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Antibody-based immunotherapy is a promising strategy for targeting chemoresistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated by using CrossMAb and knob-into-holes technology, containing a bivalent T-cell receptor–like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms tumor protein (WT1) in the context of HLA-A*02. Binding to CD3ε recruits T cells irrespective of their T-cell receptor specificity. WT1-TCB elicited antibody-mediated T-cell cytotoxicity against AML cell lines in a WT1- and HLA-restricted manner. Specific lysis of primary acute myeloid leukemia (AML) cells was mediated in ex vivo long-term cocultures by using allogeneic (mean ± standard error of the mean [SEM] specific lysis, 67 ± 6% after 13-14 days; n = 18) or autologous, patient-derived T cells (mean ± SEM specific lysis, 54 ± 12% after 11-14 days; n = 8). WT1-TCB–treated T cells exhibited higher cytotoxicity against primary AML cells than an HLA-A*02 RMF-specific T-cell clone. Combining WT1-TCB with the immunomodulatory drug lenalidomide further enhanced antibody-mediated T-cell cytotoxicity against primary AML cells (mean ± SEM specific lysis on days 3-4, 45.4 ± 9.0% vs 70.8 ± 8.3%; P = .015; n = 9-10). In vivo, WT1-TCB–treated humanized mice bearing SKM-1 tumors exhibited a significant and dose-dependent reduction in tumor growth. In summary, we show that WT1-TCB facilitates potent in vitro, ex vivo, and in vivo killing of AML cell lines and primary AML cells; these results led to the initiation of a phase 1 trial in patients with relapsed/refractory AML (#NCT04580121).

Antibody-based immunotherapy is a promising strategy for targeting chemoresistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated by using CrossMAb and knob-into-holes technology, containing a bivalent T-cell receptor–like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms tumor protein (WT1) in the context of HLA-A*02. Binding to CD3ε recruits T cells irrespective of their T-cell receptor specificity. WT1-TCBelicited antibody-mediated T-cell cytotoxicity against AML cell lines in a WT1- and HLA-restricted manner. Specific lysis of primary acute myeloid leukemia (AML) cells was mediated in ex vivo long-term cocultures by using allogeneic (mean ± standard error of the mean [SEM] specific lysis, 67 ± 6% after 13-14 days; n = 18) or autologous, patient-derived T cells (mean ± SEM specific lysis, 54 ± 12% after 11-14 days; n = 8). WT1-TCB–treated T cells exhibited higher cytotoxicity against primary AML cells than an HLA-A*02 RMF-specific T-cell clone. Combining WT1-TCBwith the immunomodulatory drug lenalidomide further enhanced antibody-mediated T-cell cytotoxicity against primary AML cells (mean ± SEM specific lysis on days 3-4, 45.4 ± 9.0% vs 70.8 ± 8.3%; P= .015; n = 9-10). In vivo, WT1-TCB–treated humanized mice bearing SKM-1 tumors exhibited a significant and dose-dependent reduction in tumor growth. In summary, we show that WT1-TCBfacilitates potent in vitro, ex vivo, and in vivo killing of AML cell lines and primary AML cells; these results led to the initiation of a phase 1 trial in patients with relapsed/refractory AML (#NCT04580121).

●Bivalent binding of forimtamig to GPRC5D conveys superior potency compared to other GPRC5D- and BCMA-targeting T cell bispecific antibodies.●Forimtamig combination with BCMA-directed T cell bispecific antibodies and Cereblon E3 Ligase Modulatory Drugs prevents tumor relapse.

