Ring Nitrogen Research Articles

Adsorption of picloram on clays nontronite, illite and kaolinite: equilibrium and herbicide-clays surface complexes

The picloram (PCM) adsorption on nontronite, illite and kaolinite was studied at pH 3, 5 and 7. The adsorption isotherms had well-fitted to Langmuir and Freundlich models equations. The interactions of PCM with the clay mineral surfaces exhibited an anionic profile adsorption, with a decrease in adsorption when the pH increases. The PCM adsorption capacity increases in the following order: kaolinite < illite < nontronite. The X-ray diffraction (XRD) analysis of PCM-clay samples revealed that the picloram molecule does not enter into the clays basal space. The interaction of PCM with clays surface sites through nitrogen of the pyridine ring was confirmed by X-ray photoelectron spectroscopy (XPS). Due to the anionic form of PCM, the adsorption onto the external and edges surface sites of the clay minerals was proposed.

Experimental and Theoretical Investigation of Optical Spectra of Methylene Green in Solutions

The hybrid multilevel approach based on molecular dynamics, quantum mechanics, and statistical theory has been applied to profiles of electronic absorption bands of a number of thiazine dyes (phenothiazine, methylene blue, and methylene green), whose photochemical and biological properties depend on the external medium. The effect of single fragments of the methylene green (MG) molecule on its spectral-luminescent properties is studied. The most preferred geometry for the MG molecule is identified, and its relations with the spectral properties and the solvent nature are established. The energies of the electron states are calculated, and their nature is revealed. The electrostatic potential is analyzed, and the places of the most probable interaction of the molecule with the medium are found. Conclusions on the mechanism of forming the MG absorption spectrum are made based on the observations and calculations performed within the framework of the present work. It is established that the formation of the N–H bonds leads to the formation of an inactive lower excited singlet state and delocalization of the electron charge upon excitation. The position of the maximum of the long-wavelength absorption band of the MG correlates with the donor number of solvents in the series acetonitrile < water < ethanol < isopropanol < dimethyl sulfoxide. The position of the MG electron transition in the region of 630 nm is determined by the interaction of nitrogen and sulfur atoms of the central ring rather than by the increased number of substituents in the structure of the molecule.

Oxaprozin: A new hope in the modulation of matrix metalloproteinase 9 activity.

Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal, analgesic and antipyretic propionic acid derivative, whose activity in treating inflammatory disorders is well known. The aim of this study was to investigate the ability of oxaprozin to modulate the activity of matrix metalloproteinase 9 (MMP-9), a zinc-dependent endopeptidase involved in a wide range of physiological and pathological events associated with extracellular matrix (ECM) remodelling. The interaction between oxaprozin and MMP-9 was firstly investigated in silico by molecular docking and analysis with LIGPLOT software. Subsequently, the potential inhibitory activity of oxaprozin against MMP-9 and the possible mechanism of the ligand-enzyme interaction were investigated in vitro. Taking into account the in silico findings, MMP-9 can be considered a potential target of oxaprozin, which seems to be able to chelate the catalytic zinc ion through the nitrogen of the oxazole ring and the carboxylate moiety. Moreover, one of the phenyl rings interact with the S1' inhibitor-binding pocket through hydrophobic interaction. Gelatin zymography and enzymatic inhibition assay confirmed the potential role of oxaprozin as a competitive inhibitor of MMP-9. These observations sound particularly interesting if we consider the pathological role of MMP-9, especially evident in inflammatory conditions and cancer. This work may represent a starting point to improve the understanding of the role of oxaprozin, as well as its structural analogues, in modulating the MMP-9 function.

