Can simple enones be useful partners for the catalytic stereoselective alkylation of indoles?

A new catalytic system for the first example of enantioselective Friedel-Crafts-type (FC) addition of indoles to simple enones is described. The use of an equimolar amount of chiral [Al(salen)Cl] and 2,6-lutidine (10 mol %) was found to be effective in promoting the conjugate addition of indoles to (E)-arylcrotyl ketones, furnishing the corresponding beta-indolyl ketones in excellent yield and high enantioselectivity (ee up to 89%). The role of the base was investigated through spectroscopic as well as computational analyses, which suggested that in situ formation of a new chiral (base.[Al(salen)]) complex was operating under our reaction conditions. In particular, a stable cationic [Al(salen)] hexacoordinate trans complex with the additive base and the enone is suggested as being responsible for the stereocontrolled reaction. Finally, detailed monitoring of the reaction course was carried out showing that a conventional FC pathway induced by [Al(salen)Cl] acting as a Lewis acid is operating.     

Lacidipine,a potential peroxynitrite scavenger: investigation of activity by liquid chromatography and mass spectrometry

Inflamed tissues are often characterised by the production of *NO and O(2)(-) radicals, which are known to react at an extremely fast rate to produce peroxynitrite (ONOO(-)). This highly oxidising entity reacts with protein-bound tyrosine to give 3-nitrotyrosine, which is considered a biochemical marker of peroxynitrite-induced damage. Lacidipine is a calcium antagonist indicated for the treatment of mild to moderate hypertension. In the present work, electrospray mass spectrometry with and without liquid chromatography was used to evaluate the capability of lacidipine and two other related molecules as ONOO(-) scavengers. This capability is compared with that associated with a number of commercial polyphenols described in the literature as efficient scavengers of this cytotoxic agent. The use of mass spectrometry provided rapid quantitative assessment of both the nitration and its reduction, and showed that lacidipine possesses a reasonable capability for reducing in vitro nitration of superoxide dismutase.     

Axially Dissymmetric Diphosphines in the Biphenyl Series: Synthesis of (6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)(‘MeO-BIPHEP’) and Analogues via an ortho-Lithiation/Iodination Ullmann-Reaction Approach

The new axially dissymmetric diphosphines (R)- and (S)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(diphenyl phosphine) ((R)- and (S)- 5a ; ‘MeO-BIPHEP’) and the analogues (R)- and (S)- 5b and 5c have been synthesized in enantiomerically pure form. These ligands have become readily available by a synthetic scheme which employs, as key steps, an ortho-lithiation/iodination reaction of the (m-methoxyphenyl)diprienylphosphine oxides 8 and a subsequent Ullmann reaction of the resulting iodides 9 to provide the racemic bis(phosphine oxides) 10 . The bis(phosphine oxides) 10 subsequently are resolved with (?)-(2R,3R)- and (+)-(2S,3S)-O-2,3-dibenzoyltartaric acid and reduced to diphosphines 5 . The Ullmann reaction constitutes a new and efficient route to 2,2′-bis(phosphinoyl)-substituted biphenyl systems. Absolute configurations were established for (R)- 5a by X-ray analysis of the derived Pd complex (R,R)- 17a , and for 5b and 5c by means of ¹H-NMR comparisons of the derived Pd complexes 16 or 17 , respectively, and by means of CD comparisons. The MeO-BIPHEP diphosphine 5a proved to be as efficient as the previously described BIPHEMP diphosphine ((6,6′-dimethylbiphenyl-2,2′-diyl)bis(diphenylphosphine)) in enantioselective isomerizations and hydrogenations.     