Gullies are widespread morphological features on Mars for which current changes have been observed. Liquid water has been one of the potential mechanisms to explain their formation and activity. However, under present-day Martian conditions, liquid water is unstable and should only be transiently present in small amounts at the surface. Yet little attention has been paid to the mechanisms by which unstable water transports sediment under low atmospheric pressure. Here we present the results of laboratory experiments studying the interaction between liquid water flowing over a sand bed under Mars-like atmospheric pressure (c.9 mbar). The experiments were performed in a Mars Simulation Chamber (at the Open University, UK), in which we placed a test bed of fine sand at a 25° slope. We chose to investigate the influence of two parameters: the temperature of the water and the temperature of the sand. We performed 27 experiments with nine different combinations of water and sand temperatures ranging from 278 to 297 K. Under all experimental conditions, the water was boiling. We investigated and compared the types and timing of sediment transport events, and the shapes, characteristics and volumes of the resulting morphologies. In agreement with previous laboratory studies we found that more intense boiling increased the volume of sediment transported for a given volume of water. We found four main types of sediment transport: entrainment by overland flow; grain ejection; grain avalanches; and levitation of saturated sand pellets. Our results showed that increasing sand temperature was the main driving parameter in increasing the sand transport and in modifying the dominant sediment transport mechanism. The temperature of the water played a negligible or minor role, apart from the duration of sand ejection and avalanches, which lasted longer at low water temperature. At low sand temperature the majority of the sand was transported by overland flow of the liquid water. At higher sand temperatures the transport was dominated by processes triggered by the boiling behaviour of the water. At the highest temperatures, sediment transport was dominated by the formation of levitating pellets, dry avalanches and ejection of the sand grains. This resulted in a transport volume about nine times greater at a sand temperature of 297 K compared with 278 K. Our heat transfer scaling shows that the boiling behaviour will be enhanced under Martian low gravity, resulting in more efficient transport of sediment by levitating sand pellets even at temperatures close to the triple point. Our results showed that the boiling intensity played an important role in the physics of sediment transport by liquid water. This implied that the amount of water required to produce morphological changes at the surface of Mars could be lower than previously estimated by assuming stable liquid water. Boiling is a critical process to be considered when assessing gully formation and modification mechanisms mobilized by liquid water. Our work could have similar implications for any water-formed landform on Mars, which could include recurring slope lineae, dark dune flows and slope streaks.

ABSTRACTThe small GTPase Rac1 is implicated in various cellular processes that are essential for normal cell function. Deregulation of Rac1 signaling has also been linked to a number of diseases, including cancer. The diversity of Rac1 functioning in cells is mainly attributed to its ability to bind to a multitude of downstream effectors following activation by Guanine nucleotide Exchange Factors (GEFs). Despite the identification of a large number of Rac1 binding partners, factors influencing downstream specificity are poorly defined, thus hindering the detailed understanding of both Rac1's normal and pathological functions. In a recent study, we demonstrated a role for 2 Rac-specific GEFs, Tiam1 and P-Rex1, in mediating Rac1 anti- versus pro-migratory effects, respectively. Importantly, via conducting a quantitative proteomic screen, we identified distinct changes in the Rac1 interactome following activation by either GEF, indicating that these opposing effects are mediated through GEF modulation of the Rac1 interactome. Here, we present the full list of identified Rac1 interactors together with functional annotation of the differentially regulated Rac1 binding partners. In light of this data, we also provide additional insights into known and novel signaling cascades that might account for the GEF-mediated Rac1-driven cellular effects.

Liquid water may exist on the Martian surface today, albeit transiently and in a metastable state under the low atmospheric surface pressure. However, the identification of liquid water on Mars from observed morphological changes is hampered by our limited understanding of how metastable liquids interact with sediments. Here, we present lab experiments in which a block of ice melts and seeps into underlying sediment, and the resulting downslope fluid propagation and sediment transport are tracked. In experiments at Martian surface pressure, we find that pure water boils as it percolates into the sediment, inducing grain saltation and leading to wholesale slope destabilization: a hybrid flow mechanism involving both wet and dry processes. For metastable brines, which are more stable under Martian conditions than pure water, saltation intensity and geomorphological impact are reduced; however, we observed channel formation in some briny flow experiments that may be analogous to morphologies observed on Mars. In contrast, under terrestrial-like experimental conditions, there is little morphological impact of seeping water or brine, which are both stable. We propose that the hybrid flow mechanism operating in our experiments under Martian surface pressure could explain observed Martian surface changes that were originally interpreted as the products of either dry or wet processes.

