradin in environmental samples and plant residues. [ABSTRACT FROM AUTHOR]

Background: In the past few years, increased resistance of microorganisms towards antimicrobial agents become a serious health problem, so there is a need for the discovery of new antimicrobial agents. On the other hand, bis-pyrimidines possess various types of biological activity. In view of this, in the present study we have designed and synthesized a new series of bis-pyrimidine acetamides by Claisen-Schmidt condensation and screened for its in vitro antimicrobial and anticancer activities. Results: The synthesized bis-pyrimidine acetamide derivatives were confirmed by IR, H/C-NMR, Mass spectral studies as well C, H, N analyses. The synthesized compounds were evaluated for their in vitro antimicrobial potential against Gram positive ( Staphylococcus aureus and Bacillus subtilis); Gram negative ( Escherichia coli, Pseudomonas aeruginosa and Salmonella enterica) bacterial and fungal ( Candida albicans and Aspergillus niger) strains by tube dilution technique and the minimum inhibitory concentration (MIC) recorded in µmol/mL was comparable to reference drugs, cefadroxil (antibacterial) and fluconazole (antifungal). The in vitro anticancer activity (IC value) determined against human colorectal carcinoma (HCT116) cancer cell line by Sulforhodamine B (SRB) technique and 5-fluorouracil used as reference drug. Conclusions: The biological study demonstrated that compounds 3, 13, 16, 17 and 18 were found to be most active antimicrobial agents with best MIC values than the cefadroxil (antibacterial) and fluconazole (antifungal) and compounds 12, 16 and 18 found to have better anticancer activity against human colorectal carcinoma (HCT116) cancer cell line with best IC value than the 5-fluorouracil (anticancer). [ABSTRACT FROM AUTHOR]

Background: Uracil derivatives have a great attraction because they play an important role in pharmacological activities. Pyrimidodiazepines, lumazines, triazolopyrimidines and xanthines have significant wide spectrum activities including anticancer, antiviral as well as antimicrobial activities. Results: A newly synthesized compounds pyrimido[4,5- b][1, 4]diazepines 5a- e, 6a- d, lumazines 7a- d, triazolo[4,5- d]pyrimidine 8 and xanthines 9, 10 was prepared in a good yields. The antimicrobial and antioxidant activities of compounds 5a, 5b, 6a, 6d and 8 exhibited a wide range activity against the pathogenic tested microbes ( Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans, and Saccharomyces cerevisiae). Compound 8 showed activity against the fungus Aspergillus niger. The highest antioxidant activity was noticed for compound 5a. Conclusions: A series of novel pyrimido[4,5- b][1, 4]diazepines 5a- e, 6a- d, lumazines 7a- d, triazolo[4,5- d]pyrimidine 8 and xanthines 9, 10 was prepared from 5,6-diamino-1-(2-chlorobenzyl)uracil 3 in good yields. Compounds 5a- e, 6a- d were prepared by sequential manipulation of 3 with α, β-unsaturated ketones. Lumazines 7a- d were obtained from 3 by treatment with phenacyl bromides in the presence of TEA. Compound 8 was prepared by treatment of 3 with HNO, while xanthines 9, 10 were obtained from 3 by consecutive acetylation then intramolecular cyclodehydration or heating with malononitrile under solvent-free condition. The antimicrobial and antioxidant activity of this series was evaluated in vitro and they showed either weak or moderate activities. [ABSTRACT FROM AUTHOR]

Background: Pyrazolo[1,5- a]pyrimidines are purine analogues. They have beneficial properties as antimetabolites in purine biochemical reactions. This division compounds have attracted wide pharmaceutical interest because of their antitrypanosomal activity. Results: The present work depicts an effective synthesis convention of pyrazolo[1,5- a]pyrimidines, pyrazolo[5,1- c]triazines, thieno[2,3- b]pyridines and polysubstituted pyridines containing 1,2,3,-triazole moiety from the reaction of sodium 3-(5-methyl-1-( p-toly)-1 H-1,2,3-triazol-4-yl)-3-oxoprop-1-en-1-olate with the fitting heterocyclic amines and its diazonium salt, and active methylene compounds, individually. Likewise, thiazoles and, 1,3,4-thiadiazoles were obtained from 2-bromo-1-(5-methyl-1-( p-tolyl)-1 H-1,2,3-triazol-4-yl)ethanone and some reagent such as hydrazonoyl chlorides and halo ketones. The newly synthesized compounds were established by elemental analysis, spectral data, and alternative synthetic route whenever possible. Conclusions: New series of pyrazolo[1,5- a]pyrimidines, pyrazolo[5,1- c]triazines, thieno[2,3- b]pyridines and polysubstituted pyridines containing the 1,2,3,-triazole moiety were synthesized via reactions of sodium 3-(5-methyl-1-( p-toly)-1 H-1,2,3-triazol-4-yl)-3-oxoprop-1-en-1-olate with the appropriate heterocyclic amines and its diazonium salt. In addition, 1,3,4-thiadiazoles and, 1,3-thiazoles were acquired in a decent yield via the reaction of substituted thiourea with the appropriate hydrazonoyl chlorides and halogenated ketenes. [ABSTRACT FROM AUTHOR]

