GPCRs as therapeutic targets: a view on adenosine receptors structure and functions, and molecular modeling support

G-protein-coupled receptors (GPCRs) represent the largest known family of signal-transducing proteins and transmit signals for light and many extracellular regulatory molecules. GPCRs are dysfunctional or dysregulated in several human diseases and are estimated to be the targets of ～40% of the drugs used in clinical medicine today. Receptors for adenosine belong to this family, and so far four subtypes, the A₁, A_2A, A_2B, and A₃, have been recognized. The activation of adenosine receptors (ARs) is largely responsible for the variety of effects produced by adenosine throughout several organ systems. Based on the wide (and often beneficial) effects attributed to the accumulation of endogenously released adenosine, it has long been considered that regulation of ARs has considerable therapeutic potential. In this review, we focus on recent work on adenosine receptors as therapeutic targets and, in particular, on molecular modelling support to adenosine receptors targeting.     

Evaluation of protein 15N relaxation times by inverse Laplace transformation

Relaxation times (T1, T2, T1rho) are usually evaluated from exponential decay data by least-squares fitting methods. For this procedure, the integrals or amplitudes of signals must be determined, which can be laborious with large data sets. Moreover, the fitting requires a priori knowledge of the number of exponential components responsible for the decay. We have adapted inverse Laplace transformation (ILT) for the analysis of relaxation data. Exponential components are resolved with ILT to reciprocal space on their corresponding relaxation rate values. The ILT approach was applied to 3D linewidth-resolved 15N HSQC experiments to evaluate 15N T1 and T2 relaxation times of ubiquitin. The resulting spectrum is a true 3D spectrum, where the signals are separated by their 1H and 15N chemical shifts (HSQC correlations) and by their relaxation rate values (R1 or R2). From this spectrum, the relaxation times can be obtained directly with a simple peak-picking procedure.     

Synthese en serie encombree. preparation de l'acide ditertiobutyl-methylacetique-tBu2 MeCCOOH et de quelques composes cetoniques derives de cette structure

The synthesis of ^tBU₂MeCCOOH, which is among the most sterically hindered known acjds is described. Only Newman's sequence via ^tBU₂CO, ^tBu₂MeCOH, ^tBu₂CCH₂, _tBu₂CHCH₂OH, ^tBu₂CHCOOH, ^tBU₂CHCOCI and ^tBu₂CCO, which has been optimized in this work by a direct access to ^tBu₂CHCOOH, permits the preparation of ^tBu₂MeCCOOH. The condensation of the corresponding chloride with a Grignard reagent yields new highly-hindered ketones ^tBu₂MeCCOR which by alkylation give more substituted structures. The limitations of each method have been studied in this work.     

DDQ induced oxidative cyclisations of 1,2-dihydronaptho[2,1-b]furans

The DDQ mediated oxidative cyclisation reactions of a series of dihydronaptho[2,1-b]furans were examined. In the presence of an acid catalyst, the reaction yielded polycyclic ethers and lactones in good to excellent yields.     

Modulation of Aggregation‐Induced Emission and Electroluminescence of Silole Derivatives by a Covalent Bonding Pattern

The deciphering of structure–property relationships is of high importance to rational design of functional molecules and to explore their potential applications. In this work, a series of silole derivatives substituted with benzo[b]thiophene (BT) at the 2,5‐positions of the silole ring are synthesized and characterized. The experimental investigation reveals that the covalent bonding through the 2‐position of BT (2‐BT) with silole ring allows a better conjugation of the backbone than that achieved though the 5‐position of BT (5‐BT), and results in totally different emission behaviors. The silole derivatives with 5‐BT groups are weakly fluorescent in solutions, but are induced to emit intensely in aggregates, presenting excellent aggregation‐induced emission (AIE) characteristics. Those with 2‐BT groups can fluoresce more strongly in solutions, but no obvious emission enhancements are found in aggregates, suggesting they are not AIE‐active. Theoretical calculations disclose that the good conjugation lowers the rotational motions of BT groups, which enables the molecules to emit more efficiently in solutions. But the well‐conjugated planar backbone is prone to form strong intermoelcular interactions in aggregates, which decreases the emission efficiency. Non‐doped organic light‐emitting diodes (OLEDs) are fabricated by using these siloles as emitters. AIE‐active silole derivatives show much better elecroluminescence properties than those without the AIE characterisic, demonstrating the advantage of AIE‐active emitters in OLED applications.     

