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Relevant academic research and scientific papers

DOTA-amide lanthanide tag for reliable generation of pseudocontact shifts in protein NMR spectra

Structural studies of proteins and protein-ligand complexes by nuclear magnetic resonance (NMR) spectroscopy can be greatly enhanced by site-specific attachment of lanthanide ions to create paramagnetic centers. In particular, pseudocontact shifts (PCS) g

AZOLE-FUSED PYRIDAZIN-3(2H)-ONE DERIVATIVES

Disclosed are compounds of Formula (1) and pharmaceutically acceptable salts thereof, wherein α, β, n, R4, R5, R6, R8, R9, R10, R11, X1, X2, X3 and X7 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula (1), to pharmaceutical compositions comprising them, and to their use for treating diseases, disorders, and conditions associated with GPR139.

A Chiral Lanthanide Tag for Stable and Rigid Attachment to Single Cysteine Residues in Proteins for NMR, EPR and Time-Resolved Luminescence Studies

A lanthanide-binding tag site-specifically attached to a protein presents a tool to probe the protein by multiple spectroscopic techniques, including nuclear magnetic resonance, electron paramagnetic resonance and time-resolved luminescence spectroscopy. Here a new stable chiral LnIII tag, referred to as C12, is presented for spontaneous and quantitative reaction with a cysteine residue to generate a stable thioether bond. The synthetic protocol of the tag is relatively straightforward, and the tag is stable for storage and shipping. It displays greatly enhanced reactivity towards selenocysteine, opening a route towards selective tagging of selenocysteine in proteins containing cysteine residues. Loaded with TbIII or TmIII ions, the C12 tag readily generates pseudocontact shifts (PCS) in protein NMR spectra. It produces a relatively rigid tether between lanthanide and protein, which is beneficial for interpretation of the PCSs by single magnetic susceptibility anisotropy tensors, and it is suitable for measuring distance distributions in double electron–electron resonance experiments. Upon reaction with cysteine or other thiol compounds, the TbIII complex exhibits a 100-fold enhancement in luminescence quantum yield, affording a highly sensitive turn-on luminescence probe for time-resolved FRET assays and enzyme reaction monitoring.

Application of amide-stabilized sulfur ylide reactivity to the stereodivergent synthesis of (R,S)- and (S,R)-reboxetine

A simple access to (R,S)- and (S,R)-reboxetine from a single chiral sulfonium salt 4 is reported. This approach, based on a stabilized sulfur ylide-mediated epoxidation, followed by a regioselective opening reaction, enables the preparation of these two p

Value of zeolites in asymmetric induction during photocyclization of pyridones, cyclohexadienones and naphthalenones

Two strategies, namely chiral inductor and chiral auxiliary approaches, have been examined within zeolites with the aim of achieving asymmetric induction during the photocyclization of cyclohexadienone, naphthalenone and pyridone derivatives. Within zeoli

Structure-activity relationships in the binding of chemically derivatized CD4 to gp120 from human immunodeficiency virus

The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.

A modular approach toward regulating the secondary coordination sphere of metal ions: Differential dioxygen activation assisted by intramolecular hydrogen bonds