Bottom-up strategies can be effectively implemented for the fabrication of atomically precise graphene nanoribbons. Recently, using 10,10′-dibromo-9,9′-bianthracene (DBBA) as a molecular precursor to grow armchair nanoribbons on Au(111) and Cu(111), we have shown that substrate activity considerably affects the dynamics of ribbon formation, nonetheless without significant modifications in the growth mechanism. In this paper we compare the on-surface reaction pathways for DBBA molecules on Cu(111) and Cu(110). Evolution of both systems has been studied viaa combination of core-level X-ray spectroscopies, scanning tunneling microscopy, and theoretical calculations. Experimental and theoretical results reveal a significant increase in reactivity for the open and anisotropic Cu(110) surface in comparison with the close-packed Cu(111). This increased reactivity results in a predominance of the molecular–substrate interaction over the intermolecular one, which has a critical impact on the transformations of DBBA on Cu(110). Unlike DBBA on Cu(111), the Ullmann coupling cannot be realized for DBBA/Cu(110) and the growth of nanoribbons viathis mechanism is blocked. Instead, annealing of DBBA on Cu(110) at 250 °C results in the formation of a new structure: quasi-zero-dimensional flat nanographenes. Each nanographene unit has dehydrogenated zigzag edges bonded to the underlying Cu rows and oriented with the hydrogen-terminated armchair edge parallel to the [1–10] direction. Strong bonding of nanographene to the substrate manifests itself in a high adsorption energy of −12.7 eV and significant charge transfer of 3.46efrom the copper surface. Nanographene units coordinated with bromine adatoms are able to arrange in highly regular arrays potentially suitable for nanotemplating.

Stable Isotope Labeling by Amino Acids (SILAC) is a commonly used method in quantitative proteomics. Because of compatibility with trypsin digestion, arginine and lysine are the most widely used amino acids for SILAC labeling. We observed that Schizosaccharomyces pombe(fission yeast) cannot be labeled with a specific form of arginine, 13C615N4-arginine (Arg-10), which limits the exploitation of SILAC technology in this model organism. We hypothesized that in the fission yeast the guanidinium group of 13C615N4-arginine is catabolized by arginase and urease activity to 15N1-labeled ammonia that is used as a precursor for general amino acid biosynthesis. We show that disruption of Ni2+-dependent urease activity, through deletion of the sole Ni2+transporter Nic1, blocks this recycling in ammonium-supplemented EMMG medium to enable 13C615N4-arginine labeling for SILAC strategies in S. pombe. Finally, we employed Arg-10 in a triple-SILAC experiment to perform quantitative comparison of G1 + S, M, and G2 cell cycle phases in S. pombe.

To quantify cell cycle-dependent fluctuations on a proteome-wide scale, we performed integrative analysis of the proteome and phosphoproteome during the four major phases of the cell cycle in Schizosaccharomyces pombe. In highly synchronized cells, we identified 3753 proteins and 3682 phosphorylation events and relatively quantified 65% of the data across all phases. Quantitative changes during the cell cycle were infrequent and weak in the proteome but prominent in the phosphoproteome. Protein phosphorylation peaked in mitosis, where the median phosphorylation site occupancy was 44%, about 2-fold higher than in other phases. We measured copy numbers of 3178 proteins, which together with phosphorylation site stoichiometry enabled us to estimate the absolute amount of protein-bound phosphate, as well as its change across the cell cycle. Our results indicate that 23% of the average intracellular ATP is utilized by protein kinases to phosphorylate their substrates to drive regulatory processes during cell division. Accordingly, we observe that phosphate transporters and phosphate-metabolizing enzymes are phosphorylated and therefore likely to be regulated in mitosis.