Background: Pyrimidine is an aromatic heterocyclic moiety containing nitrogen atom at 1st and 3rd positions and play an important role to forms the central core for different necessity of biological active compounds, from this facts, we have designed and synthesized a new class of pyrimidin-2-ol/thiol/amine derivatives and screened for its in vitro antimicrobial activity. Results and discussion: The synthesized pyrimidine derivatives were confirmed by IR, H/C-NMR, Mass spectral studies and evaluated for their in vitro antimicrobial potential against Gram positive ( S. aureus and B. subtilis), Gram negative ( E. coli, P. aeruginosa and S. enterica) bacterial strains and fungal strain ( C. albicans and A. niger) by tube dilution method and recorded minimum inhibitory concentration in µM/ml. The MBC and MFC values represent the lowest concentration of compound that produces in the range of 96-98% end point reduction of the used test bacterial and fungal species. Conclusion: In general all synthesized derivatives exhibited good antimicrobial activity. Among them, compounds 2, 5, 10, 11 and 12 have significant antimicrobial activity against used bacterial and fungal strains and also found to be more active than the standard drugs. [ABSTRACT FROM AUTHOR]

A series of D-π-A- type dyes based on pyrimidines, bearing various thiophene linkers, have been studied as sensing fluorophores. Fluorescence studies have demonstrated that the emission of all derivatives is sensitive to the presence of nitroaromatic explosives, such as 2,4,6-trinitrophenol (PA), 2,4,6-trinitrotoluene (TNT), and 2,4-dinitrotoluene (DNT), in their acetonitrile solutions. The detection limits of fluorophores to PA, TNT, and DNT proved to be in the range from 5.83 × 10 to 2.38 × 10 mol/L, 1.70 × 10 to 8.40 × 10 mol/L, and 8.39 × 10 to 6.87 × 10 mol/L, respectively. The theoretical investigation into the quenching mechanism in the presence of fluorophore has been performed. All compounds have shown a good efficiency as sensor materials when tested as elements of the original device «Nitroscan» for detecting nitro-containing explosives in vapor phase (Plant "Promautomatika", Ekaterinburg, Russia). [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Amino acids, neurotransmitters, purines, and pyrimidines are bioactive molecules that play fundamental roles in maintaining various physiological functions. Their metabolism is closely related to the health, growth, development, reproduction, and homeostasis of organisms. Most recently, comprehensive measurements of these metabolites have shown their potential as innovative approaches in disease surveillance or drug intervention. However, simultaneous measurement of these metabolites presents great difficulties. Here, we report a novel quantitative method that uses hydrophilic interaction ultra-high-performance liquid chromatography-tandem mass spectrometry (HILIC-UPLC-MS/MS), which is highly selective, high throughput, and exhibits better chromatographic behavior than existing methods. The developed method enabled the rapid quantification of 37 metabolites, spanning amino acids, neurotransmitters, purines, and pyrimidines pathways, within 6.5 min. The compounds were separated on an ACQUITY UPLC® BEH Amide column. Serum and brain homogenate were extracted by protein precipitation. The intra- and interday precision of all of the analytes was less than 11.34 %, and the accuracy was between −11.74 and 11.51 % for all quality control (QC) levels. The extraction recoveries of serum ranged from 84.58 % to 116.43 % and those of brain samples from 80.80 % to 119.39 %, while the RSD was 14.61 % or less for all recoveries. This method was used to successfully characterize alterations in the rat brain and, in particular, their dynamics in serum. The following study was performed to simultaneously test global changes of these metabolites in a serotonin antagonist p-chlorophenylalanine (PCPA)-induced anxiety and insomnia rat model to understand the effect and mechanism of PCPA. Taken together, these results show that the method is able to simultaneously monitor a large panel of metabolites and that this protocol may represent a metabolomic method to diagnose toxicological and pathophysiological states. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]