X-ray Crystal Structure Analysis Research Articles

Synthesis, X-ray crystal structure, DFT, Hirshfeld surfaces, energy frameworks, and molecular docking analysis of a bicyclic ortho-aminocarbonitrile derivative

2-Amino-4-(2, 5-dimethoxyphenyl)-4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-tricarbonitrile has been synthesized and characterized by conventional spectroscopic techniques (FT-IR and 1H NMR) and the three-dimensional structure elucidated by single crystal X-ray diffraction studies (SC-XRD). It exists in monoclinic crystal system with space group P21/c and lattice parameters: a = 14.641(13) Å, b = 8.653(4) Å, c = 16.609(10) Å, β = 116.34(3)°, and Z = 4. In the crystal packing, molecules are connected through N-H···O and N-H···N intermolecular and intramolecular C-H···O interactions. The N1-H11···N2 interaction results in the formation of a dimer corresponding to R22(12) graph-set motif. The molecular structure has been theoretically optimized by using density functional theory (DFT) with the basis set B3LYP/6-311G (d,p). The optimized bond geometry shows consistency with the SC-XRD data. Besides this, the molecular electrostatic potential (MEP), Mulliken charges, and frontier molecular orbital analysis have been described. The dnorm, shape index, curvedness, crystal voids, 2D fingerprint (FP) plots, and 3D energy frameworks using Hirshfeld surface (HS) studies have also been computed and investigated. The molecular docking studies for 2-amino-4-(2, 5-dimethoxyphenyl)-4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-tricarbonitrile with DNA gyrase/lanosterol 14α-demethylase suggest that the compound may act as an active antimicrobial drug.

Enzymatic formation of a prenyl β-carboline by a fungal indole prenyltransferase.

CdpNPT from Aspergillus fumigatus is a fungal indole prenyltransferase (IPT) with remarkable substrate promiscuity to generate prenylated compounds. Our first investigation of the catalytic potential of CdpNPT against a β-carboline, harmol (1), revealed that the enzyme also accepts 1 as the prenyl acceptor with dimethylallyl diphosphate (DMAPP) as the prenyl donor and selectively prenylates the C-6 position of 1 by the "regular-type" dimethylallylation to produce 6-(3-dimethylallyl)harmol (2). Furthermore, our X-ray crystal structure analysis of the C-His6-tagged CdpNPT (38-440) truncated mutant complexed with 1 and docking studies of DMAPP to the crystal structure of the CdpNPT (38-440) mutant suggested that CdpNPT could employ the two-step prenylation system to produce 2.

Molecular Structures and Redox Properties of Homoleptic Aluminum(III) Complexes with Azobisphenolate (azp) Ligands

To elucidate the oxidation behavior of the 2,2′-azobisphenolate (azp) ligand, a series of homoleptic 1:2 AlIII complexes of four azp derivatives (L1) with 5,5′-dichloro-, 5,5′-dimethyl-, 5,5′-di-t-butyl-, 3,3′,5,5′-tetramethyl-substituents and of one imino derivative (L2) were synthesized and obtained as TPP[Al(L)2]·solvent (TPP = tetraphenylphosphonium ion). The X-ray crystal structure analyses showed that the two ONO-tridentate ligands were meridionally coordinated to a central AlIII ion in an almost perpendicular manner to give a homoleptic octahedral coordination structure in all the AlIII complexes. The proton nuclear magnetic resonance spectra suggested that all the AlIII complexes retained the homoleptic coordination structure in solution. From the cyclic voltammetry measurements in dichloromethane solutions, all the AlIII complexes with the azp ligands showed two partially reversible oxidation waves, and an additional reversible or partially reversible reduction wave. The substitution effects on the first oxidation and reduction peak potentials were revealed in the AlIII complexes with the azp ligands. On the other hand, the imino complex showed a partially reversible oxidation wave accompanying a film deposition. The density functional theory (DFT) calculations indicated that the molecular orbital (MO) coefficients of the frontier MOs in the AlIII complexes were present on the ligands and were absent on the AlIII ion. These results confirmed that the azp ligands are susceptible to oxidation and can give a relatively stable oxidation species depending upon substituent effects.