Atomically precise graphene nanoribbons (GNRs) can be fabricated via thermally induced polymerization of halogen containing molecular precursors on metal surfaces. In this paper the effect of substrate reactivity on the growth and structure of armchair GNRs (AGNRs) grown on inert Au(111) and active Cu(111) surfaces has been systematically studied by a combination of core-level X-ray spectroscopies and scanning tunneling microscopy. It is demonstrated that the activation threshold for the dehalogenation process decreases with increasing catalytic activity of the substrate. At room temperature the 10,10′-dibromo-9,9′-bianthracene (DBBA) precursor molecules on Au(111) remain intact, while on Cu(111) a complete surface-assisted dehalogenation takes place. Dehalogenation of precursor molecules on Au(111) only starts at around 80 °C and completes at 200 °C, leading to the formation of linear polymer chains. On Cu(111) tilted polymer chains appear readily at room temperature or slightly elevated temperatures. Annealing of the DBBA/Cu(111) above 100 °C leads to intramolecular cyclodehydrogenation and formation of flat AGNRs at 200 °C, while on the Au(111) surface the formation of GNRs takes place only at around 400 °C. In STM, nanoribbons have significantly reduced apparent height on Cu(111) as compared to Au(111), 70 ± 11 pm versus 172 ± 14 pm, independently of the bias voltage. Moreover, an alignment of GNRs along low-index crystallographic directions of the substrate is evident for Cu(111), while on Au(111) it is more random. Elevating the Cu(111) substrate temperature above 400 °C results in a dehydrogenation and subsequent decomposition of GNRs; at 750 °C the dehydrogenated carbon species self-organize in graphene islands. In general, our data provide evidence for a significant influence of substrate reactivity on the growth dynamics of GNRs.

Recent advances in mass spectrometry (MS) have led to increased applications of shotgun proteomics to the refinement of genome annotation. The typical “proteo-genomic” workflows rely on the mapping of peptide MS/MS spectra onto databases derived via six-frame translation of the genome sequence. These databases contain a large proportion of spurious protein sequences which make the statistical confidence of the resulting peptide spectrum matches difficult to assess. Here we performed a comprehensive analysis of the Escherichia coliproteome using LTQ-Orbitrap MS and mapped the corresponding MS/MS spectra onto a six-frame translation of the E. coligenome. We hypothesized that the protein-coding part of the E. coligenome approaches complete annotation and that the majority of six frame-specific (novel) peptide spectrum matches can be considered as false positive identifications. We confirm our hypothesis by showing that the posterior error probability distribution of novel hits is almost identical to that of reversed (decoy) hits; this enables us to estimate the sensitivity, specificity, accuracy, and false discovery rate in a typical bacterial proteo-genomic dataset. We use two complementary computational frameworks for processing and statistical assessment of MS/MS data: MaxQuant and Trans-Proteomic Pipeline. We show that MaxQuant achieves a more sensitive six-frame database search with an acceptable false discovery rate and is therefore well suited for global genome reannotation applications, whereas the Trans-Proteomic Pipeline achieves higher specificity and is well suited for high-confidence validation. The use of a small and well-annotated bacterial genome enables us to address genome coverage achieved in state-of-the-art bacterial proteomics: identified peptide sequences mapped to all expressed E. coliproteins but covered 31.7% of the protein-coding genome sequence. Our results show that false discovery rates can be substantially underestimated even in “simple” proteo-genomic experiments obtained by means of high-accuracy MS and point to the necessity of further improvements concerning the coverage of peptide sequences by MS-based methods.

Protein kinase D (PKD) is a cytosolic serine/threonine kinase implicated in regulation of several cellular processes such as response to oxidative stress, directed cell migration, invasion, differentiation, and fission of the vesicles at the trans-Golgi network. Its variety of functions must be mediated by numerous substrates; however, only a couple of PKD substrates have been identified so far. Here we perform stable isotope labeling of amino acids in cell culture-based quantitative phosphoproteomic analysis to detect phosphorylation events dependent on PKD1 activity in human cells. We compare relative phosphorylation levels between constitutively active and kinase dead PKD1 strains of HEK293 cells, both treated with nocodazole, a microtubule-depolymerizing reagent that disrupts the Golgi complex and activates PKD1. We identify 124 phosphorylation sites that are significantly down-regulated upon decrease of PKD1 activity and show that the PKD target motif is significantly enriched among down-regulated phosphorylation events, pointing to the presence of direct PKD1 substrates. We further perform PKD1 target motif analysis, showing that a proline residue at position +1 relative to the phosphorylation site serves as an inhibitory cue for PKD1 activity. Among PKD1-dependent phosphorylation events, we detect predominantly proteins with localization at Golgi membranes and function in protein sorting, among them several sorting nexins and members of the insulin-like growth factor 2 receptor pathway. This study presents the first global detection of PKD1-dependent phosphorylation events and provides a wealth of information for functional follow-up of PKD1 activity upon disruption of the Golgi network in human cells.

