X-ray Crystal Structure Determination Research Articles

Toward the Design of Phosphorescent Emitters of Cyclometalated Earth-Abundant Nickel(II) and Their Supramolecular Study.

A series of cyclometalating tridentate N^C^N and tetradentate N^C^N^O ligand-containing complexes of earth-abundant nickel(II) has been designed and synthesized. Among them, the carbazolylnickel(II) complex demonstrates, for the first time, an orange color room-temperature luminescence. Such a complex is also found to exhibit intense luminescence with excited state lifetimes in the submicrosecond regime at 77 K, suggesting the triplet nature of the emissive state. Meanwhile, the self-assembly property of the tetradentate ligand-containing nickel(II) complex in solution has been investigated. Owing to its nearly perfect square planar geometry, as evidenced by X-ray crystal structure determination, it is found to exhibit self-assembly properties with the aid of π-π interactions and possibly weak Ni···Ni interactions, which have been supported by DFT calculations and NCI plot. Indeed, the ground-state aggregation behavior of this complex has been confirmed by concentration-dependent UV-vis absorption spectroscopy. Moreover, in the solution-induced aggregation studies, upon the addition of nonsolubilizing solvents, the emergence of low-energy absorption bands has been realized, and such a complex is found to demonstrate interesting self-assembly behaviors to offer well-defined and highly ordered supramolecular architectures.

Derivatives of the triaminoguanidinium ion, 6. Aminal-forming reactions with aldehydes and ketones

Abstract Cyclic aminals (N,N-acetals) could be prepared by the reaction of N,N′,N″-triaminoguanidinium sulfate, N,N′,N″-tris(benzylamino)guanidinium chloride or N,N′,N″-tris(benzylamino)guanidine with formaldehyde or acetone. In all cases, 1,2,4,5-tetrazinane derivatives were obtained, which were structurally confirmed by X-ray crystal structure determinations. In two cases, 1:1 cocrystals of two different tetrazinane products were isolated. On the other hand, the reaction of N,N′,N″-tris(benzylamino)guanidinium chloride with benzaldehyde yielded a 3-(2-benzylidenehydrazin-1-yl)-1H-1,2,4-triazole.

Phenylthiourea Binding to Human Tyrosinase-Related Protein 1.

Tyrosinase-related protein 1 (TYRP1) is one of the three human melanogenic enzymes involved in the biosynthesis of melanin, a pigment responsible for the color of the skin, hair, and eyes. It shares high sequence identity with tyrosinase, but has two zinc ions in its active site rather than two copper ions as in tyrosinase. Typical tyrosinase inhibitors do not directly coordinate to the zinc ions of TYRP1. Here, we show, from an X-ray crystal structure determination, that phenylthiourea, a highly potent tyrosinase inhibitor, does neither coordinate the active site zinc ions, but binds differently from other structurally characterized TYRP1-inhibitor complexes. Its aromatic ring is directed outwards from the active site, apparently as a result from the absence of polar oxygen substituents that can take the position of water molecules bound in the active site. The compound binds via hydrophobic interactions, thereby blocking substrate access to the active site.

Synthesis, structure, and reactivity of a pyridine-stabilized silanonetungsten complex.