Solvent effects on the crystallization and structure of ternary copper(ii) coordination compounds with l-threonine and 1,10-phenanthroline

Solution-based and solid-state reactions of copper(ii) compounds, 1,10-phenanthroline and l-threonine were investigated. Eight new ternary coordination compounds were obtained:[Cu(l-Thr)(H2O)(phen)]2SO4∙10H2O (1a∙10H2O), [Cu(l-Thr)(H2O) (phen)]2SO4∙4.3H2O (1a∙4.3H2O), {[Cu(μ-l-Thr)(phen)]2SO4∙3.5H2O}n (1b∙3.5H2O), [Cu(l-Thr)(H2O)(phen)][Cu(l-Thr)(CH3OH)(phen)]SO4∙2H2O∙CH3OH (1c∙2H2O∙CH3OH), [Cu(l-Thr)(H2O)(phen)][Cu(l-Thr)(CH3OH)(phen)]SO4∙4H2O (1c∙4H2O), [Cu(l-Thr)(CH3OH)(phen)]2SO4∙H2O (1d∙H2O), [Cu(l-Thr)(H2O)(phen)][Cu(l-Thr)(CH3OH)(phen)][Cu(SO4)(l-Thr)(phen)]HSO4∙H2O∙3CH3OH (1e·H2O·3CH3OH), [Cu(l-Thr)(H2O)(phen)][Cu(l-Thr)(phen)(py)]SO4 (1f) (phen = 1,10-phenanthroline, l-Thr = l-threoninate, py = pyridine). X-ray crystal structure analysis of the prepared ternary coordination compounds revealed extensive hydrogen bonding and π-interactions that link complex species, anions and solvent molecules into 3D architectures. The water/methanol solvent molecules are found in pockets and/or channels in seven solvates. ESR spectra of different types of compounds were also investigated. In all measured compounds the unpaired electron of the copper(II) ion is located in the dx2-y2 orbital which is in agreement with elongated square-pyramidal geometry. Compound 1a∙10H2O showed substantial cytotoxic activity toward human hepatocellular carcinoma (HepG2) and acute monocytic leukaemia (THP-1) cell lines.

Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands.

Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with modified linker structures, focusing on the relationship between molecular structure and targeting properties. The linker design was based on 2-naphthyl-L-alanine-tranexamic acid, the linker structure of PSMA-617. X-ray crystal-structure analysis of PSMA and structure-based design were used to generate the linker modifications, suggesting that substitution of tranexamic acid could lead to interactions with Phe546, Trp541, and Arg43 within the binding cavity. After synthesis through SPPS, analogues were labelled with indium-111 and evaluated in vitro for their specific binding, affinity, and cellular retention. Selected compounds were further evaluated in vivo in PSMA-expressing tumour-bearing mice. Based on the results, 2-naphthyl-L-alanine appears to be crucial for good targeting properties, whereas tranexamic acid could be replaced by other substituents. [111In]In-BQ7859, consisting of a 2-naphthyl-L-alanine-L-tyrosine linker, demonstrated favourable targeting properties. The substitution of tranexamic acid for L-tyrosine in the linker led to an improved tumour-to-blood ratio, highlighting [111In]In-BQ7859 as a promising PSMA-targeting radioligand.