Синтез и строение cольвата 2,6-пиридиндикарбоксилата бис(тетрафенилсурьмы) с толуолом

At interaction of pentaphenylantimony with 2,6-pyridinedicarboxylic acid (mole ratio 1:1 or 2:1) in a toluene solution, bis (tetraphenylantimony) 2,6-pyridinedicarboxylate toluene solvate (1) has been obtained for the first time (yield 72%, colorless crystals, m.p. 170 °C). The compound 1 has been characterized by IR-spectroscopy, elemental and X-ray analysis. The absorption band of a carbonyl group with the frequency 1620 cm –1 is present in the IR-spectrum, shifting towards the area of low-frequency oscillations in comparison with the spectrum of the acid (1701 cm –1 ). According to the data of X-ray analysis the unit cell crystallographic parameters of compound 1: triclinic syngony, the symmetry group P; a = 12.494(5), b = 13.788(5); c = 16.684(6) Å; V = 2550.5(16) Å3; Z = 2; ρ(calc.) = 1.455 g/сm 3 . The Sb(1) and Sb(2) atoms in a molecule have a distorted trigonal-bipyramidal coordination in different degrees. The CSb(1)O and CSb(2)O axial angles equal 178.41(10)° and 176.75(11)°, the CSb(1)C and CSb(2)C equatorial angles vary in the ranges 111.58(14)–125.24(13)°) and 103.44(13)−146.5(11)°. The Sb(1,2)−O bond lengths equal 2.301(2), 2.310(2) Å. The Sb(1,2)–Ceqv equatorial bonds (2.105(3)–2.112(3) Å and 2.140(3)–2.162(3) Å) are shorter than the Sb(1,2)–Cax axial one (2.177(3), 2.162(3) Å). The bidentate binding of carboxylate ligands is weak (the distance Sb(1)∙∙∙O(2) equals 3,263(4) Å) it has been proved by significant difference in the lengths of single (С–О 1.288(3), 1.261(4) Å) and double bonds (С=О 1.226(3), 1.236(4) Å) in the carboxylate groups. The pypidine ring nitrogen atom coordinates to the antimony atom (the distance Sb(2)∙∙∙N equals 2.947(3) Å).

Synthesis, spectroscopic characterization and DFT/TD-DFT computations of a novel charge transfer complex via hydrogen bonding between 3-amino-1,5-dimethylpyrazole with chloranilic acid in different solvents

A novel charge transfer complex including hydrogen bonding between the e-donor (H-acceptor) 3-amino-1,5-dimethylpyrazole (3-ADMP) with the e-acceptor (H-donor) chloranilic acid (CLA) has been synthesized and characterized experimentally and theoretically. The experimental work was carried out in different solvents including chloroform (CHL), ethanol (EtOH), methanol (MeOH) and acetonitrile (AN). The solution characterizations included the determining of the molecular composition of the formed CT complex where it recorded 1:1 (donor:acceptor) in all solvent. Also, estimating its formation constant by Benesie-Hildebrand equation where it recorded high values in all solvents, suggesting its high stability. Thermodynamic and some spectroscopic physical parameters were introduced and interpreted where they confirmed the presence of charge transfer besides hydrogen bonding in the formed complex. The solid complex was prepared and characterized by elemental analysis, infrared and NMR (1H and 13C) spectroscopies, the complex was formed in 1:1 ratio, with good evidences for existing both charge transfer and hydrogen bonding in its molecular structure. Density functional theory B3LYP-DFT at the basis set 6-31G (d,p) has been running out in gas phase and solution using chloroform and acetonitrile as solvents to compliment the measured results. The complex optimized structure included two hydrogen bonds between OH and CO of chloranilic acid with the adjacent ring nitrogen and amino group of pyrazole ring. The optimization energy, complexation energy, geometrical parameters, Mullikan atomic charges as well as molecular electrostatic potential maps (MEP) were calculated and interpreted; they consisted with the experimental results where the complex stability is attributed to the presence of H-bond beside e-transfer. The electronic spectra were computed using TD-DFT through adding polarizable continuum solvation method PCM, PCM-TD-DFT to compare with the experimental results. It has been found that, the measured and computed λmax are coming close to each other. The allowed singlet transitions are located and their HOMO and LUMO contributions are presented. The pictures of the frontier HOMO and LUMO molecular orbitals, participating in the first six singlet transitions were presented. A good consistency between experimental and DFT computations has been found.

