Near-planar Geometry Research Articles

The molecular basis of dapsone activation of CYP2C9-catalyzed nonsteroidal anti-inflammatory drug oxidation

Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of nonsteroidal anti-inflammatory drugs invitro. Here, we conducted molecular dynamics simulations (MDS) together with enzyme kinetic investigations and site-directed mutagenesis to elucidate the molecular basis of the activation of CYP2C9-catalyzed S-flurbiprofen 4'-hydroxylation and S-naproxen O-demethylation by dapsone. Supplementation of incubations of recombinant CYP2C9 with dapsone increased the catalytic efficiency of flurbiprofen and naproxen oxidation by 2.3- and 16.5-fold, respectively. MDS demonstrated that activation arises predominantly from aromatic interactions between the substrate, dapsone, and the phenyl rings of Phe114 and Phe476 within a common binding domain of the CYP2C9 active site, rather than involvement of a distinct effector site. Mutagenesis of Phe114 and Phe476 abrogated flurbiprofen and naproxen oxidation, and MDS and kinetic studies with the CYP2C9 mutants further identified a pivotal role of Phe476 in dapsone activation. MDS additionally showed that aromatic stacking interactions between two molecules of naproxen are necessary for binding in a catalytically favorable orientation. In contrast to flurbiprofen and naproxen, dapsone did not activate the 4'-hydroxylation of diclofenac, suggesting that the CYP2C9 active site favors cooperative binding of nonsteroidal anti-inflammatory drugs with a planar or near-planar geometry. More generally, the work confirms the utility of MDS for investigating ligand binding in CYP enzymes.

Open-Ended Transmission Coaxial Probes for Sarcopenia Assessment.

We developed a handheld, side-by-side transmission-based probe for interrogating tissue to diagnose sarcopenia—a condition largely characterized by muscle loss and replacement by fat. While commercial microwave reflection-based probes exist, they can only be used in a lab for a variety of applications. The penetration depth of these probes is only in the order of 0.3 mm, which does not even traverse the skin layer, and minor motion of the coaxial feedlines can completely dismantle the calibration. Our device builds primarily on the transmission-based concept that allows for substantially greater signal penetration depth operating over a very broad bandwidth. Additional features were integrated to further improve the penetration, optimize the geometry for a more focused planar excitation, and juxtapose the coaxial apertures for more controlled interrogation. The larger coaxial apertures further increased the penetration depth while retaining the broadband performance. Three-dimensional printing technology made it possible for the apertures to be compressed into ellipses for interrogation in a near-planar geometry. Finally, fixed side-by-side positioning provided repeatable and reliable performance. The probes were also not susceptible to multipath signal corruption due to the close proximity of the transmitting and receiving apertures. The new concept worked from 100 MHz to over 8 GHz and could sense property changes as deep as 2–3 cm. While the signal changes due to deeper feature aberrations were more subtle than for signals emanating from the skin and subcutaneous fat layers, the large property contrast between muscle and fat is a sarcopenic indication that helps to distinguish even the deepest objects. This device has the potential to provide needed specificity information about the relevant underlying tissue.

The synthesis of lactone-bridged 1,3,5-triphenylbenzene derivatives as pi-expanded coumarin triskelions

Two triply lactone-bridged 1,3,5-triphenylbenzene derivatives with solubilizing moieties have been synthesized in five and six steps from commercially available starting materials. Compounds containing the 1,3,5-triphenylbenzene core with two atom bridges are relatively unknown. This new class of pi-expanded coumarins contain triskelion architectures and X-ray crystallographic studies of one of the triskelions indicates that the 1,3,5-triphenylbenzene core adopts a near-planar geometry. This is the only known example of a two atom-bridged 1,3,5-triphenylbenzene derivative to adopt a planar structure.

Expanded Cyclo[8]pyrroles Made Easy

Cyclo[8]isoindole 3 is prepared by retro-Diels-Alder reaction of 2 under thermal conditions. The optimized synthesis of compound 2 is based on oxidative homocoupling of 1 in the presence of Ce(IV) as oxidant and SO4 ²- as template. Optical properties of compound 2 and 3 are explored and rationalized based on magnetic circular dichroism spectroscopy and DFT calculations. X-ray crystallography revealed that cyclo[8]pyrrole 2 possesses a near-planar geometry, whereas compound 3 is strongly distorted owing to steric hindrance between the neighboring benzene rings.