Pincer-type bisnitroxide radicals involving tetramethylenedioxy and o-xylylenedioxy bridges

Two new pincer-type bisnitroxides have been synthesized, where tetramethylenedioxy and o-xylylenedioxy are chosen as a bridge between the p-position of two tert-butyl phenyl nitroxide moieties. The X-ray crystal structure analysis clarified the linear and U-shaped molecular structures for the former and latter compounds, respectively. In the toluene solution ESR of the tetramethylenedioxy derivative, five hyperfine splitting lines were recorded, but a center signal was somewhat lowered. The ESR spectra of the o-xylylenedioxy derivative displayed a typical 1/2/3/2/1 five-line pattern at 370 K, and an “alternating line-width” effect appeared in 210–230 K. These spectra were reproduced by simulation, based on the proposed model where a few conformers have differing exchange couplings. The contribution showing strong exchange is reasonably ascribable to the U-shaped conformer. Thus, the solid and solution experimental results are compatible with each other.Keywards: biradical, nitroxide, aminoxyl, ESR, exchange interaction.

Development of a detector tube for rapid detection of tadalafil in adulterated dietary supplements

ABSTRACT Introduction Products marketed as dietary supplements for improving sexual performance at times include phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil and analogues. The ingestion of these dietary supplements is extremely dangerous as these are not evaluated for their efficacy and safety as pharmaceuticals, and their manufacture is not controlled. For this reason, regulatory authorities conduct inspections on these products to prevent the occurrence and spread of health hazards. Tadalafil is one of the PDE5 inhibitors, and its analogues are found as the most major adulterants in sexual products after analogues of sildenafil. Tadalafil has two chiral carbons that are both R configuration, which is important for PDE5 inhibitory activity. To confirm the molecular configuration of the tested compound, it is subject to instrumental analysis such as circular dichroism detection or X-ray crystal structure analysis. Therefore, it takes longer for testing tadalafil than for other compounds that do not require these processes. Meanwhile, in 2020, the product containing 120 times more tadalafil than the normal dosage was detected in Tokyo, making it an urgent issue to remove these dangerous products from the market. This study proposes a simple and rapid method to detect tadalafil with a newly devised detector tube. Objective Development of a detector tube for the rapid screening of tadalafil with simple functioning. Methods Approximately 80 mg of silica gel powder impregnated with sulfuric acid was filled in a glass tube, having a 3-mm inner diameter, to prepare a detector tube. The measuring method of this detector tube is quite simple; first, both tips of the detector tube are cut, then the sample solution is aspirated, and a decision is made by the colour of the detector tube after 5 minutes. It was defined as a positive result when the detector tube turned violet and negative when it showed other colours. First, the reaction of tadalafil and analogues were confirmed using the prepared detector tube. Then, specificity was tested for active pharmaceutical ingredients and common additives. The tube was also tested for the applicability to some commercially available dietary supplements. Results All tested tadalafil and analogues showed positive results in the test. The limit of detection was 5 μg/mL for tadalafil. Except for levomepromazine, results for additives and any pharmaceutical ingredients tested were negative. This tube was able to detect all real samples containing tadalafil and analogues. None of the real samples that did not contain tadalafil and analogues gave false positives. Conclusions The developed detector tube could rapidly detect tadalafil and analogues with high sensitivity in a simple procedure. It was suggested that false-positive results could occur only if levomepromazine was included in the sample. Other than that, no significant interference that leads to false results was observed in tested common adulterants and additives of supplements. Furthermore, the tube was able to detect tadalafil and analogues in all tested real samples. Accordingly, the proposed test method has the potential for the use of preliminary screening of tadalafil.

Regio- and stereoselective synthesis of dispiropyrrolizidines through 1,3-dipolar cycloaddition reaction: Inhibition of KRAS expression

