Chlorine Atom In Ortho Position Research Articles

Variously substituted 2-oxopyridine derivatives: Extending the structure-activity relationships for allosteric modulation of the cannabinoid CB2 receptor.

We previously reported the 2-oxopyridine-3-carboxamide derivative EC21a as the first small synthetic CB2R positive allosteric modulator which displayed antinociceptive activity invivo in an experimental mouse model of neuropathic pain. Herein, we extended the structure-activity relationships of EC21a through structural modifications regarding the p-fluoro benzyl moiety at position 1 and the amide group in position 3 of the central core. The characterization invitro was assessed through radioligand binding experiments and functional assays (GTPγS, cAMP, βarrestin2). Among the new compounds, the derivatives A1 (SV-10a) and A5 (SB-13a) characterized respectively by fluorine atom or by chlorine atom in ortho position of the benzylic group at position 1 and by a cycloheptane-carboxamide at position 3 of the central core, showed positive allosteric behavior on CB2R. They enhanced the efficacy of CP55,940 in [35S]GTPγS assay, and modulated CP55,940-dependent βarrestin2 recruitment and cAMP inhibition. The obtained results extend our knowledge of the structural requirements for interaction with the allosteric site of CB2R.

Extensive study on physicochemical properties of polychlorinated biphenyls in a commercial ion trap mass spectrometer, relevance in analytical and environmental chemistry.

Polychlorinated biphenyls (PCBs) exist as 209 congeners, consisting of biphenyl molecules, where the number and substitution positions of halogen atoms are known to affect industrial uses, environmental transport mechanisms, distribution, fate, and toxicity. The complexity of the problem requires accurate physicochemical studies of an increasing number of congeners in order to understand the environmental and biological processes at play. This work presents a systematic study on the thermodynamic and kinetic properties of PCBs by quadrupole ion trap mass spectrometry. A clear relationship between structure and behavior of PCBs in mass spectrometry experiments has been observed. Overall data demonstrate that di-ortho congeners show lower thermodynamic stability and higher fragmentation rate than non/mono-ortho. Congeners follow different fragmentation mechanisms according to the number of chlorine atoms in ortho position of the biphenyl system. Experimental kinetic curves of mono/non-ortho and di-ortho congeners show a strong similarity with classical first-order kinetics curves; in particular, di-ortho congeners follow a first-order consecutive reaction, while mono/non-ortho follow a first-order parallel reaction. For each studied congener, the kinetic constant of reaction (fragmentation) has been determined. Data support environmental levels and biochemical transformations described in literature. The general picture of the PCB behavior inside a quadrupole ion trap provides the basis for the development of reliable and cost-effective analytical methods to the determination of ultra-low level trace of PCB congeners.

PCB-153 shows different dynamics of mobilisation from differentiated rat adipocytes during lipolysis in comparison with PCB-28 and PCB-118.

BackgroundPolychlorinated biphenyls (PCBs) are persistent organic pollutants. Due to their lipophilic character, they are preferentially stored within the adipose tissue. During the mobilisation of lipids, PCBs might be released from adipocytes into the bloodstream. However, the mechanisms associated with the release of PCBs have been poorly studied. Several in vivo studies followed their dynamics of release but the complexity of the in vivo situation, which is characterised by a large range of pollutants, does not allow understanding precisely the behaviour of individual congeners. The present in vitro experiment studied the impact of (i) the number and position of chlorine atoms of PCBs on their release from adipocytes and (ii) the presence of other PCB congeners on the mobilisation rate of such molecules.Methodology/Principal FindingsDifferentiated rat adipocytes were used to compare the behaviour of PCB-28, -118 and -153. Cells were contaminated with the three congeners, alone or in cocktail, and a lipolysis was then induced with isoproterenol during 12 hours. Our data indicate that the three congeners were efficiently released from adipocytes and accumulated in the medium during the lipolysis. Interestingly, for a same level of cell lipids, PCB-153, a hexa-CB with two chlorine atoms in ortho-position, was mobilised slower than PCB-28, a tri-CB, and PCB-118, a penta-CB, which are both characterised by one chlorine atom in ortho-position. It suggests an impact of the chemical properties of pollutants on their mobilisation during periods of negative energy balance. Moreover, the mobilisation of PCB congeners, taken individually, did not seem to be influenced by the presence of other congeners within adipocytes.Conclusion/SignificanceThese results not only highlight the obvious mobilisation of PCBs from adipocytes during lipolysis, in parallel to lipids, but also demonstrate that the structure of congeners defines their rate of release from adipocytes.