The principle of determining lipophilicity contribution values fi of atomic fragments assumes the additive character of the logarithm of the partition coefficient of a molecule to be log 4;P=Σ aifi, where ai is a numerical factor indicating the frequency of a given atomic fragment (i) in the structure i.e. the number of times this atomic fragment appears in the molecule. However, two phenomena induce unresolved fi values due to the generation of identical equations. We propose to name these phenomena “fragmental isofrequency” and “fragmental induction”.

Abstract. Since the three-dimensional structure of the NMDA receptor has not been determined experimentally, indirect computer-assisted molecular modeling techniques appear to be of great usefulness in the characterization of the common pharmacophore of all NMDA receptor noncompetitive antagonists, despite their structural differences. Indeed, the conformational analysis of three different chemical families (MK801, PCP, dexoxadrol and their analogues), has allowed us to visualize the different conformations and configurations of each molecule. Superimposition with configurations 1 and 2 of the MK801 molecule has allowed us to propose active conformations and thereafter a geometrical characterization of the pharmacophore, especially the determination of the orientation of the nitrogen lone pair (NLP) related to the phenyl. On the other hand, electrostatic studies, combined with geometrical features, have allowed us to schematize the interaction mode of an active conformation to the binding site. Finally, studies of the molecular lipophilic potential (MLP) have provided us information on the position of lipophilic and hydrophilic zones of the pharmacophore.

Computational chemistry and molecular modeling sites have proliferated on the Internet's world wide web. This paper provides present links to some of the more most useful ones for small organic molecule modeling, and offering free resources.

AbstractPolycyclic Aromatic Compounds containing one sulfur atom i.e. Polycyclic Aromatic Sulfur Heterocycles (PASH) form a very diversified subclass of compounds and the number of compounds increases with alkylation. Nonsubstituted as well as mono- and dimethylated PASH are found in crude oils. Identification and analysis of these compounds is a difficult challenge that can be facilitated by theoretical calculations up-side.The purpose of this study was to use quantum mechanics calculations to generate properties such as molecular shape or thermodynamic stability that could be related to chromatographic indices. Tricyclic (dibenzothiophene, naphthothiophenes) and tetracyclic (phenanthrothiophenes, anthrathiophenes and benzonaphthothiophenes) parent molecules and mono- and di-methylated analogues have been studied. A special attention has been paid to compounds with a crowded bay region that results in a twisted molecular geometry.The results from semi-empirical methods (AMPAC 6.51-MNDO, AM1) and ab initioHartree-Fock methods (RHF/6-31G) have been compared to X-ray determined geometries when available and attempts have been made to correlate enthalpies of formation and chromatographic behaviour and/or relative abundance or presence in petroleum samples.

AbstractShape complementarity, electrostatic and hydrophobic matching, were used to model drugs and receptors. From known experimental data on α1A/α2A−adrenergic ligands and α1A/α2A−alrenoceptors, a model for the ligand binding sites, based on the structure of bacteriorhodopsin as a template, was proposed and built. Agonists and antagonists have overlapping but different binding sites. Emphasis was given on the role of the disulphide bridge and on the role of the sodium site. The model was extended to other G-protein coupled receptors.