A facile three components (3 + 2) cycloaddition of two novel dispiropyrrolizidines was achieved using (2E)-2-(2-bromobenzylidine)-1-indanone and azomethine ylide that was generated in situ from acenapthenequinone and l-proline. Unprecedented regioselectivity was observed when different reaction times and solvents were used in this cycloaddition, leading to the formation of regioisomers (1S,1′S,2′R,7a'S)-1′-(2-bromophenyl)-5′,6′,7′,7a'-tetrahydro-1′H,2H-dispiro[acenaphthylene-1,3′-pyrrolizine-2′,2′'-indene]-1′',2(3′'H)‑dione (6) and (1S,1′S,2′R,7a'S)-2′-(2-bromophenyl)-5′,6′,7′,7a'-tetrahydro-2H,2′H-dispiro[acenaphthylene-1,3′-pyrrolizine-1′,2′'-indene]-1′',2(3′'H)‑dione (7) with two adjacent spirocarbons through endo/exo approaches. 6 was ascribed to the endo-approach of the S-shaped azomethine ylide while that of 7 was ascribed to the exo-approach of the W-shaped ylide. It was observed that the endo-selectivity of the reaction diminishes with increasing reaction time. Longer reaction time showed exo preference in the cycloaddition reaction. The structures of the cycloadducts were elucidated by NMR and ESI-MS. The regiochemistry and structures of the cycloadducts were confirmed by X-ray crystal structure analysis. Using Western blot analysis, we show that the two novel compounds were capable of down-regulating KRAS expression in SW480 human colorectal cancer cell line.

Synthesis and biological evaluation of conformationally restricted GluN2B ligands derived from eliprodil

N-Methyl-d-aspartate (NMDA) receptors containing one or two GluN2B subunits play a crucial role in a variety of neurodegenerative diseases, such as Alzheimer's and Huntington's disease. In order to increase selectivity for GluN2B NMDA receptors, the piperidine ring of eliprodil (2) was conformationally restricted by introduction of an ethano bridge across C-2 and C-6 resulting in a tropane scaffold. Benzylidenetropanes 15 and 16 and benzyltropanes 17 and 18 were prepared by nucleophilic opening of enantiomerically pure phenyloxiranes 13 and 14 with racemic secondary amines (Z/E)-11 and diastereomeric mixtures (r/s)-12. The diastereomers were separated by preparative HPLC to obtain enantiomerically pure test compounds 15–18. The absolute and relative configuration of the products were determined by X-ray crystal structure analysis. Benzylidenetropanes 15 and 16 as well as benzyltropanes 17 and 18 display very high GluN2B affinity in receptor binding studies. Benzylidinetropanes with the phenyl moiety oriented towards C-5 of the tropane system showed higher GluN2B affinity than their analogs with the phenyl moiety oriented towards C-1. In benzyltropanes endo-configured stereoisomers exhibit higher GluN2B affinity than exo-configured diastereomers. Unfortunately, tropanes 15–18 show also high σ1 and σ2 affinity with the same trends for the stereoisomers as for GluN2B affinity. The high-affinity GluN2B ligand (R,r)-17b was able to inhibit the ion flux in two-electrode voltage clamp experiments using GluN1a/GluN2B expressing oocytes.

Synthesis, characterization, X-ray crystal structure and Hirshfeld surface analysis of Ni(II) complex of 1,2-bis(pyridin-2-ylmethylene)hydrazine

We report the synthesis, characterization, X-ray crystal structure and Hirshfeld surface analysis of Ni(II) perchlorate complex (1, Ni2L3·4ClO4·2CH3CN) of 1,2-bis(pyridin-2-ylmethylene)hydrazine (L) ligand. The X-ray crystallographic study of complex 1 reveals that in the presence of Ni(II) ions,the ligand L forms a dimeric triple helix with a Ni(II)-Ni(II) distance of 3.794 Å. Crystal data for C40H36Cl4N14Ni2O16: Monoclinic, space group P21/c (no. 14), a = 20.7558(19) Å, b = 13.1937(12) Å, c = 20.0181(18) Å, β = 96.9510(10)°, V = 5441.6(9) Å3, Z = 4, T = 293.15 K, μ(MoKα) = 0.965 mm-1, Dcalc = 1.498 g/cm3, 38075 reflections measured (1.976° ≤ 2Θ ≤ 43.728°), 6557 unique (Rint = 0.0695, Rsigma = 0.0466) which were used in all calculations. The final R1 was 0.0518 (I > 2σ(I)) and wR2 was 0.1270 (all data). The Hirshfeld surface analysis of complex 1 shows that C···H, H···H, N···H and O···H interactions of 10.9, 26.4, 6.7, and 33.4%; respectively, which exposed that the main intermolecular interactions were H···H intermolecular interactions.