A pyridine-stabilized silanonetungsten complex Cp*(OC)2W{O[double bond, length as m-dash]SiMes2(py)}(SiMe3) (1b, Cp* = η5-C5Me5, Mes = 2,4,6-Me3C6H2, py = C5H5N) was obtained by the reaction of a silyl(silylene) complex Cp*(OC)2W([double bond, length as m-dash]SiMes2)(SiMe3) (3) with pyridine-N-oxide in pyridine. X-ray crystal structure determination revealed that complex 1b shows a similar geometry to that observed for a previously synthesized DMAP-stabilized analogue, Cp*(OC)2W{O[double bond, length as m-dash]SiMes2(DMAP)}(SiMe3) (1a, DMAP = 4-NMe2C6H4N). The Si[double bond, length as m-dash]O and W-O bond distances in 1b are comparable to those observed in 1a, but the nitrogen to silicon coordination bond of 1b is slightly longer (ca. 0.05 Å) than that of 1a, indicating the weaker coordination of pyridine than that of DMAP. The reaction of 1b with excess PMe3 in C6D6 at r. t. proceeded via elimination of pyridine to afford a five-membered metallacyclic carbene complex, Cp*(OC)W([double bond, length as m-dash]C(SiMe3)OSiMes2O)(PMe3) (5), but that of 1a with PMe3 did not proceed at all. Complex 5 was further transformed in C7D8 at 100 °C for 4 h to give a four-membered W-O-Si-O metallacyclic complex with carbyne and PMe3 ligands, Cp*W(OSiMes2O)([triple bond, length as m-dash]CSiMe3)(PMe3) (7). The structural features of complexes 1b, 5, and 7 are comparable to those suggested theoretically as intermediates in the reaction of 3 with a sulfuration reagent to afford a six-membered metallacyclic carbene complex, Cp*W(S){[double bond, length as m-dash]C(SiMe3)C([double bond, length as m-dash]O)OSiMes2S} (6), indicating that complex 1b and the theoretically proposed silanethione complex are transformed via a similar reaction pathway.

Binuclear and tetranuclear Zn(ii) complexes with thiosemicarbazones: synthesis, X-ray crystal structures, ATP-sensing, DNA-binding, phosphatase activity and theoretical calculations.

Two Zinc(ii) complexes [Zn4(L1)4]·2H2O (1) and [Zn2(L2)2]·2H2O (2) of pyruvaldehydethiosemicarbazone ligands are reported. The complexes were characterized by elemental analysis, IR, NMR, UV-vis spectroscopy and by single-crystal X-ray crystallography. X-ray crystal structure determinations of the complexes show that though Zn : ligand stoichiometry is 1 : 1 in both the complexes, the molecular unit is tetranuclear for 1 and binuclear for 2. Both the complexes show selective sensing of ATP at pH 7.4 (0.01 M HEPES) in CH3CN–H2O (9 : 1) medium in the presence of other anions like AcO−, NO3−, F−, Cl−, H2PO4−, HPO42− and P2O72−. The UV-titration experiments of complexes 1 and 2 with ATP results in binding constants of 2.0(±0.07) × 104 M−1 and 7.1(±0.05) × 103 M−1 respectively. The calculated detection limits of 6.7 μM and 1.7 μM for 1 and 2 respectively suggest that the complexes are sensitive detectors of ATP. High selectivity of the complexes is confirmed by the addition of ATP in presence of an excess of other anions. DFT studies confirm that the ATP complexes are more favorable than those with the other inorganic phosphate anions, in agreement with the experimental results. Phosphatase like activity of both complexes is investigated spectrophotometrically using 4-nitrophenylphosphate (NPP) as a substrate, indicating the complexes possess significant phosphate ester hydrolytic efficiency. The kinetics for the hydrolysis of the substrate NPP was studied by the initial rate method at 25 °C. Michaelis–Menten derived kinetic parameters indicate that rate of hydrolysis of the P–O bond by complex 1 is much greater than that of complex 2, the kcat values being 212(±5) and 38(±2) h−1 respectively. The DNA binding studies of the complexes were investigated using electronic absorption spectroscopy and fluorescence quenching. The absorption spectral titrations of the complexes with DNA indicate that the CT-DNA binding affinity (Kb) of complex 1 (2.10(±0.07) × 106 M−1) is slightly greater than that of 2 (1.11(±0.04) × 106 M−1). From fluorescence spectra the apparent binding constant (Kapp) values were calculated and they are found to be 5.41(±0.01) × 105 M−1 for 1 and 3.93(±0.02) × 105 M−1 for 2. The molecular dynamics simulation demonstrates that the Zn(ii) complex 1 is a good intercalator of DNA.

Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6.

Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.

Influence of the hydrogen bond on the iteroselective O-alkylation of calix[4]resorcinarenes

The effect of the hydrogen bond on the reactivity of hydroxyl groups of tetra( p -hydroxyphenyl)calix[4]resorcinarene with glycidyl methacrylate was studied. When the O -alkylation reaction was carried out with tetra( p -methoxyphenyl)calix[4]resorcinarene, the exposed hydroxyl groups of the upper rim did not react in the presence of NaOH or pyridine. When the O -alkylation reaction of tetra( p -hydroxyphenyl)calix[4]resorcinarene was carried out in the presence of NaOH, the expected tetraalkylation product in the lower rim was obtained, whereas the monoalkylation product in the lower rim was obtained, when the reaction was carried out with pyridine as base. Spectroscopic evidence showed that the reaction is selective for one hydroxyl group in the lower rim without affecting the hydroxyl groups in the upper rim. Suitable crystals of tetra( p -hidroxyphenyl)calix[4]resorcinarene in DMSO were obtained from the reaction and were characterized through an X-ray crystal structure determination and showed that asymmetric unit contains eight molecules of DMSO, and analysis indicated that calix[4]resorcinarene prefers a chair configuration in the solid state. In the crystal array, classical hydrogen bond O–H⋯O interactions and intermolecular contacts were observed. The formation of these crystals confirms the low reactivity of this conformer in the process. • O -Alkylation is regioselective. • Crown conformer is reactive. • Resorcinarene in chair conformation does not react.

Structure Defines Function: Clinically Relevant Mutations in ErbB Kinases.

The ErbB receptor tyrosine kinase family members EGFR (epidermal growth factor receptor) and Her2 are among the prominent mutated oncogenic drivers of non-small cell lung cancer (NSCLC). Their importance in proliferation, apoptosis, and cell death ultimately renders them hot targets in cancer therapy. Small-molecule tyrosine kinase inhibitors seem well suited to be tailor-made therapeutics for EGFR mutant NSCLC; however, drug resistance mutations limit their success. Against this background, the elucidation and visualization of the three-dimensional structure of cancer-related kinases provide valuable insights into their molecular functions. This field has undergone a revolution because X-ray crystal structure determinations aided structure-based drug design approaches and clarified the effect of activating and resistance-conferring mutations. Here, we present an overview of important mutations affecting EGFR and Her2 and highlight their influence on the kinase domain conformations and active site accessibility.

Complexes of palladium(II) chloride with 3-(pyrazol-1-yl)propanamide (PPA) and related ligands

Four new derivatives of the versatile polyfunctional ligands 3-(pyrazol-1-yl)propanamide (1, = PPA) and 3-(3,5-dimethylpyrazol-1-yl)-propanamide (2, = Me2PPA) have been prepared, in which one of the amide hydrogens on 1 and 2 is formally replaced by alkyl residues. X-Ray diffraction studies revealed that, in contrast to 1 and 2, the N-isopropyl substituted derivatives 3 and 4 form supramolecular hydrogen-bonded chains rather than two-dimensional arrays, and the N-(2-methyl-4-oxypentan-2-yl) (=MOP) substituted compounds 5 and 6 exist as cyclic dimers in the solid state. Reactions of PdCl2(COD) (COD = 1,5-cyclooctadiene) with 2 equiv. of the corresponding ligands 1–6 in all cases afforded trans-PdCl2(L)2 complexes (7–12). X-ray crystal structure determinations of 8, and 10–12 revealed κN-monodentate coordination of the PPA-type ligands.