Metal ion function depends on the regulation of properties within the primary and second coordination spheres. An approach toward studying the structure-function relationships within the secondary coordination sphere is to construct a series of synthetic complexes having constant primary spheres but structurally tunable secondary spheres. This was accomplished through the development of hybrid urea-carboxamide ligands that provide varying intramolecular hydrogen bond (C-bond) networks proximal to a metal center. Convergent syntheses prepared ligands [(N′-tert-butylureayl)-N- ethyl]-bis(N″-R-carbamoylmethyl)amine (H41R) and bis[(N′-tert-butylureayl)-N-ethyl]-(N″-R-carbamoylmethyl)amine (H52R), where R = isopropyl, cyclopentyl, and (S)-(-)-α-methylbenzyl. The ligands with isopropyl groups H 41iPr and H52iPr were combined with tris[(N′-tert-butylureayl)-N-ethyl]amine (H6buea) and bis(N-isopropylcarbamoylmethyl)-amine (H3OiPr) to prepare a series of Co(II) complexes with varying H-bond donors. [CoIIH 22iP7]- (two H-bond donors), [Co IIH1iPr]- (one H-bond donor), and [Co IIOiPr]- (no H-bond donors) have trigonal monopyramidal primary coordination spheres as determined by X-ray diffraction methods. In addition, these complexes have nearly identical optical and EPR properties that are consistent with S = 3/2 ground states. Electrochemical studies show a linear spread of 0.23 V in anodic potentials (Epa) with [CoIIH22iPr]- being the most negative at -0.385 V vs [Cp2Fe]+/[Cp2Fe]. The properties of [CoIIH3buea]- (H3buea, tris[(N′-tert-butylureaylato)-N-ethyl]aminato that has three H-bond donors) appears to be similar to that of the other complexes based on spectroscopic data. [CoIIH3buea]- and [Co IIH22iPr]- react with 0.5 equiv of dioxygen to afford [CoIIIH3buea(OH)]- and [CoIIIH22iPr(OH)]-. Isotopic labeling studies confirm that dioxygen is the source of the oxygen atom in the hydroxo ligands: [CoIIIH3buea(16OH)] - has a ν(O-H) band at 3589 cm-1 that shifts to 3579 cm-1 in [CoIIIH3buea(18OH)] -; [CoIIIH22iPr(OH)]- has ν(16O-H) = 3661 and ν(18O-H) = 3650 cm -1. [CoIIH1iPr]- does not react with 0.5 equiv of O2; however, treating [CoIIH1 iPr]- with excess dioxygen initially produces a species with an X-band EPR signal at g = 2.0 that is assigned to a Co-O2 adduct, which is not stable and converts to a species having properties similar to those of the CoIII-OH complexes. Isolation of this hydroxo complex in pure form was complicated by its instability in solution (kint = 2.5 × 10-7 M min-1). Moreover, the stability of the CoIII-OH complexes is correlated with the number of H-bond donors within the secondary coordination sphere; [CoIIIH3buea(OH) ]- is stable in solution for days, whereas [CoIIIH 22iPr(OH)]- decays with a kint = 5.9 × 10-8 M min-1. The system without any intramolecular H-bond donors [CoIIOiPr]- does not react with dioxygen, even when O2 is in excess. These findings indicate a correlation between dioxygen binding/activation and the number of H-bond donors within the secondary coordination sphere of the cobalt complexes. Moreover, the properties of the secondary coordination sphere affect the stability of the CoIII-OH complexes with [CoIIIH 3buea(OH)]- being the most stable. We suggest that the greater number of intramolecular H-bonds involving the hydroxo ligand reduces the nucleophilicity of the CoIII-OH unit and reinforces the cavity structure, producing a more constrained microenvironment around the cobalt ion.

Regioselective alkylation of 3,4-dihydro-2H-pyran by xanthate-mediated free radical nonchain process

An intermolecular xanthate-mediated free radical nonchain addition reaction is introduced for the regioselective alkylation of 3,4-dihydro-2H-pyran. Additionally, we observed that the free radical nonchain reaction depends on the nature of the radical precursor.

Chiral recognition by CD-sensitive dimeric zinc porphyrin host. 1. Chiroptical protocol for absolute configurational assignments of monoalcohols and primary monoamines

A general microscale protocol for the determination of absolute configurations of primary amino groups or secondary hydroxyl groups linked to a single stereogenic center is described. The chiral substrates are linked to the achiral trifunctional bidentate carrier molecule (3-aminopropylamino)acetic acid (1, H2NCH2CH2CH2NHCH2COOH) and the resultant conjugates are then complexed with dimeric zinc porphyrin host 2 giving rise to 1:1 host/guest sandwiched complexes. These complexes exhibit exciton-coupled bisignate CD spectra due to stereodifferentiation leading to preferred porphyrin helicity. Since the chiral sense of twist between the two porphyrins in the complex is dictated by the stereogenic center of the substrate, the sign of the couplet determines the absolute configuration at this center. The twist of the porphyrin tweezer in the complex can be predicted from the relative steric sizes of the groups flanking the stereogenic center, such that the bulkier group protrudes from the complex sandwich. In certain α-hydroxy esters and α-amino esters, electronic factors and hydrogen bonding govern the preferred conformation of the complex, and hence the CD spectra.

Syntheses, characterizations, and redox behavior of optically active viologens and bisviologens

Optically active viologens, containing [1-(1-naphthyl)-, 1-phenyl-, and 1-cyclohexylethyl]carbamoylmethyl groups, have been synthesized and characterized. The redox behavior of the chiral viologens was studied compared with achiral viologens. The monoviologens containing naphthyl groups show an intermolecular charge-transfer interaction between the bipyridinium and naphthyl groups in aqueous solution. The association constants are dependent on the chirality of the viologens and larger in the (S,S)- and (R,R)-isomers than in the (R,S)-one. Chiral bisviologens, in which two viologen units are linked with a trimethylene chain, have also been synthesized and characterized. Although the intermolecular charge-transfer interaction between the bipyridinium and viologen units of bisviologens was very weak in solution, such an interaction was appreciably observed in a solid state, which was confirmed by X-ray crystallography. Monoradical trications produced by a one-electron reduction of bisviologens disproportionate more easily in the (R,S)-isomers than in the (S,S)- and (R,R)-ones. The disproportionation is controlled by the steric bulk of the chiral substituents in intramolecular association between two viologen radical units of diradical dications.