AbstractThe 2-amino-2-imidazoline moiety is currently used not only in drugs, but also in insecticides, and fungicides. Ab initiocalculations are performed to evaluate the molecular properties of the two tautomeric forms and the protonated form with extended basis sets ranging from 6-31G* to 6-311 + +G**at Hartree-Fock and density functional (BLYP and B3LYP) levels. Moller-Plesset perturbation is tested at the MP2/6-31G* level only. Optimized geometry structures, energies and thermochemical properties are generated. Basis set and correlation effects on geometries, tautomer equilibrium constant and protonation enthalpy are carefully analysed. Although observed for the isolated molecule, these results may be extrapolated to chemical and biochemical systems of interest.

Carbaryl belongs to a series of compounds that activate the CYP1A1 gene. This study demonstrates the inability of carbaryl to compete with 2,3,7,8-tetrachlorodibenzo-p-dioxin for binding to the rat aryl hydrocarbon (dioxin) receptor. Structural and physicochemical properties of this insecticide, in relation to the requirements for binding to the aryl hydrocarbon receptor, are described. The crystal structure was determined experimentally using X-ray diffraction. A conformational search using molecular mechanics was performed by means of a Monte-Carlo-type method and a stochastic dynamics simulation. Lipophilicity calculations, log P, and molecular lipophilicity potential are also presented. Common and discriminating properties of carbaryl and aryl hydrocarbon receptor ligands are discussed.

The reaction between ethyl(ethoxymethylene)cyanoacetate and 5-phenoxymethyl-2-amino-2-oxazoline leads to a 1,4-adduct and to a 2,3-dihydrooxazolo[3,2-a]pyrimidin-5-one. The structures were assigned by spectroscopy and, for the cyclocondensation compound, by X-ray crystallography. The question of regioselectivity was studied by a theoretical approach in order to determine the more reliable reaction pathways. An unexpected mechanistic scheme is proposed to explain the formation of the cyclocondensed compound.

2-Acetoxy-3-(3-methoxy-4-acetoxy-5-chlorophenyl)-propenoic acid 2was synthesized from the azlactone of 5-chlorovanillin and its structure confirmed by X-ray crystallography and nuclear magnetic resonance methods. Compound 2crystallized with a molecule of acetic acid in the P-1(#2) space group (Z= 2) and with cell dimensions a= 6.303(2), b= 9.779(1), c= 15.528(3) Å, α = 101.46(2), β = 100.71(2) and γ = 90.21(2)°. This study reveals the formation of an α-acetoxy propenoic acid with a transextended side acid side chain conformation. The 1H and 13C NMR spectral values of 2also show the existence of the enolic ester in solution.

The azlactone of 6-chloroveratraldehyde 3(4-(2-chloro-4,5-dimethoxybenzylidene)-2-methyl-5-oxazolone) was synthesized from 6-chloroveratraldehyde 2and its structure investigated using X-ray crystallographic and nuclear magnetic resonance methods. Compound 3crystallized in the P21/c(#14) space group (Z= 4) with cell dimensions a= 9.148(2), b= 22.938(2), c= 6.707(1) Å, and β = 111.50(2)°. The X-ray study shows that azlactone 3exists as the Z-isomer and crystallizes as a planar structure, i.e., both the phenyl and azlactone ring systems, as well as the functional groups attached to them, lie in the same plane. The 1H and 13C NMR spectral values also support the formation of the Z-isomer only, during the synthesis of 4-(2-chloro-4,5-dimethoxybenzylidene)-2-methyl-5-oxazolone.

The reaction of methyl 15-O-acctylisocupressate with SeO2/MeOH yielded, in addition to the expected products of allylic oxidation, ≈20% of selenepanes and selenocanes. The formation of cyclic selenium compounds from diolefins in this reaction is similar to that observed from acetyllinalool. The mechanistic proposal through a double electrophilic attack to both double bonds explains the structural variation of the selenium containing products in this and in previous cases.