2-Phenyl-5-(p-tol-yl)-1,3,4-oxadiazole.

The title compound, C15H12N2O, adopts the expected near-planar geometry, the phenyl and tolyl rings being inclined relative to the oxadiazole ring by 3.8 (3) and 8.3 (2)°, respectively. This allows adjacent mol­ecules to pack in a parallel fashion and form stacking along [010] via π–π inter­actions [centroid–centroid distances = 3.629 (2) and 3.723 (2) Å]. Further inter­molecular inter­actions include C—H⋯π inter­actions and weak C—H⋯N hydrogen bonds, giving rise to a crossed herringbone packing motif.

Partial Proton Transfer in the Nitric Acid Trihydrate Complex

Four isotopologues of the gas-phase complex HNO(3)-(H(2)O)(3) have been observed by microwave spectroscopy in a supersonic jet. Rotational and nuclear electric quadrupole coupling constants have been obtained and the experimentally derived inertial defect has been used to infer a near-planar geometry for the complex. The data identify the observed species from among several structures predicted by theory, favoring a 10-membered ring geometry with the HNO(3) hydrogen-bonded to the first water, a series of water-water hydrogen bonds, and ring completion with the third water acting as a hydrogen-bond donor to an unprotonated HNO(3) oxygen. This structure corresponds to the lowest energy form predicted computationally in several prior studies as well as in this work using the MP2/6-311++G(2df,2pd) level/basis set. Although its observation does not rigorously establish its status as the lowest energy form, the concurrence between the predicted low-energy conformer and that observed in the ultracold supersonic jet strongly suggests that it is indeed the minimum-energy structure. The a-type spectra show evidence of internal dynamics, likely resulting from large amplitude motion of one or more of the water subunits. This complex represents the third step in the sequential hydration of HNO(3), and both the theoretical structure and experimental (14)N quadrupole coupling constants have been used to track the degree of ionization of the acid as function of hydration number. Based on (14)N quadrupole coupling constants, transfer of the HNO(3) proton to its nearest water molecule is about one-third complete in the trihydrate.

Twisting Dynamics in the Excited Singlet State of Michler's Ketone

Ultrafast relaxation dynamics of the excited singlet (S(1)) state of Michler's ketone (MK) has been investigated in different kinds of solvents using a time-resolved absorption spectroscopic technique with 120 fs time resolution. This technique reveals that conversion of the locally excited (LE) state to the twisted intramolecular charge transfer (TICT) state because of twisting of the N,N-dimethylanilino groups with respect to the central carbonyl group is the major relaxation process responsible for the multi-exponential and probe-wavelength-dependent transient absorption dynamics of the S1 state of MK, but solvation dynamics does not have a significant role in this process. Theoretical optimization of the ground-state geometry of MK shows that the dimethylanilino groups attached to the central carbonyl group are at a dihedral angle of about 51 degrees with respect to each other because of steric interaction between the phenyl rings. Following photoexcitation of MK to its S1 state, two kinds of twisting motions have been resolved. Immediately after photoexcitation, an ultrafast "anti-twisting" motion of the dimethylanilino groups brings back the pretwisted molecule to a near-planar geometry with high mesomeric interaction and intramolecular charge transfer (ICT) character. This motion is observed in all kinds of solvents. Additionally, in solvents of large polarity, the dimethylamino groups undergo further twisting to about 90 degrees with respect to the phenyl ring, to which it is attached, leading to the conversion of the ICT state to the TICT state. Similar characteristics of the absorption spectra of the TICT state and the anion radical of MK establish the nearly pure electron transfer (ET) character of the TICT state. In aprotic solvents, because of the steep slope of the potential energy surface near the Franck-Condon (FC) or LE state region, the LE state is nearly nonemissive at room temperature and fluorescence emission is observed from only the ICT and TICT states. Alternatively, in protic solvents, because of an intermolecular hydrogen-bonding interaction between MK and the solvent, the LE region is more flat and stimulated emission from this state is also observed. However, a stronger hydrogen-bonding interaction between the TICT state and the solvent as well as the closeness between the two potential energy surfaces due to the TICT and the ground states cause the nonradiative coupling between these states to be very effective and, hence, cause the TICT state to be weakly emissive. The multi-exponentiality and strong wavelength-dependence of the kinetics of the relaxation process taking place in the S1 state of MK have arisen for several reasons, such as strong overlapping of transient absorption and stimulated emission spectra of the LE, ICT, and TICT states, which are formed consecutively following photoexcitation of the molecule, as well as the fact that different probe wavelengths monitor different regions of the potential energy surface representing the twisting motion of the excited molecule.