Host-guest inclusion systems of tetra(alkyl)resorcin [4]arenes with choline in DMSO: Dynamic NMR studies and X-ray structural characterization of the 1:1 inclusion complex

The host-guest complex of C-tetra(methyl)calix[4]resorcinarene (1), C-tetra(pentyl)calix[4]resorcinarene (2), and C-tetra(nonyl)calix[4]resorcinarene (3) with choline in DMSO was examined via dynamic NMR. Under these conditions, only C-tetra(methyl)calix[4]resorcinarene formed a complex with choline. In order to establish the role of DMSO during the solubilization/complexation process, titration was carried out with resorcinarenes and DMSO in CDCl3. Our careful NMR analysis was based on the assignment of 1H NMR signals of the resorcinarenes in CDCl3 after the addition of variable amounts of DMSO, which showed an interesting host-guest interaction with C-tetra(pentyl)calix[4]resorcinarene. With both solvents, it is possible to define stable cone conformational arrangements based on the signals shown in the spectra of all the experiments. The results show the formation of a 1:1 inclusion complex between DMSO and C-tetra(pentyl)calix[4]resorcinarene. Suitable crystals of C-tetra(pentyl)resorcinarene in DMSO were characterized through an X-ray crystal structure determination and showed the inclusion of a molecule of DMSO in the cavity of the resorcinarene. The asymmetric unit contains one molecule of water and five molecules of DMSO, and analysis indicated that resorcinarene prefers a cone configuration (rccc conformation) in the solid state. In the crystal array, classical hydrogen bond O–H⋯O interactions and intermolecular contacts were observed.

X-ray crystal structure determination of LTA4H:4MDM:PGP analogue complex and characterization of the aminopeptidase enzyme mechanism

X-ray crystal structure determination of LTA₄H:4MDM:PGP analogue complex and characterization of the aminopeptidase enzyme mechanism

Origin of the Selectivity and Activity in the Rhodium-Catalyzed Asymmetric Hydrogenation Using Supramolecular Ligands

The reaction mechanism of the asymmetric hydrogenation of functionalized alkenes catalyzed by a supramolecular rhodium complex has been investigated. In-depth NMR analysis combined with X-ray crystal structure determination show that hydrogen bonds are formed between the catalyst and the substrate in the early stages of the mechanism. Detailed kinetic data obtained from UV–vis stopped-flow experiments and gas-uptake experiments confirm that the hydrogen bonds are playing a crucial role in the mechanism. A complete DFT study of the various competitive paths of the reaction mechanism allowed us to identify how these hydrogen bonds are involved in the determining steps of the reaction.

Facile, mild and efficient synthesis of azines using phosphonic dihydrazide

Several bis(N'-arylpropanehydrazonoyl chlorides) were synthesized in good yields from condensation reactions of hydrazonoyl chlorides and phosphonic dihydrazide. Under the conditions employed, none of the expected phosphorylhydrazines were isolated. Nucleophilic substitution of bis(N'-arylpropanehydrazonoyl chlorides) with thiophenol, sodium phenylsulfinate, hydroxyl amine, and piperidine afforded the corresponding azines. Similarly, 1,2-bis(heteroaryl)ethylidene)hydrazines were produced from reaction of phosphonic dihydrazide and heteroaryl methyl ketones. The structures of the products were confirmed by NMR and IR spectral data along with X-ray crystal structure determination and their purities were confirmed by the elemental analyses.

Utilization of Ternary Europium Complex for Organic Electroluminescent Devices and as a Sensitizer to Improve Electroluminescence of Red-Emitting Iridium Complex.

