New designs for inhibitors of the NF-κB: DNA binding

We present a series of new inhibitors of the association between nuclear factor kappa B (NF-B) and the corresponding B site in DNA. They were designed using the lead compound 15-deoxy-^12,14 -prostaglandin J₂ (PGJ2), which is a natural product with demonstrated inhibitory efficiency for this system. First, the binding mode of PGJ2 to NF-B was unraveled by GOLD docking calculation. Subsequently, substitutions were made to PGJ2 to optimize its association with NF-B. Care was taken not to strongly increase the reactivity of the new compounds, and to keep the overall shape, size and hydrophilicity of the lead compound, which should render them a similar bioavailability. Molecular mechanics calculations were performed to decide on the suitability of the substitutions, and to evaluate the energies of association with NF-B. Density functional theory calculations were performed also to study the overall reactivity of the substituted drugs towards NF-B. Important general conclusions were obtained, concerning the improvement of these natural inhibitors; namely, a set of rational methodologies were deduced to improve the association between the PGJ2 derivatives and NF-B, and their efficiency demonstrated by generating a set of substituted complexes, some of them with a very much increased affinity for NF-B, opening new doors to enlarge the therapeutic capabilities of this class of drugs.     

Ion pairing, H-bonding, and π–π interactions in copper(II) complex-organo-networks derived from a proton-transfer compound of the 1,10-phenanthroline-2,9-dicarboxylic acid

The one-pot reaction between the novel proton transfer compound (pydaH₂)²⁺(phendc)²⁻, LH₂, and Cu(II) afforded the compounds (pydaH)₂[Cu(phendc)₂]·10H₂O, 1, and (pydaH)₂[Cu(phendc)(phendcH)]₂·5H₂O, 2, where pyda=2,6-diaminopyridine, and phendcH₂=1,10-phenanthroline-2,9-dicarboxylic acid. The single crystal X-ray diffraction analysis of 1 and 2 revealed that these are two novel self-assembled 3D Cu(II) complex-organo-networks, in which (pydaH)⁺ ions and [Cu(phendc)₂]²⁻ or complex units are held together by ion pairing, H-bonding, and π–π interactions. Magnetic measurements over the temperature range 1.8–310 K revealed no significant magnetic coupling between Cu(II) centers in 1 or 2.     

The state of conservation of painted surfaces in the presence of accelerated ageing processes monitored by use of FT-Raman spectroscopy and multivariate control charts

A new method has been developed for monitoring the degradation of paintings. Two inorganic pigments (ultramarine blue and red ochre) were blended with linseed oil and spread on canvas. Each canvas was subjected to simulated accelerated ageing in the presence of typical degradation agents (UV radiation and acidic solution). Periodically the painted surfaces were analysed by FT-Raman, to investigate the status of the surface. The data obtained were analysed by principal component analysis (PCA). Finally the Shewhart and cumulative sum control charts based on the relevant principal components (PC) and the so called scores monitoring and residuals tracking (SMART) charts were built. The method based on the use of PC to describe the process was found to enable identification of the presence of relevant modification occurring on the surface of the samples studied.Electronic supplementary material Supplementary material is available for this article at     

On the cycle index of point groups

In this brief work we express the cycle index of the molecular point groups as a function of a limited number of initial geometrical parameters. Such parameters are the number of elements composing the domain D of sites of substitutions in the molecule belonging to the point group G, and the numbers of sites of D lying on the symmetry elements for G.     

Do charge-remote fragmentations occur under matrix-assisted laser desorption ionization post-source decompositions and matrix-assisted laser desorption ionization collisionally activated decompositions?

The precursor ions of tetraphenylporphyrins that are substituted with fatty acids can be introduced into the gas phase by matrix-assisted laser desorption ionization (MALDI) and undergo post-source and collisionally activated decompositions (CAD) in a time-of-flight mass spectrometer. The goal of the research is to obtain a better understanding of post-source decompositions (PSD); specifically, we asked the question of whether ions undergoing PSD have sufficient energy to give charge-remote fragmentations along an alkyl chain. We chose the porphyrin macrocycle because we expected it to act as an inert "support," allowing the molecule to be desorbed by MALDI and to be amenable to charge-remote fragmentation. MALDI-PSD and MALDI-CAD spectra are similar to high-energy CAD spectra and considerably more informative than low-energy CAD spectra, showing that charge-remote fragmentations of the fatty acid moieties do occur upon MALDI-PSD and MALDI-CAD.     

Nucleotide Analogues Bearing a C2′ or C3′-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors

The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2′ or C3′ is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2′ was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.     