New insight into the oxidative chemistry of noradrenaline: competitive o-quinone cyclisation and chain fission routes leading to an unusual 4-[bis-(1H-5,6-dihydroxyindol-2-yl)methyl]-1,2-dihydroxybenzene derivative

Oxidation of 5×10⁻³ M noradrenaline in aqueous phosphate buffer, pH 7.4, with K₃Fe(CN)₆, NaIO₄ or Fe²⁺/EDTA/H₂O₂ followed by extraction with ethyl acetate and acetylation with Ac₂O/Pyr led to a main reaction product which was isolated and identified as 4-[bis-(1H-5,6-diacetoxyindol-2-yl)methyl]-1,2-diacetoxybenzene, an unprecedented [bis-(indol-2-yl)methyl]-benzene derivative unsubstituted on the 3-position of the indole rings. This product was also obtained in 40% yield by reaction of 5,6-dihydroxyindole with 3,4-dihydroxybenzaldehyde. Other components of the oxidation mixture were 1-acetyl-3,5,6-triacetoxyindole, derived from noradrenolutin, and 5,6-diacetoxyindole, originating from cyclisation/dehydration of the o-quinone of noradrenaline, along with some 3,4-diacetoxybenzaldehyde. Inspection of the aqueous phase revealed the presence of 3,4-dihydroxymandelic acid and 3,4-dihydroxybenzaldehyde, derived from oxidative breakdown of the 2-amino-1-hydroxyethyl chain via a p-quinomethane intermediate. These results disclose new aspects of the oxidative chemistry of noradrenaline beyond the aminochrome stage and provide a route to novel [bis-(indol-2-yl)methyl]-benzene derivatives of potential pharmacological interest.     

Influence of the 4,6-O-benzylidene, 4,6-O-phenylboronate, and 4,6-O-polystyrylboronate protecting groups on the stereochemical outcome of thioglycoside-based glycosylations mediated by 1-benzenesulfinyl piperidine/triflic anhydride and N-iodosuccinimide/trimethylsilyl triflate

The effect of 4,6-O-benzylidene acetals, 4,6-O-phenylboronate esters, and 4,6-O-polystyrylboronate esters on the stereoselectivity of couplings to galacto-, gluco-, and mannopyranosyl thioglycosides, otherwise protected with benzyl ethers, has been investigated by the benzenesulfinyl piperidine/trifluoromethanesulfonic anhydride (BSP), diphenyl sulfoxide/trifluoromethanesulfonic anhydride (Ph(2)SO), and N-iodosuccinimide/trimethylsilyl trifluoromethanesulfonate (NIS/TMSOTf) methods. The BSP and Ph(2)SO methods give comparable results in all three systems whereas the NIS method affords significantly different stereoselectivities in both the gluco and manno, but not the galacto series. The benzylidene acetal and boronate esters influence the stereochemistry in a similar manner in the beta-selective manno series and the alpha-selective galacto series but show significant differences with the glucose donors. The differences between the glucose, galactose, and mannose series reflect the established differences in reactivity and, especially for mannose, those in the anomeric effect and are best interpreted in terms of changes in the relative energetics between the alpha- and beta-covalent triflate intermediates and the various contact ion pairs with which they are necessarily in equilibrium.     

New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds

Antimicrobial resistance (AMR) poses a serious threat to our society from both the medical and economic point of view, while the antibiotic discovery pipeline has been dwindling over the last decades. Targeting non-essential bacterial pathways, such as those leading to antibiotic persistence, a bacterial bet-hedging strategy, will lead to new molecular entities displaying low selective pressure, thereby reducing the insurgence of AMR. Here, we describe a way to target (p)ppGpp (guanosine tetra- or penta-phosphate) signaling, a non-essential pathway involved in the formation of persisters, with a structure-based approach. A superfamily of enzymes called RSH (RelA/SpoT Homolog) regulates the intracellular levels of this alarmone. We virtually screened several fragment libraries against the (p)ppGpp synthetase domain of our RSH chosen model Rel_Seq, selected three main chemotypes, and measured their interaction with Rel_Seq by thermal shift assay and STD-NMR. Most of the tested fragments are selective for the synthetase domain, allowing us to select the aminobenzoic acid scaffold as a hit for lead development.     