During the synthesis of a series of new antiarhythmic drugs, the reaction between epichlorohydrin and hindered amines was reinvestigated. With primary amines, 3-azetidinols were formed in fair yields. The X-ray structure elucidation of one of these compounds (1: P21/n, a = 17.210, b = 6.665, c = 23.585, β = 102.29, and R = 0.064 for 2005 observed reflections) and NMR studies led to the conclusion that both the hydroxy group and the bulky nitrogen substituent are on the same side of the azetidine ring. With secondary amines, the reaction was very complex, leading to diamino dioxane, diamino alcohols, amino alcohol ethers, and one glycol. X-ray analysis and 1H and 13C NMR studies allowed complete assignments for all compounds. All but one exhibited a slow interconversion of the nitrogen visible in the 13C NMR spectra. Keywords: epichlorohydrin, hindered amines, azetidinol, adamantane, alkanol amines.

A series of anti-thrombotic aryl thienyl-ketones and -thioketones was assayed in vitro for their inhibitory effect on malondialdehyde (MDA) production induced by arachidonic acid in human platelets. For several compounds MDA formation was strongly inhibited indicating that the anti-platelet target was situated on the cyclooxygenase pathway. A comparison between the inhibition constant K1 and the IC50 values revealed competitive inhibition kinetics. The molecular structure of one active compound was analysed by X-ray diffraction and theoretical calculations to provide information on its electronic and lipophilic properties.

Abstract: The X-ray crystal structures of (–)-syn-4-phenyl-3-bromo-2-butyl camphanate (I) and (+-anti-4-phenyl-3-bromo-2-butyl camphanate (II) have been determined. Thesyn diastereoisomer of bromohydrin has the (2S,3S) absolute configuration whereas theanti diastereoisomer has the (2S,3R) absolute configuration. The crystallized derivatives I and II have been obtained by the reaction of each stereoisomer of bromohydrin, synthesized by reduction with baker's yeast, with (1S)-camphanic chloride. Crystal data: (I) C20H25BrO4:M w: 409.32; orthorhombic,P212121;a=11.245(3),b=12.086(1),c=14.512(4) å; Z=4; finalR=0.053 for 1819 observed reflections. (II) C20H25BrO4;M w=409.32; monoclinic, P21;a=11.352(1),b=6.378(1),c=14.255(2) å,Bgr=110.38(1)order;Z=2; finalR=0.045 for 1672 observed reflections.

NMR spectroscopy and single-crystal X-ray analysis have been used to characterize polymorphism of the racemate of the N-phenyl-N'-[1-(3-(phenyl-4-piperazinyl)propan-2-ol)urea displaying an analgesic activity. The crystal structures of the monoclinic form,Rm witha=4.788(1),b=9.432(7),c=40.791(5) Å, ß=90.93(1)°, space groupP21/n,Z=4 and of the orthorhombic form,Ro witha=10.948(3),b=8.896(3),c=38.857(6) Å, space groupPbca,Z=8, have been determined. In addition, the crystal structure of an enantiomer orthorhombic,Eo, isolated from a conglomerate, witha=4.787(3),b=9.461(2),c=40.809(10) Å, space groupP212121, Z=4, has also been determined. The three conformations have been compared when the molecules have the same relative configurations.

The structure and conformation of (1)-Centbutindole, a newly marketed neuroleptic compound, has been investigated by X-ray crystallography. It crystallizes in the monoclinic system and the non-centrosymmetric space group P21 (Z=2) with cell dimensionsa=8.434(6),b=6.620(3),c=18.419(9)Å, and ß=95.07(6)°. The chain conformation istrans extended. The embedded ?3 piperidine ring exists in ahalf-chair conformation whereas the embedded piperazine ring exists in achair conformation. The propylene side chain is equatorial relative to the piperazine. A systematic conformational analysis of centbutindole and of a related molecule, Haloperidol, followed by a Monte Carlo search and a stochastic dynamics simulation, have been performed. Electronic and lipophilic properties have been computed and, molecular electrostatic potential (MEP) maps and molecular lipophilicity potential (MLP) maps, have been displayed for two selected conformers satisfying a reported pharmacophore. The two molecules exhibit very similar molecular properties.