1-[(2-Chlorophenyl)(4-chlorophenylimino)methyl]ferrocene

The title compound, [Fe(C5H5)(C18H12Cl2N)], a new Schiff base containing a ferrocenyl (Fc) group, has been synthesized and characterized structurally. The compound is a trans isomer. The CFc—C—N—C linkage has a near-planar geometry, indicating conjugation. There are no obvious inter­molecular inter­actions.

Realization of molecular interconnection for molecular electronics: Theoretical aspects

The structural and electronic properties of conducting polymer covered with cyclodextrin molecules (CDs) have been investigated using quantum mechanical simulations. Thus, the results of calculations showed that the structure of polyaniline, in the cases of β-CDs and molecular nanotube of cross-linking α-CDs has near-planar geometry, with the electronic configuration of the optimized structure being practically same as the one in the planar conformation. It has also been found that in these cases, there are no charge transfer between polymer fragment and frameworks of CDs. The doping effect on the geometric and electronic properties of polyaniline encapsulated by CDs has been also investigated. It has been shown that the doped polymer chain can be stabilized inside the molecular nanotube of cross-linking α-CDs. These results support the realization of molecular electronic device based on this complex.

Trans-4-(Ferrocenylideneamino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one

The title compound, [Fe(C5H5)(C17H16N3O)], a new Schiff base containing a ferrocenyl group, has been characterized structurally. The central C—N=C—C linkage has a near-planar geometry, indicating extensive conjugation.

Theoretical prediction and direct observation of the hot molecules of pyrazolotriazole azomethine dyes by steady state fluorescence

Pyrazolotriazole (PT) azomethine dyes in the S1 electronic state were studied by emission spectroscopy and ab initio CI-singles and MCSCF methods. Electronically excited molecules are predicted to follow a barrierless relaxation trajectory involving a twisting of the arylamino fragment. Conformational searching yielded the only minimum on the CI-singles S1 potential energy surface (PES), with characteristic features being a twisted geometry and small S1–S0 gap (<0.3 eV). These features preclude its assignment to an experimentally observed fluorescent state (FS) characterized by the emission maximum at 550–600 nm. It is suggested that the FS is a non-Boltzmann population of vibrationally hot molecules with near-planar geometry in a relatively flat region of the S1 PES. The predicted nonclassical nature of the FS coincides with a remarkable observation of the unprecedented dependence of the fluorescence spectra on the excitation wavelength. In excellent agreement with computational models, a shift of the excitation towards longer wavelengths results in an emission band shift of comparable magnitude along with a significant decrease in a relative fluorescence quantum yield.

Synthesis and coordination chemistry of the tetradentate ligands 6,6′-bis(3-pyrazolyl)-2,2′-bipyridine and 6,6′-bis(2-hydroxyphenyl)-2,2′-bipyridine: intramolecular hydrogen-bonding in complexes of Cu(II), and a dinuclear double helicate with Ag(I)

Simple syntheses of the potentially tetradentate chelating ligands 6,6′-bis(3-pyrazolyl)-2,2′-bipyridine ( H 2 L 1), and 6,6′-bis(2-hydroxyphenyl)-2,2′-bipyridine (H 2L 2) are described: H 2L 1 is a new ligand, whereas H 2L 2 is known, but investigation of its coordination chemistry has been hampered by the lack of a simple synthesis. Complexes of both have been structurally characterised and reveal many interesting features. [Cu(HL 1)(H 2O)][PF 6] is square pyramidal with an axial H 2O ligand, but, in the solid state, forms a hydrogen-bonded dimer in which the peripheral pyrazolyl groups of HL 1 (one protonated, one deprotonated) in one complex unit form a two-point ‘chelating’ hydrogen-bonding interaction with the axial water ligand of the second, and vice versa. In contrast, [Ag 2(L 1) 2][BF 4] 2 is a dinuclear double helicate because of the preference of Ag(I) ions for a pseudo-tetrahedral geometry. [Cu(L 2)] has a typical near-planar geometry with a N 2O 2 donor set, and monomeric units are associated into centrosymmetric dimers in the crystal via weak axial Cu⋯O(phenolate) interactions to give an asymmetric [Cu 2(μ-phenolate) 2] core. In {[Cu(L 2)] 2H}(PF 6), the two monomeric [Cu(L 2)] units are also associated via axial phenolate interactions to give a dimer with a [Cu 2(μ-phenolate) 2] core, but, in addition, the extra proton per dimer unit is located at the centre of a short, strong O⋯H⋯O hydrogen-bond that links a phenolate group from each of the two monomer units. The geometry of dimer formation is changed in order to allow the phenolate groups to approach one another closely enough for this hydrogen-bond to form.