Epoxydibenzo[b,f][1,5]diazocines: From a Hidden Structural Motif to an Efficient Solvent-Free Synthetic Protocol

AbstractEpoxydiazocines belong to the rare class of small V-shaped molecules, closely related to Tröger’s base. Due to their intriguing, unique structure, they could serve as molecular building blocks for supramolecular chemistry. An extensive review on their synthesis is contained in this article. Moreover, our recent findings devoted to efficient and easily scalable synthesis of fluorinated epoxy[1,5][b,f]diazocines through solvent-free base-catalyzed condensation of ortho-aminophenones is provided. The unique V-shaped structure was confirmed by X-ray crystal structure analysis. Furthermore, the rigidity of the epoxy­diazocine skeleton allowed for racemate separation and the configuration of enantiomers was established by combining quantum chemical calculations and chiroptical methods.1 Introduction2 Synthetic Efforts Towards Epoxydibenzo[b,f][1,5]diazocines3 Synthetic Efforts Towards Fluorinated Epoxydibenzo[b,f][1,5]diazocines4 Conclusion

Chiral Symmetry Breaking of Monoacylated Anhydroerythritols and meso-1,2-Diols through Crystallization-Induced Deracemization.

We developed a chiral symmetry breaking method for monoacylated meso diols. The X-ray crystal structure analysis of monoacylated 1,4-anhydroerythritols, meso cyclic diols with a cis configuration, revealed that the O-(p-anisoyl) derivative crystallized as a racemic conglomerate of the P21 21 21 crystal system. It was confirmed that the substrate racemized by intramolecular transfer of the acyl group in the presence of a catalytic amount of base. Evaporating the solvent gradually from the solution or Viedma ripening to promote crystallization-induced deracemization efficiently led to enantiomer crystals. These results provide the first successful example of asymmetric expression and amplification by deracemization of sugar derivatives without an external chemical chiral source. Furthermore, we applied this methodology to acyclic meso-1,2-diols. Three O-monoacylated substrates were successfully deracemized to 99 % ee by Viedma ripening. We also developed asymmetric desymmetrization of meso-1,2-diols by combining acylation and crystallization-induced deracemization.

Synthesis, characterization, spectral studies and evaluation of noncovalent interactions in co-crystal of μ-oxobridged polymeric copper(II) complex derived from pyrazolone by theoretical studies

The new co-crystal of μ-oxobridged polymeric copper(II) complex {[0.714(9) CuII2(HL-CH2OH)2].[0.286(9) CuII2(HL-CHO2H)2]}n with Schiff base ligand derived from pyrazolone, (HL = 4-[(2-hydroxy-3-methoxybenzylidene)amino-1,5-dimethyl-2-phenyl-1H-pyrazol-3-one), was synthesized and characterized by spectral and analytical techniques. The optimal and unexpected quality structures of the copper (II) polymer complex were determined using X-ray. Crystals are monoclinic, a = 7.8472(2), b = 12.5860(3), c = 17.0842(3) Å, β = 97.140(2)° and space group P21/c. The complexes are 4 + 1 coordinated, with four standard coordination distances in a square-planar geometry and a fifth, longer, secondary coordination distance at the square pyramid's apex. The basic complexes have a Ci-symmetrical Cu2L2 composition and extend into polymeric chains along the x crystallographic axis due to the longer contact. The electrochemical properties of complex in DMSO displayed the electronic effects on the groups on redox potential. The density functional theory by B3LYP method with (6-311 G) basis set was used to optimize the molecular geometry of the copper complex. Following the optimized DFT, FT-IR spectroscopy was used to determine geometric characteristics such as bond length and bond angle, which were then compared to experimental data. The intermolecular interactions were characterized using X-ray crystal structure analysis, HS (Hirshfeld surface analysis) and FPs (fingerprint diagrams). In addition, QTAIM (Quantum Theory of Atoms in Molecules) analysis was studied to determine the type of bonds and the energies of the metal-ligand bond. The adsorption process of complexes (1) and (2) in the aqueous phase on graphene oxide (GO) was calculated by the Monte Carlo adsorption locator. The results showed complex (2) had a high binding efficiency on GO compared with complex (1). The molecular docking study was also carried out for the copper complex to find its binding affinity to protein B-cell lymphorna (BCL-2, PDB ID: 4LXD).