The Synthesis and Characterization of a New Layered Chlorozincophosphate Zn(HPO4)Cl[C4H10N]

Along a systematic study of open-framework materials aiming at producing new molecular sieves, we characterized a new zincophosphate Zn(HPO₄)Cl[C₄H₁₀N]. It was synthesized under mild conditions (r.t.) in the presence of pyrrolidinium as an organic-structure directing agent. The structure of this compound, determinated by single crystal X-ray diffraction, consists of anionic parallel [Zn(HPO₄)Cl]^? sheets alternating with thick slabs of organic molecules (C₄H₁₀N)⁺. These latters are linked to the anionic sheets through hydrogen bonds. Zn(HPO₄)Cl[C₄H₁₀N] crystallizes in the monoclinic system and the space group C2/c (No. 9) with cell parameters a = 24,83(9), b = 9,258(5), c = 8.778(3), β = 110,45(4), Z = 8, V = 1891.0(14) Åt³, R = 0.045, and R_w = 0.07. Solid state ³¹P and ¹³C MAS NMR spectroscopies are in agreement with the X-ray structure.     

Antioxidative and DNA Protective Effects of Bacillomycin D-Like Lipopeptides Produced by B38 Strain

In the present study, we evaluated the antioxidant and the scavenging ability of C14, C15 and C16 bacillomycin D-like lipopeptides produced by B38 strain. They all displayed strong reducing power activity, hydroxyl and superoxide anion radicals scavenging activities and inhibition of lipid peroxidation. In addition, they were found to protect plasmid DNA damage from hydroxyl radical oxidation. Data suggested that their antioxidant potency can be attributed to the hydrophobic and aromatic side-chain groups of their amino acids as well as to the aliphatic chain of their beta amino fatty acids. Note that the hydrocarbon chain length did not interfere with the antioxidant power. Overall, such bacillomycin D lipopeptides which exhibit antioxidant and radical scavenging activities may be useful for cosmetic, therapeutic or pharmaceutical purposes in order to delay or prevent oxidative deterioration of manufactured products.     

Ion sensing film optodes based on chromogenic calix[4]arene: application to the detection of Hg2+, Ni2+ and Eu3+ ions

The development of sensors for the detection of transition metal ions has attracted a special attention because of the toxic impact of these elements on our environment. Due to their sensitivity, reliable, inexpensive and easy use for on site analysis, optical chemical sensors (optodes) have received an increasing attention for a rapid determination of toxic species in water. A new chromogenic calix[4]arene has been investigated on the basis of the high recognition properties of calixarenes associated to the optical response provided by their functionalization with a phenyl azo group. Thin tetrakis-(phenylazo) calix[4]arene amide derivative layers deposited on a glass suprasil substrate have been characterized by contact angle measurements showing a good surface coverage whereas a uniform morphology of the calixarene membrane in acetonitrile solvent was observed by scanning electron microscopy (SEM). The ability of the tetrakis-(phenylazo) calix[4]arene amide derivative thin film to complex Hg²⁺, Ni²⁺ and Eu³⁺ ions have been demonstrated by the modification of the calixarenes main absorption band at 343?nm and appearance of a new absorption band at 500?nm upon addition of Eu³⁺. The different sensors could be regenerated with hydrochloric acid. The dynamic concentration range, ion selectivity, response time, repeatability and reproducibility are discussed. These results are suitable to the development of optodes for the detection of metal pollutants.