Modular synthesis of phenanthro[9,10-c]thiophenes by a sequence of C-H activation, suzuki cross-coupling and photocyclization reactions.

A total number of 15 different 3,4-diarylthiophenes were synthesized, which bear a chlorine atom in ortho-position of one of the aryl substituents. One aryl group was introduced by an oxidative cross-coupling reaction, involving a CH activation at C4(3) of the thiophene core. The other aryl group was in most cases introduced by a Suzuki cross-coupling reaction, which succeeded the oxidative cross-coupling step. Photocyclization reactions of the 3,4-diarylthiophenes were performed in a solvent mixture of benzene and acetonitrile (50:50 v/v) at λ=254 nm and proceeded to the title compounds in yields of 60-82 %. The selectivity of the photocyclization was determined at the ortho-chloro-substituted aryl ring by the position of the chlorine substituent. At the other ring, a single regioisomer was observed for phenyl and para-substituted phenyl groups. For 2-naphthyl and ortho-substituted phenyl rings a clear preference was observed in favor of a major regioisomer, while meta-substitution in the phenyl ring led to a about 1:1 mixture of 5- and 7-substituted phenanthro[9,10-c]thiophenes. Mechanistically, the photocyclization is likely to occur as a photochemically allowed, conrotatory [(4n+2)π] process accompanied by elimination of HCl. It was shown for two phenanthro[9,10-c]thiophene products that they can be readily brominated in positions C1 and C3 (74-77 %), which in turn allows for further functionalization at these positions, for example, in the course of halogen-metal exchange and polymerization reactions.

Comparative assessment of polychlorinated biphenyls’ toxic potential in ovary cells

PCBs are considered as potential endocrine disruptors with various deleterious effects on female reproductive system. Although, the environmental PCB levels have been declining due to legislation, in the Republic of Croatia risk is still high due to destructions of the facilities containing PCBs during the Patriotic War (1991–1995). The toxic profiles of PCBs are congener-specific and the major structural factor in determining the toxic properties is the presence of chlorine atom in ortho position. A comparative assessment of dioxin-like, coplanar PCB 77 and non-dioxin-like, ortho-substituted PCB 153 effects has been performed in this study to evaluate the potential risk and mode of action for inducing cytotoxicity in Chinese hamster ovary cells. In order to assess and quantify toxic effects of PCBs (10–100 μM) three in vitro methods with distinct endpoints were chosen: Trypan blue (TB), Neutral red (NR) and Kenacid blue assays (KB). Overall, a dose dependent cytotoxicity for PCB-77 was confirmed with all assays applied, whereas for PCB-153 only with TB and NR. Extent of the cellular viability loss and accelerated cell death were greater for non-ortho-substituted PCB-77 (after 72 h: IC50-TB = 24.0 μM ; IC50-NR = 55.4 μM ; IC50-KB = 94.2 μM) than for di-ortho-substituted congener PCB-153 (after 72 h: IC50-TB = 55.5 μM ; IC50-NR = 51.0 μM ; IC50-KB = 111.1 μM). To determine if exposure to PCBs perturbs cellular proliferation, CHO-K1 cells were incubated with 50 μM PCB-77 or PCB-153 for 6 or 48 h and assayed for cell cycle phase distributions using flow cytometry. Major induced alterations were detected for PCB 77 with a slight increase in apoptotic peak vs. no observed effect for PCB-153.

Ferroelectric, antiferroelectric and TGB phases in lactic acid derivatives

We prepared a series of rod-like mesogens with two biphenyls laterally substituted by a chlorine atom in ortho position to oxygen atoms in the molecular core, having two lactate units and chiral methylbutyl chain in the chiral part. The sequences of phases and transition temperatures were ascertained by differential scanning calorimetry measurements, polarising optical microscopy, dielectric spectroscopy and electro-optical studies. X-ray diffraction studies were performed, phases confirmed and their structural parameters established. In the studied compounds twist grain boundary (TGBA and TGBC) phases were detected in a rather wide temperature range. In addition, the antiferroelectric SmC*A phase was observed. The properties of this homologue series are compared with those established previously for analogous compounds having the same molecular core and differing only in the number of lactate units in the chiral part.