Synthesis, spectroscopic studies and DFT/TD-DFT/PCM calculations of molecular structure, spectroscopic characterization and NBO of charge transfer complex between 5-amino-1,3-dimethylpyrazole (5-ADMP) with chloranilic acid (CLA) in different solvents

New charge transfer complex between the n- and π-donor 5-amino-1,3-dimethyl pyrazole (5-ADMP) with the π-acceptor chloranilic acid was synthesized and characterized experimentally and theoretically. The experimental work was carried out in solution and solid state. The selected solvents were chloroform (CHL), methanol (MeOH), ethanol (EtOH) and acetonitrile (AN). upon mixing the donor with acceptor a change in color takes place immediately to pink one with absorption maxima at λmax 530, 531, 530 and 522 nm in CHL, EtOH, MeOH, and AN, respectively. The complex was stable for more than 2 h. The stability constant was calculated using Bensie-Hildebrand equation where it recorded the highest value in chloroform and the least one in methanol. Thermodynamic parameters were calculated where the enthalpy of formation recorded high value in chloroform. The solid complex was prepared where elemental analysis confirmed its composition at 1:1 in concordant with that in solution. The infrared spectra of the formed complex confirmed the existence of proton transfer hydrogen bond beside charge transfer interaction. A theoretical computations using DFT at the basis set B3LYP/6-31 G(d,p) was applied to support the experimental results. Optimization energy and geometrical parameters confirmed the high stability of the complex due to the presence of CT beside PT in its chemical structure. Reactivity parameters strongly recommended that 5-ADMP is good electron donor and CLA is good electron acceptor. MEP maps confirmed the presence of proton transfer hydrogen bond where OH of CLA is the electrophile and the pyridinic-like ring nitrogen of 5-ADMP is the nucleophile. The origin of electronic spectra was computed by TD-DFT using PCM as solvation model. Two absorption maxima were recorded in the calculated spectra attributing to π-π⁎ and n-π⁎ transitions in all media. Natural population analysis was applied to estimate the natural atomic charges and natural bond orbital (NBO). Both confirmed the existence of strong proton transfer hydrogen bonding beside charge transfer in the produced complex.

Biosynthesis of the Central Piperidine Nitrogen Heterocycle in Series a Thiopeptides

Summary of main observation and conclusionThiopeptides, arising from complex posttranslational modifications of a genetically encoded precursor peptide, are of great interest due to their structural complexity and important biological activities. All of these antibiotics share a macrocyclic peptidyl core that contains a central, six‐membered nitrogen heterocycle and are classified into five series a—e based on the oxidation state of the central nitrogenous ring. Here, we report that the biosynthesis of the central piperidine heterocycle of series a thiopeptides relies on the activity of homologues of an F420H2‐dependent reductase TppX4 by exploiting and characterizing the piperidine‐containing thiopeptin biosynthetic gene (tpp) cluster in Streptomyces tateyamensis. In vitro reconstruction of TppX4 activity demonstrated that the piperidine heterocycle of thiopeptins was transformed from a dehydropiperidine heterocycle, and TppX4 tolerated the changes in the C‐termini and macrocyclic peptidyl core of substrate and also tolerated dehyropiperidine‐containing monocyclic or bicyclic thiopeptides. The identification of TppX4 and its substrate tolerance enriches the biosynthetic toolbox for development of additional thiopeptide analogs for clinical drug screening.

Experimental and density functional theory insights into the effect of withdrawing ligands on the fluorescence yield of Ru(II)‐based complexes

The quality of emission spectra of metal complexes gives good insights into their performance in many optoelectronic applications. Herein, the effect of the number and position of various ligand structures on the emission spectra of Ru bipyridine complexes was studied. Specifically, the use of a different number of withdrawing groups (COOH) was investigated in detail. The complexes were first investigated using density functional theory (DFT) and time‐dependent DFT calculations and then confirmed experimentally. The bandgap energy, reactivity, emission spectra and Stokes shift were found to depend on the number and position of the withdrawing groups attached to the Ru(bpy)22+ complexes. Upon increasing the number of withdrawing groups, the electrons were found to be withdrawn from the carbon orbitals and resonated to reach the metal, and accumulated around it, thus enhancing the metal‐to‐ligand charge transfer mechanism instead of the ligand‐to‐ligand charge transfer mechanism. The complexes with more withdrawing groups showed spectra with more intense emission peaks with shorter lifetime, indicating the enhancement in the photoactivity of the complexes. Ligands with ring nitrogens with two COOH groups showed the greatest effect on the enhancement of the emission spectra with a lifetime of 0.5359 ns. The resulting collective emission spectra covered a wide wavelength range, making the investigated complexes a good choice for many optoelectronic applications.