Two new lanthanide complexes [Ln(hfaa)3(Py-Im)] [hfaa = hexafluoroacetylacetone, Py-Im = 2-(2-pyridyl)benzimidazole and Ln = Eu(III) (1) and Tb(III) (2)] were synthesized and characterized. An X-ray crystal structure determination confirms that complex 1 is eight-coordinate with a distorted trigonal dodecahedral geometry. It shows typical vivid red Eu(III) emission in the solid state, in solution, and in a polymer matrix. The observed lifetime (τobs) of complex 1 in the solid state, in dichloromethane (DCM) solution, and in thin films is 833.01, 837.95, and 626.16-715.69 μs, respectively, with a photoluminescence quantum yield QEuL ≈ 33% in DCM solution. Complex 2 displays a yellowish-green emission in the solid state (τobs ≈ 36.99 μs), while a near white-light emission in solution (x; 0.2574: y; 0.3371) and in thin films. Therefore, it is a potential candidate for generating single-component white light-emitting materials for solid-state lighting applications. The kinetic scheme for modeling energy-transfer processes shows that the main donor state for 1 is the ligand triplet state (T1) and that energy transfer occurs to both the 5D1 (56.55%) and 5D0 (40.58%) levels. We fabricated a series of single- and double-layer organic light-emitting devices using complex 1. The luminance of the optimized double-layer electroluminescence (EL) device was 373 cd/m2 with very low turn-on voltage of ∼4.2 V. Complex 1 was further utilized as a sensitizer to improve the EL of a red-emitting iridium complex PQ2Ir(dpm) (PQ = phenylquinoly-N,C2', dpm = dipivaloylmethane). The codoped device achieved a maximum brightness and maximum current efficiency (ηc) of 93 224 cd/m2 and 36.38 cd/A, respectively.

Crystal structure of F95Q epi-isozizaene synthase, an engineered sesquiterpene cyclase that generates biofuel precursors β- and γ-curcumene

The saturated hydrocarbon bisabolane is a diesel fuel substitute that can be derived from sesquiterpene precursors bisabolene or curcumene. These sesquiterpenes are generated from farnesyl diphosphate in reactions catalyzed by eponymous terpenoid cyclases, but they can also be generated by engineered terpenoid cyclases in which cyclization cascades have been reprogrammed by mutagenesis. Here, we describe the X-ray crystal structure determination of F95Q epi-isozizaene synthase (EIZS), in which the new activity of curcumene biosynthesis has been introduced and the native activity of epi-isozizaene biosynthesis has been suppressed. F95Q EIZS generates β- and γ-curcumene regioisomers with greater than 50% yield. Structural analysis of the closed active site conformation, stabilized by the binding of 3 Mg2+ ions, inorganic pyrophosphate, and the benzyltriethylammonium cation, reveals a product-like active site contour that serves as the cyclization template. Remolding the active site contour to resemble curcumene instead of epi-isozizaene is the principal determinant of the reprogrammed cyclization cascade. Intriguingly, an ordered water molecule comprises part of the active site contour. This water molecule may also serve as a final proton acceptor, along with inorganic pyrophosphate, in the generation of curcumene regioisomers; it may also contribute to the formation of sesquiterpene alcohols identified as minor side products. Thus, the substitution of polar side chains for nonpolar side chains in terpenoid cyclase active sites can result in the stabilization of bound water molecules that, in turn, can serve template functions in isoprenoid cyclization reactions.

Preparation and crystal structure of the boranehydrazine complex [RuCl(κ1-NH2NH2BPh3){P(OEt)3}4]BPh4

Unlike what was previously reported, the reaction of the hydrazine derivative [Ru(NH2NH2)2{P(OEt)3}4](BPh4)2 with p-tolyldiazonium tetrafluoroborate in CH2Cl2 afforded the boranehydrazine complex [RuCl(κ1-NH2NH2BPh3){P(OEt)3}4]BPh4. The complex was characterised spectroscopically (IR and NMR) and by X-ray crystal structure determination.

Synthesis of a new 24-membered tetramide macrocycle and X-ray crystal structure determination

The synthesis and characterization of a new 24-membered tetramide macrocycle (6) related to Leigh's macrocycles and catenanes is reported. The replacement of p-xylylenediamine (Leigh) by m-xylylenediamine (this work) strongly modifies the geometry and properties of the new macrocycle. NMR spectroscopy (in DMSO‑d6 solution) and X-ray crystallography have been used to characterize compound 6. The structural features in the crystal (conformational aspects and H-bonding) have been discussed comparatively to two similar macrocycles NEWHIJ and UJUNOC.