The structures and conformation of 3-methoxy-4-hydroxy-5-chloro-phenylpyruvic acid3and its acetate ester4have been investigated by X-ray crystallography and by spectroscopic methods. Three independent molecules crystallized for the ester4with the triclinic symmetry and the centrosymmetric space group (Z=6) and with the cell dimensionsa=11.764(6),b=13.549(5),c=13.978(15) Å. α=100.08(7), β=94.62(8), γ=115.06(4)°. The three conformers of4exist as the enolate tautomers and not the keto form.Transextended side pyruvic acid side chains were observed for the three conformers. The crystalline cohesion was ensured by a strong network of hydrogen bonds. The NMR spectra of the phenylpyruvic acid3and the acetate ester4exhibited each a single proton on the benzylic carbon atom and chemical shift values supporting the existence of the enolate tautomer form for these phenylpyruvic acid compounds in solution.

2‐Methylquinoxaline reacts with ethyl bromopyruvate giving 2‐substituted pyrrolo[1,2‐α]quinoxalines. The yield of the condensation depends on the functionalization of starting materials, and optimization is obtained with 2‐dimethylamino‐3‐methylquinoxaline (1c). Reactivity of the resulting pyrrolo[1,2‐a]‐quinoxalines was investigated and supported by a theoretical approach (AM1 calculation performed with the MOPAC 6.0 software). X‐ray analysis of 5which crystallizes in the monoclinic system, space group P21/n, with a = 9.095(1), b = 8.972(1), c = 17.749(3) A, β = 96.56(1)°, is also reported.

The reaction of 2amino2oxazolines with ethoxycarbonyl isocyanate was investigated in order to access to fused 1,3,5triazine2,4diones with a potential 5HT2antagonist activity. The reaction leads to 2,3,6,7tetrahydro4Hoxazolo3,2a1,3,5triazine2,4diones and to 1carbethoxy32iminooxazolidineureas. During the carbamoylation the regioselectivity seems to be related to the strong nucleophilic character of the endo nitrogen atom of 2amino2oxazolines. The structures of two compounds were studied by Xray crystallography. NSubstituted compounds have been prepared by alkylation of the 2,3,6,7tetrahydro7phenoxymethyl4Hoxazolo3,2a1,3,5triazine2,4dione.

The reaction of some 2-amino-2-oxazolines with isocyanates and arylisothiocyanates yields 3-monosubstituted or 2,3-disubstituted 2-iminooxazolidines depending on the experimental conditions and on the nature of the electrophile reactants. The structures of a mono- and a disubstituted derivative were established by X-ray analysis. The chemical behaviour of the compounds was investigated by molecular and quantum mechanics calculations. An intramolecular transposition during the second step of the reaction was found. Keywords: 2-amino-2-oxazolines, iso(thio)cyanates, transposition. X-ray structure, MOPAC calculations.

A new mechanism is proposed for the formation and the migration of planar defects in ABO3+x, perovskite-type compounds.

The paraacetate ester azlactone of vanillin 2was synthesized from vanillin 1and hydrolyzed with sodium hydroxide. The yielded product 3was investigated with X-ray Crystallographic and nuclear magnetic resonance techniques. Compound 3crystallized in the orthorhombic Pbca space group (Z= 8) and with cell dimensions a= 14.732(2), b= 12.756(3), c= 12.747(6)Å revealing the enolate tautomer and not the keto form of 3-methoxy-4-hydroxyphenylpyruvic acid as the acetate ester. The structure exhibited the pyruvic acid side chain in the transextended conformation. A single proton on the benzylic carbon atom further suggested the existence of the enolate tautomer form of 3in solution. The chemical shift values and peak integration in the NMR spectra add additional support to this finding.

The effects of hydrogen gas excited in a radiofrequency discharge on oxygen-free solutions of thymine have been followed chemically. Two main reaction products have been identified: 5,6-dihydrothymine and 5,6-thymine glycol. The latter product was found to be the only significant species if discharge-excited argon was pumped through the solutions instead of hydrogen. Although dihydrothymine clearly is the reaction product of atomic hydrogen generated in the hydrogen discharge, the glycol requires the formation of OH radicals in the solution. A mechanism is proposed by which this species is produced through (super) excitation and decay of water molecules by energy transfer from the excited gas.

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