Enhanced resolution of Mentha piperita volatile fraction using a novel medium‐polarity ionic liquid gas chromatography stationary phase

The evaluation of a novel medium‐polarity ionic‐liquid‐based gas chromatography column, SLB‐IL60, towards the analysis of a complex essential oil, namely, a peppermint essential oil sample, is reported. The SLB‐IL60 30 m column was subjected to bleeding measurements, by means of conventional gas chromatography with mass spectrometry. The SLB‐IL60 column was then evaluated in the analysis of pure standard compounds, chosen as typical constituents of peppermint essential oil. Resolution and peak symmetry (expressed as tailing factors at 10% of peak height) were measured and the results were compared to those obtained on the most widely used columns in such an application, namely a medium‐polarity [100% poly(ethyleneglycol)] stationary phase, and an apolar 5% diphenyl/95% dimethyl siloxane. The final part of the evaluation was dedicated to the gas chromatography with mass spectrometry analysis of a peppermint essential oil sample and again the data were compared to those obtained on the 100% poly(ethyleneglycol) and the 5% diphenyl/95% dimethyl siloxane phase. Linear retention indices were determined for all the identified components on the ionic liquid capillary.     

The photophysical determination of the minimum hydrotrope concentration of aromatic hydrotropes

A method based on the aggregate to monomol emission ratio, I(aggr)/I(monomol), was used to determine the minimal hydrotropic concentration (MHC) of aromatic hydrotropes. The main advantage of this method is that it does not require the use of probes or other additives, which might disrupt the aggregation process. Also, it relies on spectrophotometric measurements, which are more sensitive and less arduous than others, like conductivity, light scattering and surface tension.     

Evidence for the intermediacy of Wheland-Meisenheimer complexes in SEAr reactions of aminothiazoles with 4,6-dinitrobenzofuroxan

Reactions of DNBF with a series of 2-aminothiazoles (1 a-f) to afford thermodynamically stable C-bonded sigma-adducts have been investigated in acetonitrile. A most significant finding emerged on recording NMR spectra immediately after mixing of equimolar amounts of DNBF and the unsubstituted 2-aminothiazole (1 a) in Me2SO: namely, that the formation of 9 a is preceded by that of a short-lived intermediate species X. From the 1H NMR parameters characterizing this intermediate, as well as the dependence of its lifetime on the experimental conditions-the presence of excess DNBF over 1 a increases the lifetime of X while an excess of base (1 a) accelerates its conversion into 9 a--it is convincingly demonstrated that the structure of X combines the presence of a positively charged Wheland complex moiety (with regard to the thiazole ring) with that of a negatively charged Meisenheimer complex moiety (with regard to the benzofuroxan system). So far, only one intermediate of this type (noted WM) has been successfully characterized, in the reactions of DNBF with 1,3,5-tris(N,N-dialkylamino)benzenes. Among the key features supporting the intermediacy of X along the reaction coordinate leading to 9 a is the fact that the reactions of DNBF with 1 a in the presence of an alcohol (MeOH, EtOH, nPrOH) produce new adducts arising from the addition of an alcohol molecule to the thiazole moiety of WM-1 a. Reflecting the presence of three chiral centres, these species are formed as mixtures of several diastereomers that could all be characterized in their racemic forms in ethanol. These findings generalize the previous report on the formation of Wheland-Meisenheimer carbon-carbon complexes in homocyclic series.     

One-electron reduction of methanesulfonyl chloride. The fate of MeSO2Cl(.)(-) and MeSO2(.) intermediates in oxygenated solutions and their role in the cis-trans isomerization of mono-unsaturated fatty acids

The one-electron reduction of methanesulfonyl chloride (MeSO2Cl) leads, in the first instance, to an electron adduct MeSO2Cl(.)(-) which lives long enough for direct detection and decays into sulfonyl radicals MeSO2(.) and Cl(-), with k = 1.5 x 10(6) s(-1). Both, MeSO2Cl(.)(-) and MeSO2(.) showed a similar absorption in the UV with lambdamax of 320 nm. In the presence of oxygen, MeSO2Cl(.)(-) transfers an electron to O(2) and establishes an equilibrium with superoxide. The rate constant for the forward reaction was measured to 4.1 x 10(9) M(-1) s(-1), while for the back reaction only an interval of 1.7 x 10(5) to 1.7 x 10(6) M(-1) s(-1) could be estimated, with a somewhat higher degree of confidence for the lower value. This corresponds to an equilibrium constant in the range of 2.4 x 10(3) to 2.4 x 10(4). With reference to E degrees (O2/O2(.)(-)) = -155 mV, the redox potential of the sulfonyl chloride couple, E degrees (MeSO2Cl/MeSO2Cl(.)(-)), thus results between being equal to -355 and -414 mV (vs NHE). MeSO2Cl(.)(-) reduces (besides O2) 4-nitroacetophenone. The underlying electron transfer took place with k = 1.5 x 10(9) M(-1) s(-1), corroborating an E degrees for the sulfonyl chloride couple significantly exceeding the above listed lower value. The MeSO2(.) radical added to oxygen with a rate constant of 1.1 x 10(9) M(-1) s(-1). Re-dissociation of O2 from MeSO2OO(.) occurred only very slowly, if at all, that is, with k < 10(5) s(-1). MeSO2(.) radicals can act as the catalyst for the cis-trans isomerization of several Z- and E-mono-unsaturated fatty acid methyl esters in homogeneous solution. The effectiveness of the isomerization processes has been addressed, and in the presence of oxygen the isomerization is completely suppressed.