Roberto Rittner

EGFR Tyrosine Kinase Inhibitor (PD153035) Improves Glucose Tolerance and Insulin Action in High-Fat Diet–Fed Mice

OBJECTIVE In obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to low-grade inflammation and insulin resistance. Epidermal growth factor receptor (EGFR) mediates both chemotaxis and proliferation in monocytes and macrophages. However, the role of EGFR inhibitors in this subclinical inflammation has not yet been investigated. We investigated, herein, in vivo efficacy and associated molecular mechanisms by which PD153035, an EGFR tyrosine kinase inhibitor, improved diabetes control and insulin action. RESEARCH DESIGN AND METHODS The effect of PD153035 was investigated on insulin sensitivity, insulin signaling, and c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-κB activity in tissues of high-fat diet (HFD)-fed mice and also on infiltration and the activation state of adipose tissue macrophages (ATMs) in these mice. RESULTS PD153035 treatment for 1 day decreased the protein expression of inducible nitric oxide synthase, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in the stroma vascular fraction, suggesting that this drug reduces the M1 proinflammatory state in ATMs, as an initial effect, in turn reducing the circulating levels of TNF-α and IL-6, and initiating an improvement in insulin signaling and sensitivity. After 14 days of drug administration, there was a marked improvement in glucose tolerance; a reduction in insulin resistance; a reduction in macrophage infiltration in adipose tissue and in TNF-α, IL-6, and free fatty acids; accompanied by an improvement in insulin signaling in liver, muscle, and adipose tissue; and also a decrease in insulin receptor substrate-1 Ser307 phosphorylation in JNK and inhibitor of NF-κB kinase (IKKβ) activation in these tissues. CONCLUSIONS Treatment with PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice.

DNA Nucleobase Synthesis at Titan Atmosphere Analog by Soft X-rays †

Titan, the largest satellite of Saturn, has an atmosphere chiefly made up of N(2) and CH(4) and includes traces of many simple organic compounds. This atmosphere also partly consists of haze and aerosol particles which during the last 4.5 gigayears have been processed by electric discharges, ions, and ionizing photons, being slowly deposited over the Titan surface. In this work, we investigate the possible effects produced by soft X-rays (and secondary electrons) on Titan aerosol analogs in an attempt to simulate some prebiotic photochemistry. The experiments have been performed inside a high vacuum chamber coupled to the soft X-ray spectroscopy beamline at the Brazilian Synchrotron Light Source, Campinas, Brazil. In-situ sample analyses were performed by a Fourier transform infrared spectrometer. The infrared spectra have presented several organic molecules, including nitriles and aromatic CN compounds. After the irradiation, the brownish-orange organic residue (tholin) was analyzed ex-situ by gas chromatographic (GC/MS) and nuclear magnetic resonance ((1)H NMR) techniques, revealing the presence of adenine (C(5)H(5)N(5)), one of the constituents of the DNA molecule. This confirms previous results which showed that the organic chemistry on the Titan surface can be very complex and extremely rich in prebiotic compounds. Molecules like these on the early Earth have found a place to allow life (as we know) to flourish.

1hJFH coupling in 2-fluorophenol revisited: Is intramolecular hydrogen bond responsible for this long-range coupling?

The present study shows that a hydrogen bond between the OH group and the fluorine atom is not involved in the 1hJFH spin–spin coupling transmission either for 4‐bromo‐2‐fluorophenol or 2‐fluorophenol. In fact, according to a quantum theory of atoms in molecules analysis, no bond critical point is found between O‐H and F moieties. The nature of the transmission mechanism of the Fermi contact term of the 1hJFH spin–spin coupling is studied by analyzing canonical molecular orbitals (see J. Phys. Chem. A 2010, 114, 1044), and it is observed that virtual orbitals play only a quite minor role in its transmission. This is typical of a Fermi contact term transmitted mainly through exchange interactions owing to the overlap of proximate electronic clouds; therefore, it is suggested to identify them as nTSJFH coupling where n stands for the number of formal bonds separating the coupling nuclei. In the cases studied in this work is n = 4. Results presented in this work could provide an interesting rationalization for different experimental signs known in the current literature for proximate JFH couplings. Copyright

The F⋯HO intramolecular hydrogen bond forming five-membered rings hardly appear in monocyclic organofluorine compounds

This paper emphasizes that fluorine atoms in organic molecules need special geometric requirements to experience intramolecular hydrogen bonds (H-bonds). Calculations at the B3LYP/aug-cc-pVDZ theoretical level and using the quantum theory of atoms in molecules applied over a series of monocyclic compounds, which have similar CC(F)–C(OH)C fragments, predict that the F⋯HO intramolecular H-bond does not exist when forming five-membered rings. Indeed, it is shown that the geometric restrictions imposed by the rigid rings are the main reasons in preventing fluorine participating in such a F⋯HO intramolecular H-bond.