Tetrakis(trialkylsilyl)digermenes. Salient Effects of Trialkylsilyl Substituents on Planarity around the GeGe Bond and Remarkable Thermochromism

X-ray structural analyses of tetrakis(trialkylsilyl)digermenes have shown that the trialkylsilyl substituents enforce near-planar geometry around the GeGe bonds, in accordance with theoretical pred...

4-Methylbenzylammonium 4-Methylbenzylcarbamate

The title structure, C8H12N+.C9H10NO2−, consists of infinite bilayers, parallel to the ab plane, incorporating both cations and anions. Within each bilayer, anions and cations are stacked in a herringbone fashion and the layers are generated by three N—H⋯O hydrogen bonds. The NHCOO− moiety displays near-planar geometry.

Transmetallation reaction of Schiff-base-type arylmercury compounds with 4-ethoxyphenyltellurium(IV) trichloride and the crystal structure of (4-ethoxyphenyl)[(2-benzylideneamino-5-methyl)phenyl]tellurium(IV) dichloride

A series of new asymmetric diaryltellurium dichlorides were synthesized by the transmetallation reaction of Schiff-base-type arylmercury compounds with 4-ethoxyphenyltellurium trichloride. All the asymmetric diaryltellurium dichlorides prepared were characterized by elemental analysis, IR, 1H nuclear magnetic resonance and mass spectroscopy. The crystal structure of (4-ethoxyphenyl) [(2-benzylideneamino-5-methyl)phenyl]tellurium dichloride shows that the coordination on tellurium can be considered as essentially pseudo-octahedral, with lone pair electrons occupying the forth equatorial site. The TeN distance of 2.905(2) Å is shorter than the sum of the van der Waals radii of Te and N (about 3.7 Å), indicating the substantial secondary intramolecular coordination between Te and N. The N → Te intramolecular coordination holds the Schiff base moiety in near-planar geometry.

Rotational spectrum, structure, and chlorine nuclear quadrupole tensor of the vinyl fluoride–HCl dimer

The ground-state rotational spectrum of the dimer formed between vinyl fluoride and hydrogen chloride has been detected by using a pulsed-nozzle Fourier-transform microwave spectrometer. The rotational constants A0, B0, and C0; the centrifugal distortion constants ΔJ, ΔJK, δJ and δJK; and the components χaa, χbb−χcc, and χab of the Cl nuclear quadrupole coupling tensor have been determined for each of the three isotopomers CH2CHF⋅⋅⋅H 35Cl, CH2CHF⋅⋅⋅H 37Cl, and CH2CHF⋅⋅⋅D 35Cl. An accidental near degeneracy of the 211 and 303 levels allows an accurate evaluation of the off-diagonal component χab. Interpretation of the rotational constants establishes a near-planar geometry for CH2CHF⋅⋅⋅HCl, with HCl forming a hydrogen bond to F and RF⋅⋅⋅Cl=3.382(3) Å. The angle CF⋅⋅⋅H is 116.1(1)° and there is some evidence that the HCl subunit lies slightly out of the plane (φ=8.0±1.5°). Diagonalization of the Cl nuclear quadrupole coupling tensor to give the principal components χxx, χyy, and χzz leads to an angle of 30.8° between the a axis of the dimer and the H–Cl(z) axis. Comparison with the corresponding angle available from the geometry suggests that the z axis may be bent away by ≊10° from the F⋅⋅⋅H line in the F⋅⋅⋅HCl system. The preference for hydrogen-bond formation to F rather than to the π bond in vinyl fluoride is consistent with the Legon–Millen rules for angular geometries and can also be rationalized by the numerical Buckingham–Fowler model.