Selective Synthesis of the Aminobutadiene Intermediate and Mechanistic Analysis of 1,4-Dihydropyridine Formation Reaction in Water.

We previously isolated an aminobutadiene derivative as a by-product in the synthesis of a 1,4-dihydropyridine (1,4-DHP) derivative by the reaction of methyl propiolate with excess ammonium acetate in water, and we proposed that it is an intermediate in the formation of 1,4-DHP. Here, to test this idea and to investigate the reaction mechanism, we selectively synthesized the aminobutadiene derivative in EtOH and examined its reactivity. The yield of the aminobutadiene derivative was increased in the presence of excess ammonium salt. X-Ray crystal structure analysis indicated the presence of an intramolecular hydrogen bond between the terminal amine and ester carbonyl oxygen, together with a short C-N bond length consistent with enamine-imine equilibrium. Direct cyclization of the aminobutadiene derivative with methyl propiolate to afford the 1,4-DHP derivative did not proceed well, but the yield was increased in the presence of morpholine salt as an additive. These results suggest that the predominant reaction pathway from the intermediate to 1,4-DHP in water involves Michael addition of a second amine molecule and reaction with methyl propiolate, followed by intramolecular cyclization and elimination of amine.

Spacers directed self-assembly of heterobimetallic copper(II)-lanthanide(III) [Ln = Nd and Gd] moieties: Syntheses, structural diversities and magnetic properties

Three new 3d-4f heteronuclear one and two dimensional coordination polymers (CPs), {[Cu(L12−)Nd(NO3)(µ-NO3)(H2O)2].NO3}n (1), [Cu(L22−)Nd(IN−)(NO3)2]n (2) and [Cu(L22−)Gd(IN)(NO3)2]n (3), have been synthesized and characterized by using FT-IR, elemental analysis, Hirshfeld surface analysis and single crystal X-ray diffraction study. Complex 1 represents the first example of a nitrate bridged Cu(II)-Nd(III) zigzag one dimensional chain, to the best of our knowledge. The X-ray crystal structure analysis reveals that complexes 2 and 3 are isomorphous two dimensional coordination polymers whose heterometallic dinuclear units of Cu-Nd in 2 and Cu-Gd in 3 are connected by the isonicotinate anion as a spacer. A magnetic study reveals that antiferromagnetic interactions exist between the Cu(II) and Nd(III) ions in 1 and 2, however ferromagnetic interactions exist between the Cu(II) and Gd(III) ions in 3.

Synthesis of an Organometallic Alkyl-Co(III) Complex with Amidoquinoline Directing Groups via C(sp3)–H Activation and Its UV–vis/NMR Spectroscopic, Crystallographic, DFT, and Electrochemical Studies

Abstract The use of earth-abundant and inexpensive Co catalysts for carbon-hydrogen (C–H) bond activation has received increasing attention because of the advantages including air stability. Although directing groups have been effectively introduced in substrates to promote C(sp3)–H activation through chelation assistance, there is a lack of basic information about the isolated alkyl-Co complexes containing directing groups as polydentate ligands. In this study, we report the synthesis and characterization of an alkyl-Co(III) complex 2Co, prepared from a N,N′-bis(8-quinolyl)malonamide derivative, the malonyl fragment of which was disubstituted by two ethyl groups. 2Co was straightforwardly obtained from a Co(II) salt without any use of chemical oxidants but in the presence of air, through selective β-C(sp3)–H activation. The combined NMR spectroscopic and X-ray crystal structural analyses revealed that the malonamide substrate was converted into a pentadentate ligand with an N4C set, acquiring a helical configuration around the Co(III) center. The non-innocent ligand properties of 2Co were unambiguously confirmed by UV–vis spectroscopic, electrochemical, and DFT studies. Thermolysis of 2Co enabled C(sp3)–N reductive elimination in the absence of chemical oxidants. The present study provides important insights into the reactivity of alkyl-Co(III) complexes with a defined coordination geometry around the Co center toward designing elaborate C(sp3)–H functionalization systems.