Conformational studies of α-substituted carbonyl compounds. Part 1. Conformation and electronic interaction in hetero-substituted acetones by infrared and ultraviolet spectroscopy

νCO Frequencies and intensities and n→π* transition energies were measured for some heterosubstituted ketones (XCH2COMe : X = F, Cl, Br, I, NMe2, OMe, SMe, or SEt) and compared with the corresponding unsubstituted ketone. The stability of the gauche-conformers is discussed in terms of hyperconjugative interactions between σC – X and πCO orbitals and repulsive interactions between CO and C – X dipoles. The carbonyl frequency shifts, induced by inductive (ΔνI), field (ΔνF), and hyperconjugative effects (ΔνH), are estimated separately. A close relationship is shown to exist between the ΔνH values and the energies of the n→π* transition.

In silico prediction of novel phosphodiesterase type-5 inhibitors derived from Sildenafil, Vardenafil and Tadalafil

A series of drug-like compounds derived from Sildenafil, Vardenafil and Tadalafil analogues were modelled through the MIA-QSAR (multivariate image analysis applied to quantitative structure-activity relationships) ligand-based approach. A highly predictive model was achieved and novel compounds, miscellany of substructures of these three representative phosphodiesterase type-5 (PDE-5) inhibitors were predicted using the calibration parameters obtained through partial least squares (PLS) regression. The high bioactivities of eight promising compounds were corroborated by docking evaluation. Calculated ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) profiles for such compounds suggest advantages of some of them over the currently available, most common drugs used for the treatment of erectile dysfunction.

Interaction in trans-2-halocyclohexanols — an infrared and theoretical study

Abstract The O–H and C–O stretching frequencies of trans -2-halocyclohexanols in CCl 4 solutions have been measured and theoretical calculations have been performed to elucidate the main interactions, which are responsible for the conformational equilibria in these systems. It can be concluded that hydrogen bonding is predominant for trans -2-fluorocyclohexanol, leading to a stabilization of the eq–eq conformation, while for the chlorine, bromine and iodine derivatives, besides hydrogen bonding, gauche and steric interactions are also present.

Halogenated six-membered rings: a theoretical approach for substituent effects in conformational analysis

Abstract Studies on the conformational equilibria of a series of dihalosubstituted cyclohexanes ( I ) and halocyclohexanones ( II ) are reported. Theoretical calculations using the B3LYP method and the 6-311+g(d,p) basis set were applied to determine the energy differences (Δ E ) between the conformers of I and II , as well Δ E between the conformers of monohalocyclohexanes, in order to obtain the intramolecular interaction energies, which govern the conformational equilibria of I and II . It is shown that while the intramolecular interactions for 1,3- and 1,4-disubstituted cyclohexanes, as well as for 3- and 4-halocyclohexanones, are due to classical effects (steric and electrostatic), for the 2-halocyclohexanones it becomes evident that orbital interactions between n halo and π ∗ CO drive the equilibria towards the axial conformers. Moreover, the gauche effect seems to be irrelevant for the trans -1,2-dihalocyclohexane equilibria, opposite to several reports from the literature on other trans -1,2-disubstituted cyclohexanes bearing electronegative substituents.

Does intramolecular hydrogen bond play a key role in the stereochemistry of α- and β-D-glucose?

Four α- and three β-isomers of the d-glucose were optimized in gas phase using ab initio (MP2) and DFT (ωB97X-D) methods, both using the aug-cc-pVDZ basis set. While earlier works suggest that the orientation of the hydroxyl groups is due to intramolecular hydrogen bonds (H-bonds), the present study reveals that most H-bonds forming five-membered rings are either weak or even do not exist. The quantum theory of atoms in molecules (QTAIM) analysis showed only a few cases of H-bond in d-glucose, particularly for those H-bonds forming six-membered rings, while the non-covalent interactions (NCI) analysis indicated that most intramolecular H-bonds are not strong enough to justify the counter-clockwise arrangement of the OH⋯O chains. Natural bond orbital analysis supported the findings obtained from QTAIM and NCI analyses and indicated that the anomeric effect for d-glucose in the gas phase is governed by a balance of steric, electrostatic, and hyperconjugative interactions.

The utility of infrared spectroscopy for quantitative conformational analysis at a single temperature

The carbonyl stretching vibration of 2-bromocyclohexanone (1) has been measured in a variety of solvents. It is shown that its component intensities are not only dependent on the populations of the axial and equatorial conformers, but are also dependent on the molar absorptivities (epsilon ) which are specific for each conformer in each solvent. In CCl(4), the axial and equatorial conformers have epsilon values of 417 and 818 l mol(-1) x cm(-1), respectively, while in CH(3)CN solution, the values were 664 and 293 l mol(-1) x cm(-1). These results are supported by results of theoretical calculations of frequencies, which gave an intensity of 223.8 kM mol(-1) x(1782 cm(-1)) for the axial and 174.4 kM mol(-1) x (1802 cm(-1)) for the equatorial conformer, indicating that the axial conformer presents a larger molar absorptivity than the equatorial one in the vapor phase. Moreover, the results presented here clearly demonstrate that although infrared spectroscopy at a single temperature can be an important auxiliary technique for conformational analysis, it must not be used to quantify conformational preferences of a molecule if the absorption molar coefficients for each conformer are not known or not amenable to experimental determination.