Tunable Supramolecular Nanoarchitectures Constructed by the Complexation of Diphenanthro-24-Crown-8/Cesium(I) with Nickel(II) and Silver(I) Ions.

Tunable supramolecular nanoarchitectures have received enormous attention because of their potential in materials fabrication. Herein, a variety of morphologically intriguing nanoarchitectures have been constructed from diphenanthro-24-crown-8 ether (DPC) and metal ions. SEM and TEM showed that the self-assembled nanofibers undergo a CsI -induced transformation into regular nanoribbons, and further into nanospheres and nanoparticles by the complexation of NiII and AgI ions because of the strong ion-dipole interaction. Moreover, the X-ray crystal structure determination and powder X-diffraction data further confirmed that these morphological transformations resulted from the different complexation between DPC and metal ions. This result provides a new strategy for the subtle manipulation of supramolecular assemblies.

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α.

A class of extracellular stimuli requires activation of IKK1/α to induce generation of an NF-κB subunit, p52, through processing of its precursor p100. p52 functions as a homodimer or heterodimer with another NF-κB subunit, RelB. These dimers in turn regulate the expression of hundreds of genes involved in inflammation, cell survival, and cell cycle. IKK1/α primarily remains associated with IKK2/β and NEMO as a ternary complex. However, a small pool of it is also observed as a low molecular weight complex(es). It is unknown if the p100 processing activity is triggered by activation of IKK1/α within the larger or the smaller complex pool. Constitutive activity of IKK1/α has been detected in several cancers and inflammatory diseases. To understand the mechanism of activation of IKK1/α, and enable its use as a drug target, we expressed recombinant IKK1/α in different host systems, such as E. coli, insect, and mammalian cells. We succeeded in expressing soluble IKK1/α in baculovirus infected insect cells, obtaining mg quantities of highly pure protein, crystallizing it in the presence of inhibitors, and determining its X-ray crystal structure. Here, we describe the detailed steps to produce the recombinant protein, its crystallization, and its X-ray crystal structure determination.

The Important Role of the Nuclearity, Rigidity, and Solubility of Phosphane Ligands in the Biological Activity of Gold(I) Complexes.

A series of 4-ethynylaniline gold(I) complexes containing monophosphane (1,3,5-triaza-7-phosphaadamantane (pta; 2), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (3), and PR3 , with R=naphthyl (4), phenyl (5), and ethyl (6)) and diphosphane (bis(diphenylphosphino)acetylene (dppa; 7), trans-1,2-bis(diphenylphosphino)ethene (dppet; 8), 1,2-bis(diphenylphosphino)ethane (dppe; 9), and 1,3-bis(diphenylphosphino)propane (dppp; 10)) ligands have been synthesized and their efficiency against tumor cells evaluated. The cytotoxicity of complexes 2-10 was evaluated in human colorectal (HCT116) and ovarian (A2780) carcinoma as well as in normal human fibroblasts. All the complexes showed a higher antiproliferative effect in A2780 cells, with the cytotoxicity decreasing in the following order 5>6=9=10>8>2>4>7>3. Complex 4 stands out for its very high selectivity towards ovarian carcinoma cells (IC50 =2.3 μm) compared with colorectal carcinoma and normal human fibroblasts (IC50 >100 μm), which makes this complex very attractive for ovarian cancer therapy. Its cytotoxicity in these cells correlates with the induction of the apoptotic process and an increase of intracellular reactive oxygen species (ROS). The effects of the nuclearity, rigidity, and solubility of these complexes on their biological activity were also analyzed. X-ray crystal structure determination allowed the identification of short N-H⋅⋅⋅π contacts as the main driving forces for the three-dimensional packing in these molecules.