Synthesis of tropane-based σ1 receptor antagonists with antiallodynic activity

Following the concept of conformational restriction to obtain high affinity σ1 ligands, the piperidine ring of eliprodil was replaced by the bicyclic tropane system and an exocyclic double bond was introduced. The envisaged benzylidenetropanes 9 were prepared by conversion of tropanone 10 into the racemic mixture of (Z)-14 and (E)-14. Reaction of racemate (Z)-14/(E)-14 with enantiomerically pure (R)- or (S)-configured 2-phenyloxirane provided mixtures of diastereomeric β-aminoalcohols (R,Z)-9 and (R,E)-9 as well as (S,Z)-9 and (S,E)-9, which were separated by chiral HPLC, respectively. X-ray crystal structure analysis of (S,Z)-9 allowed the unequivocal assignment of the configuration of all four stereoisomers. In receptor binding studies with radioligands, (R,E)-9 and (S,Z)-9 showed subnanomolar σ1 affinity with eudismic ratios of 8.3 and 40. In both compounds the 4-fluorophenyl moiety is oriented towards (S)-configured C-5 of the tropane system. Both compounds display high selectivity for the σ1 receptor over the σ2 subtype but moderate selectivity over GluN2B NMDA receptors. In vivo, (R,E)-9 (Ki(σ1) = 0.80 nM) showed high antiallodynic activity in the capsaicin assay. The effect of (R,E)-9 could be reversed by pre-administration of the σ1 agonist PRE-084 confirming the σ1 antagonistic activity of (R,E)-9.

Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site.

Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 (52) targeting a unique, previously unreported binding site, while exhibiting significant anti-inflammatory activities in vitro and in vivo. The X-ray crystal structural analysis of ZL0590 in complex with human BRD4 BD1 and the associated mutagenesis study illustrate a first-in-class nonacetylated lysine (KAc) binding site located at the helix αB and αC interface that contains important BRD4 residues (e.g., Glu151) not commonly shared among other family members and is spatially distinct from the classic KAc recognition pocket. This new finding facilitates further elucidation of the complex biology underpinning bromodomain specificity among BRD4 and its protein-protein interaction partners.

Substitution of Hyp (Hyp = Si(SiMe3)3) at metalloid [Ge9(Hyp)3]- clusters using phosphine stabilized Au(I)Cl.

We present two new intermetalloid cluster compounds [(nBu3P)AuGe9(Hyp)2Au(PnBu3)]2 (1) and [Au(iPr2POC6H4OPiPr2)AuGe9(Hyp)2]2 (2) which are obtained from the reaction of KGe9(Hyp)3 (Hyp = Si(SiMe3)3) with the respective Au(I) phosphine precursors. The products are characterized via X-ray crystal structure analysis and the reaction course is analysed via NMR spectroscopy. We also show that in the resulting compound 1 the hypersilyl substituents can be reintroduced via the reaction with Hyp-Cl to obtain nBu3PAuGe9(Hyp)3.

Effect of chalcogen bonding interactions on molecular structures; theoretical and crystallographic studies on two palladium(ii) acetate complexes

New palladium complexes, [Pd(L)(OAc))], have been synthesized. The complexes and their ligand have been characterized by X-ray crystal structure analysis. Interestingly, the molecular structures of the two complexes are stabilized by S⋯O chalcogen bonds.