Biological Evaluation of Synthesized N‐Cinnamoyl Phenothiazine Derivatives

N-Cinnamoyl phenothiazines were synthesized and characterized by various spectroscopic techniques including vibrational, nuclear magnetic resonance and mass spectrometry. The potential applications of these compounds as antioxidants and antibacterials were evaluated. Compound 2 with –NO2 substituted cinnamoyl moiety in the phenothiazine ring nitrogen showed better antioxidant activity (77.8 μM for hydroxyl radicals and 85.0 μM for diphenyl picrylhydrazyl radicals). A moderate antibacterial activity (202-330 μM) was observed for all the derivatives of phenothiazine against Gram-positive and Gram-negative bacteria, while the parent phenothiazine did not show any inhibitory activity up to 500 μM, indicating that the observed activity could be induced by the added cinnamoyl moiety. Nucleic acid and protein binding affinities were investigated for their applications as biomolecular probes. Both experimental and computational docking studies revealed an intercalative mode of binding with nucleic acids and 1:1 binding to bovine serum albumin.

Intra-annual variability in isotopic and total nitrogen in tree rings of old growth Sitka spruce from coastal British Columbia

Tree-ring studies using increment cores have increasingly measured elemental (N) and isotopic (δ15N) nitrogen values to evaluate environmental changes in the nitrogen cycle. The paucity of nitrogen in wood has constrained tree-ring analyses to annual resolution. Based on 77 rings and 310 sub-rings, we provide evidence for substantial intra-annual variability in N and δ15N values in the heartwood of 11 geographically widely separated, old growth Sitka spruce [Picea sitchensis (Bong.) Carrière] trees from coastal British Columbia. The range of N and δ15N values within rings (intra-annual level) was on average equal to or up to seven-times the range among rings (inter-annual level). Most rings showed a seasonal reduction in N values from early to late growth and a corresponding increase to the early growth of the following season (P &lt; 0.05 to 0.001, Mann–Whitney–Wilcoxon test). By contrast, intra-annual changes in δ15N values were highly variable among years and among trees, ranging from pronounced oscillations (4.0‰) to reasonable consistency. Our results allude to the potential importance of such intra-ring data for interpreting seasonal trends in nitrogen use and increasing understanding of ecological processes in the marine–terrestrial interface.

Exploring 6-Azaindole and 7-Azaindole Rings for Developing Cannabinoid Receptor 1 Allosteric Modulators.

Introduction and Objective: Org27569 is a prototypical allosteric modulator of the cannabinoid receptor 1 (CB1). It belongs to the indole-2-carboxamide scaffold and has been intensively investigated in pharmacology and in structure–activity relationship (SAR) studies. Although azaindoles are rare in natural products and differ only by the presence of an extra ring nitrogen, they were demonstrated as valuable bioisosteres in many pharmacologically important molecules. To extend the SAR investigation of the indole-2-carboxamide class of CB1 allosteric modulators, azaindole (pyrrolopyridine) rings were used to replace the indole ring of Org27569 analogs to explore the potential of azaindole-2-carboxamides as CB1 allosteric modulators. Using 6- and 7-azaindole in lieu of the indole moiety within this class of CB1 allosteric modulators indeed improved the aqueous solubility.Materials and Methods: We synthesized 6- and 7-azaindole-2-carboxamides and their indole-2-carboxamide counterparts. The molecules were evaluated by [3H]CP55,940 binding and [35S]GTPγS binding assays for their allosteric modulation of the CB1 receptor.Results: The 7-azaindole-2-carboxamides lost the ability to bind to the CB1 receptor. The 6-azaindole-2-carboxamides (e.g., 3c and 3d) showed markedly reduced binding affinities to the CB1 receptor in comparison with their indole-2-carboxamide counterparts. However, they behaved similarly as indole-2-carboxamides in potentiating the orthosteric agonist binding and inhibiting the orthosteric agonist-induced G-protein coupling. The results indicated that some azaindole scaffolds (e.g., 6-azaindole) are worth further exploration, whereas the 7-azaindole ring is not a viable bioisostere of the indole ring in the Org27569 class of CB1 allosteric modulators.