Identification of Human Dihydroorotate Dehydrogenase Inhibitor by a Pharmacophore-Based Virtual Screening Study

Human dihydroorotate dehydrogenase (hDHODH) is an enzyme belonging to a flavin mononucleotide (FMN)-dependent family involved in de novo pyrimidine biosynthesis, a key biological pathway for highly proliferating cancer cells and pathogens. In fact, hDHODH proved to be a promising therapeutic target for the treatment of acute myelogenous leukemia, multiple myeloma, and viral and bacterial infections; therefore, the identification of novel hDHODH ligands represents a hot topic in medicinal chemistry. In this work, we reported a virtual screening study for the identification of new promising hDHODH inhibitors. A pharmacophore-based approach combined with a consensus docking analysis and molecular dynamics simulations was applied to screen a large database of commercial compounds. The whole virtual screening protocol allowed for the identification of a novel compound that is endowed with promising inhibitory activity against hDHODH and is structurally different from known ligands. These results validated the reliability of the in silico workflow and provided a valuable starting point for hit-to-lead and future lead optimization studies aimed at the development of new potent hDHODH inhibitors.     

Thermodynamic equilibrium between locally excited and charge-transfer states through thermally activated charge transfer in 1-(pyren-2′-yl)-o-carborane

Reversible conversion between excited-states plays an important role in many photophysical phenomena. Using 1-(pyren-2′-yl)-o-carborane as a model, we studied the photoinduced reversible charge-transfer (CT) process and the thermodynamic equilibrium between the locally-excited (LE) state and CT state, by combining steady state, time-resolved, and temperature-dependent fluorescence spectroscopy, fs- and ns-transient absorption, and DFT and LR-TDDFT calculations. Our results show that the energy gaps and energy barriers between the LE, CT, and a non-emissive ‘mixed’ state of 1-(pyren-2′-yl)-o-carborane are very small, and all three excited states are accessible at room temperature. The internal-conversion and reverse internal-conversion between LE and CT states are significantly faster than the radiative decay, and the two states have the same lifetimes and are in thermodynamic equilibrium.

Reversible conversion between excited-states is key to many photophysical phenomena. We studied the equilibrium between LE and CT states by time-resolved and temperature-dependent fluorescence, fs- and ns-transient absorption, and LR-TDDFT calculations.     

Anti-Inflammatory and Antinociceptive Activities of the Essential Oil of Tagetes parryi A. Gray (Asteraceae) and Verbenone

Tagetes parryi is a plant empirically used to treat gastrointestinal and inflammatory diseases, its essential oil (EOTP) was obtained from the aerial parts, and the composition was elucidated by GC-MS. The in vivo and in vitro anti-inflammatory activities and the antinociceptive activity of EOTP and (1S)-(-)-verbenone (VERB) were assessed. The major compounds identified for EOTP were verbenone (33.39%), dihydrotagetone (26.88%), and tagetone (20.8%). EOTP and VERB diminished the ear oedema induced with TPA by 93.77 % and 81.13 %, respectively. EOTP and VERB decreased inflammation in a 12-O-tetradecanoylphorbol-13-acetate (TPA) chronic model with ED₅₀ = 54.95 mg/kg and 45.24 mg/kg, respectively. EOTP (15 µg/mL) inhibited the in vitro production of the pro-inflammatory mediators NO (67.02%), TNF-α (69.21%), and IL-6 (58.44%) in LPS-stimulated macrophages. In the acetic induced writhing test, EOTP and VERB showed antinociceptive effects with ED₅₀ = 84.93 mg/kg and ED₅₀ = 45.24 mg/kg, respectively. In phase 1 of the formalin test, EOTP and VERB showed no antinociceptive effects, whereas in phase 2, EOTP (ED₅₀ = 35.45 mg/kg) and VERB (ED₅₀ = 24.84 mg/kg) showed antinociceptive effects. The antinociceptive actions of ETOP and VERB were blocked with the co-administration of L-NAME. This study suggests that EOTP and VERB might be used in the treatment of pain and inflammatory problems.     

Detection of unexploded ordnance by PGNAA based borehole-logging

The performance of a borehole-logging system, based on prompt-gamma-neutron-activation-analysis (PGNAA), for explosive detection was studied by Monte-Carlo simulations. The prompt gamma of nitrogen, which is a constituent of common explosive, was used to identify the unexploded ordnance (UXO). Our results show that the minimum counting time depends on the soil moisture, the cladding thickness and the explosive composition. In conjunction with the standard detection by magnetometry, the PGNAA is a promising analytical technique for definitive identification of deep buried UXOs.