Modification of n‐Type Organic Semiconductor Performance of Perylene Diimides by Substitution in Different Positions: Two‐Dimensional π‐Stacking and Hydrogen Bonding

Perylene diimides (PDIs) and their derivatives are active n-type semiconducting materials widely used in organic electronic devices. A series of PDI derivatives have been investigated by quantum chemistry calculations combined with Marcus-Hush electron-transfer theory. The substitution of three different sites of a PDI induces large changes in its electron-transfer mobility. 2,5,8,11-Tetrachloro-PDI with four chlorine atoms in ortho positions shows both large electron- and hole-transfer mobilities of 0.116 and 0.650 cm(2) V(-1) s(-1) , respectively, indicative of a potentially highly efficient ambipolar organic semiconducting material. The calculated electron-transfer mobility of 1,6,7,12-tetrachloro-PDI is 0.081 cm(2) V(-1) s(-1) , which is in good agreement with the experimental result. Octachloro-PDIs have the largest electron mobility among these derivatives, although the π system of the central core is twisted. 2D π-stacking and hydrogen bonds formed at the imide positions are responsible for the large mobility. Simulated anisotropic transport mobility curves of these materials prove the magnitude of the mobility that appears when the measuring transistor channel is along the a-axis of the crystal, which is the direction of hydrogen bond formation.

Luminescence of meso-pyrimidinylcorroles: relationship with substitution pattern and heavy atom effects

The luminescence properties of a series of corroles containing multiple meso-pyrimidinyl groups have been studied. In particular, nine corroles containing two pyrimidinyl moieties, four corroles containing three pyrimidinyl groups and one corrole carrying a single pyrimidinyl substituent have been investigated, and their properties have been compared with some model species. The results indicate that the energy of the emissive π-π* corrole-core-based state is not significantly perturbed by the various substituents, whereas the emission lifetimes and quantum yields depend on the number of appended meso-dichloropyrimidinyl substituents. In particular, both emission lifetime and quantum yield decrease with increasing the number of meso-dichloropyrimidinyl substituents, whereas pyrimidinyl substituents which do not carry further electron withdrawing groups such as the chlorine atoms do not affect the corrole emission properties. Two hypotheses are taken into consideration to rationalize the results: (i) the presence of meso-dichloropyrimidinyl substituents could introduce low-lying CT states which mix with the corrole π-π* emissive level, so reducing emission efficiency; (ii) the ortho,ortho'-chlorine groups of the meso-pyrimidinyl substituents, which lie in the proximity of the corrole macrocycle, can increase the intersystem crossing rate constant of the corrole-based fluorescent state via the heavy-atom effect. A comparison of the results of the studied corrole compounds with formerly investigated species and the linear dependence of the radiationless decay rate constants and emission quantum yields on the squared spin-orbit coupling constants, calculated considering the number of chlorine atoms in ortho-position of the corrole meso-substituents, suggest that hypothesis (ii) is most likely the valid one. These results are of particular interest for the design of (a) corrole compounds featuring highly efficient triplet formation and (b) multicomponent systems containing photo-active corrole subunits and pyrimidinyl spacers.

Density functional calculation of conformations and potentials of internal rotation in polychlorinated biphenyls

Full geometry optimization for all 209 isomers of polychlorinated biphenyls (PCBs) and calculations of internal rotation potentials for 154 isomers have been performed by density functional method B3LYP/6-31G(d, p). Conformations and internal rotation barriers in PCBs were proved to depend on a number of chlorine atoms in ortho-positions and, less, the presence of chlorine atoms in adjacent meta-positions. Subject to the number of chlorine atoms in ortho-and adjacent meta-positions, 209 PCB isomers were classified into 18 groups, within each of them molecules having very close conformations and potentials of internal rotation. It makes possible to evaluate with high accuracy the potential functions of the last 55 PCB molecules for which potential curve calculations have not been made.