Development of a Novel Class of Agents Targeting the RNA-Splicing Machinery in Myeloid Malignancies

SF3B1 is a splicing factor gene whose mutations are pathognomonic of MDS with ring sideroblasts. Because of the ubiquitous importance of splicing, a major barrier in targeting cells with spliceosomal mutations is the discovery of agents decreasing the competitiveness of mutant cells while preserving the integrity of wild type cells. To date no specific therapies are FDA approved for SF3B1 mutant (SF3B1MT) MDS and few agents are in early clinical testing. We describe a novel targeted approach to drug development for SF3B1MT malignancies.Our investigative strategy started with a high throughput drug screen. We introduced K700E mutation into myeloid cells using CRISPR/Cas9. We then subjected K562+/K700E and matched-parental K562 cells to high throughput drug screen of a library of 3,000 mechanistically annotated, non-redundant, bioactive compounds. Top hits were validated by dose response testing (8 concentrations in half-log dilutions). Our interest focused on compounds with cytostatic activity towards K562+/K700E cells. Among these, a 4-pyridyl-2-anilinothiazole (PAT) showed preferential inhibition of growth in K562+/K700E cells with an IC50 of 3uM. Dose response showed that K562+/K700E cells were significantly sensitive to PAT with a growth inhibition of 20%, 32%, 51%, 65%, 95% at .3uM (P=.01), 1uM (P=.002), 3uM (P<.0001), 10uM (P<.0001), and 20uM (P=.01). High doses (10, 20uM) were toxic to parental cells. PAT treatment did not induce growth arrest in other myeloid cells (THP1, MOLM13FLT3, OCI-AML3DNMT3A, SIG-M5TET2/DNMT3A, K562PHF6) including cells with mutations in other splicing factors (K562U2AF1, K562LUC7L2). PAT induced similar effects in primary SF3B1MT MDS cells at 3uM while it did not induce significant growth inhibition in primary MDS cells with other mutations, including other spliceosomal mutations (e.g.,U2AF1) (N=6). In normal bone marrow cells (N=6), complete growth arrest of erythroid and myeloid cells was observed at high doses (20uM).Using PAT as our lead, we employed a fragment based reiterative medicinal chemistry approach to synthesize selective compounds and improve therapeutic index. Libraries were constructed following Lipinski rules with ease of synthetic construction in mind. Pilot libraries were constructed via the classic Hantsch thiazole synthesis which involves condensation of α-halo ketones with substituted thioureas. This enterprise investigated SAR modifications of PAT by considering features such as regiochemistry and basicity of the nitrogen of the pyridine ring in the head region; replacement of the spacer 2,4-disubstituted thiazole ring with heteroatom containing rings (5,6,7 membered aromatic or aliphatic ring structures); alternatives for the aniline of the tail region e.g., sulfonamide, amide, and substituted amine linkers and substituted aromatic and aliphatic ring structures for the phenyl substituent. A major challenge in drug development of agents targeting spliceosomal mutations is the identification of key clusters of aberrantly spliced genes restored by drug treatment, e.g., identification of a pharmacodynamic endpoint that could be used to prove that that the drug reached its target. SF3B1 mutations induce aberrant 3′-ss selection by promoting use of alternative branch points. To identify biomarkers of splicing changes to screen our libraries, K562+/K700E and parental cells were treated with PAT (3uM) and RNA libraries were subjected to RNA Seq. The splicing pattern of parental cells was used as reference. We identified 328 cassette exons (±25% splicing inclusion difference, pFDR<.05) in K562+/K700E cells of whom the splicing of 22 exons was partially or completely restored upon treatment. Among these, PAT treatment restored the splicing of exons in sensitive 3′-ss sequences (ENOSF1), RNA binding SR-related factors (ACIN1), zing fingers (ZC3H7A) already associated with SF3B1 downregulation, histone modifiers (HMGN3), mitochondrial genes (TMEM126B), proto-oncogenes (CREB1) and heat shock proteins (DNAJC24). Ongoing experiments include tests of the ability of PATs to restore the splicing of misspliced exons and its efficacy in reducing the percentage of SF3B1MT cells in xenografts of K562+/K700E and primary SF3B1MT cells and Sf3b1+/K700E mice.In sum, we described novel classes of compounds that inhibit the expansion of SF3B1MT cells by restoring the splicing defects intrinsically associated with SF3B1. DisclosuresCarraway:Novartis: Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy.

Residue upgradation with slurry phase catalyst: Effect of feedstock properties

Hydroprocessing of vacuum residue is a difficult process in which highly contaminated vacuum residue is converted into a lighter middle distillate fraction. The high boiling point vacuum residue contains many heteroatoms such as nitrogen, sulfur, and metals (Ni, V) present in porphyrin rings. These will affect the activity of the slurry phase hydrocracking catalysts. Therefore, in this study, the effect of feedstock properties on the slurry phase hydrocracking catalyst was investigated. The catalytic activities were compared with the thermal activities for all feedstock studied. It was observed that the catalytic HDM activity of a slurry catalyst was higher than that from a thermal reaction, irrespective of the feed used. The maximum catalytic conversion was obtained with the feed (MGL-VR) that contained a high amount of Ni metal. A smaller amount of hydrogen was produced with catalytic tests, confirming that hydrogenation occurs in the presence of a catalyst. Also, the higher production of lighter hydrocarbons such as methane and ethane in the catalytic process was observed. The catalytic reaction with the feed having the highest amount of asphaltene (ESR-VR) generated more than 22% of methane. This occurs because of the severe cracking of side chains of the large polyaromatic compounds. The two conversion factors were obtained at thermal (TRC) and catalytic (CRC) conditions. A correlation between the difference of residue conversion (DCn) and feedstock properties has been evaluated. The results suggest that besides the amount of asphaltene in the feed, the amount of boiling fraction above 550 °C is an important parameter to be considered during slurry phase residue upgradation. It was found that the microcarbon residue (MCR) property of the feedstock can help to predict the residue conversions. The hardness properties of the coke samples evaluated using thermogravimetric analysis (TGA) showed that in catalytic reactions relatively soft coke is produced compared with that produced in thermal reactions.

Synthesis, spectral, thermal, kinetic and antibacterial studies of transition metal complexes with benzimidazolyl-2-hydrazones of o-hydroxyacetophenone, o-hydroxybenzophenone and o-vanillin

A novel series of Schiff base metal complexes of the type [M(L)2].nH2O, where L= 2-(α-methylsalicylidenehydrazino) benzimidazole (L1), 2-(α-phenylsalicylidenehydrazino)benzimidazole (L2), 2-(o-vanillinidenehydrazino)benzimidazole (L3), M = Cu(II), Co(II), Ni(II) and Zn(II), have been synthesized and characterized. The results are in consistent with tridentate chelation of ligand with azomethine nitrogen, ring nitrogen and a deprotonated phenolic oxygen atom. All these compounds have been screened for their antibacterial activities against B. subtilis, B. stearothermophilus, E. coli and S. typhi. KEY WORDS: Schiff base, Metal complexes, Spectral studies, Thermal studies, Kinetic studies, Antibacterial studies Bull. Chem. Soc. Ethiop. 2018, 32(3), 437-450. DOI: https://dx.doi.org/10.4314/bcse.v32i3.3

Heterobiaryl synthesis by contractive C-C coupling via P(V) intermediates.

Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C-C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C-H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.

Heterocycles meet and marry on phosphorus

Organic Chemistry Metals such as palladium are routinely used to link together carbon rings in pharmaceutical synthesis. However, the presence of nitrogen in both rings can trip up this process. Hilton et al. report a versatile alternative process in which phosphorus takes the place of the metal. The phosphorus binds successively to both rings at the sites opposite the nitrogen, and treatment with acidic ethanol then pushes them off, bound to each other. Theory implicates a five-coordinate phosphorus intermediate that kinetically favors coupling of the two nitrogen-bearing rings over reactions of the other all-carbon substituents. Science , this issue p. [799][1] [1]: /lookup/doi/10.1126/science.aas8961

Fluorometric determination of morphine via its effect on the quenching of fluorescein by gold nanoparticles through a surface energy transfer process.