Effect of Polychlorinated Biphenyls on the Uptake of Dopamine into Rat Brain Synaptic Vesicles: A Structure–Activity Study

PCBs are neurotoxic compounds that have a known effect on the dopaminergic system in the brain. In a previous work it was established that PCBs are potent inhibitors of the uptake of dopamine into rat brain synaptic vesicles. In this work we further investigated the vesicular dopamine uptake in response to different PCBs to explore the structure–activity relationship involved in this effect. Twenty PCB congeners were selected, based on multivariate chemical characterization, to cover the chemical variation within tetra- to hepta-chlorinated PCBs. PCBs of large structural variation were tested and the general finding was that only the ortho-substituted PCBs inhibited the dopamine uptake. The most active congeners were the penta- and hexa-chlorinated PCBs. Furthermore, the uptake was correlated with parameters describing the absolute hardness, the octanol–water partition coefficient, and the Henry's law constant. These parameters are correlated to the number of chlorine atoms in ortho positions and to the size of the molecule. Notably the most active PCBs are highly prevalent in the environment and are disposed to bioaccumulate in wildlife. Thus, these neurotoxic effects should be included in the risk assessment of PCBs.

The internal barriers of rotation for the 209 polychlorinated biphenyls

The internal barrier of rotation (Erot) was calculated for all 209 polychlorinated biphenyls (PCBs) by using a semi-empirical method, viz. the Austin Model 1 (AMI) Hamiltonian. The difference in total energy between a forced planar state and an optimised twisted structure was defined as Erot. The Erot values were in the range of 8.33 to 483 kJ/mol, and were significantly influenced by the number of chlorine atoms in ortho position. An additional structural characteristic of the PCBs influencing Erot of ortho substituted congeners was substitution by chlorine atoms in vicinal meta positions, which is assumed to prevent outward bending of ortho substituents. This so-called buttressing effect contributed with 4 to 31 kJ/mol per added chlorine atom. In conclusion, the internal barrier of rotation, calculated for all 209 PCBs, provides an important structure dependent physico-chemical parameter for multivariate modelling of future quantitative structure-activity and structure-property relationships (QSARs/QSPRs).

Ultraviolet absorption spectra of all 209 polychlorinated biphenyls evaluated by principal component analysis

The ultraviolet absorption spectra of all 209 polychlorinated biphenyls (PCBs) were recorded in the range 200–300 nm and displayed two important absorption maxima, viz., the main-band, λmax 200–225 nm, and the κ-band, λmax 245–265 nm. By utilising principal component analysis, substitution related spectral characteristics of the PCBs, underlying the main patterns of the spectra, were examined. Captured in the multivariate evaluation were e.g., the importance of chlorine atoms in ortho positions, determining the intensity and existence of the κ-band, chlorine substitution in para-para position, and the total number of chlorine atoms. The measured UV-spectra of all 209 polychlorinated biphenyls provide important physico-chemical descriptors for use in future quantitative structure-activity and structure-property relationship (QSAR/QSPR) studies.

An automated HPLC separation method with two coupled columns for the analysis of PCDD/Fs, PCBs AND PACs

A new automated separation method is described for the analysis of polychlorinated dibenzo- p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polycyclic aromatic compounds (PACs) and related compounds in complex environmental matrices. This high performance liquid chromatography (HPLC) method utilises a coupled column system consisting of an amino column and a porous graphitic carbon (PGC) column and allows for elution of the columns in both directions individually and in combination. The method combines the group separating properties of the amino column with the high selectivity of the carbon column for planar aromatic compounds. The switching of the columns is made in an automated mode and the system delivers five relevant fractions ready for injection on GC/MS. These fractions contain /1/ aliphatic/monoaromatic compounds, /2/ polycyclic aromatic compounds, /3/ PCBs with 2 or more chlorine atoms in ortho position (di-tetra-ortho PCBs), /4/ PCBs with one chlorine atom in ortho position (mono-ortho PCBs) and /5/ non-ortho PCBs and PCDD/Fs. The HPLC separation method presented reduces the time for analysis and improves the reproducibility.