A method is described for sensitive and selective fluorometric determination of morphine. It is based on the effect of morphine on quenching of the fluorescence of fluorescein by gold nanoparticles (AuNPs) via surface energy transfer. When fluorescein is added to solutions of colloidal AuNPs, its fluorescence becomes quenched due to nanometal surface energy transfer (NSET) because the absorption of AuNPs strongly overlaps the emission spectrum of fluorescein. In the presence of morphine, which contains both a tertiary nitrogen ring atom and a phenolic hydroxy group, it will coordinate to the AuNPs, and this causes recovery of fluorescence. The presence of a tertiary nitrogen ring atom and a phenolic hydroxy group (both required for the effect to occur) in morphine make the probe highly selective and sensitive for morphine. A paper strip assay also was developed by utilizing this detection scheme. The turn-on fluorescent probe was successfully applied to the determination of morphine in spiked serum and urine samples. The method has a 53 pM limit of detection. The paper strip was applied tothe determination of morphine in sweat, urine and other biological fluids. It is perceived to be useful for early detection of drug abuse by adolescent. Graphical abstract Schematic of the mechanism of fluorescence turn on detection of morphine using Au NPs (gold nanoparticles) acting asquencher of the fluorescence of fluorescein.

Selective C8-Metalation of Purine Nucleosides via Oxidative Addition

8-Bromo-2′-deoxy-3′,5′-di-O-acetylguanosine (1), 8-bromo-2′,3′,5′-tri-O-acetylguanosine (2), 8-bromo-2′-deoxy-3′,5′-di-O-acetyladenosine (3), and 8-bromo-2′,3′,5′-tri-O-acetyladenosine (4) react with [Pd(PPh3)4] via a C8–Br oxidative addition to give the C8-palladated azolato complexes [5]–[8] featuring an unprotonated N7 ring nitrogen atom. The complexes feature diastereotopic trans-disposed triphenylphosphine ligands, which allowed the determination of 2JPP for complexes of the type trans-[PdL2(PPh3)2] (2JPP = 442 Hz for [7]). In addition, two complex molecules of [7] form a trans-Watson–Crick/Hoogsteen AA base pair in the solid state. N7-protonation of the guanosine-derived complexes [5] and [6] with HBF4·Et2O and of adenosine-derived complexes [7] and [8] using lutidinium triflate yields complexes [9]BF4 and [10]BF4 and complexes [11]OTf and [12]OTf bearing protic NH,NR-NHC ligands derived from guanosine and adenosine, respectively.

Regioselectivity in the Reaction of 2‐Aminobenzothiazoles and 2‐Aminobenzimidazoles with Enaminonitriles and Enaminones: Synthesis of Functionally Substituted Pyrimido[2,1‐b][1,3]benzothiazole and Pyrimido[1,2‐a]benzimidazole Derivatives

A variety of new polyfunctionally substituted benzo[d]pyrimido[2,1‐b][1,3]thiazole and benzo[4,5]imidazo[1,2‐a]pyrimidine derivatives have been synthesized. The general synthetic procedure used for this purpose involves the condensation of 2‐aminobenzothiazole and 2‐aminobenzimidazole with a variety of enaminonitriles, enaminones, and acrylaldehyde. The regioselectivity for initial attack of either endocyclic ring nitrogen or exocyclic amino group was studied and rationalized for. It has been concluded that ring nitrogen is the most reactive cite in acidic medium, and cyclic intermediate can also be isolated, attesting to this conclusion upon cyclization. However, in basic or neutral medium, the exocyclic amino group was found to be the most reactive center. All structures of the newly synthesized compounds were elucidated by elemental analysis, spectral data, and alternative synthetic route whenever possible.

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives.

Alkaloids, a category of natural products with ring structures and nitrogen atoms, include most U.S. Food and Drug Administration approved plant derived anti-cancer agents. Evodiamine is an alkaloid with attractive multitargeting antiproliferative activity. Its high content in the natural source ensures its adequate supply on the market and guarantees further medicinal study. To the best of our knowledge, there is no systematic review about the antiproliferative effects of evodiamine derivatives. Therefore, in this article the review of the antiproliferative activities of evodiamine will be updated. More importantly, the antiproliferative activities of structurally modified new analogues of evodiamine will be summarized for the first time.