Anti-Staphylococcal Activity of the Auranofin Analogue Bearing Acetylcysteine in Place of the Thiosugar: An Experimental and Theoretical Investigation

Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt₃]⁺. Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against Staphylococcus aureus, whereas it is about 20 times less effective against Staphylococcus epidermidis. Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt₃]⁺ fragment. Additionally, AF-AcCys appeared capable of binding the dodecapeptide Ac-SGGDILQSGCUG-NH₂, corresponding to the tryptic C-terminal fragment (488–499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au–S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply.     

Comparison of analytical methods for the quality control of a new formulation containing soy extract and melatonin

Three analytical methods have been developed and compared for the quality control of a new formulation (Soymen GN(R) capsules) containing soy extract and melatonin for the treatment of menopausal symptoms. The first method is based on MEKC with diode-array detection, using a mixture of basic carbonate buffer (95%) and methanol (5%), containing 55 mM SDS, as the BGE. The second method is an HPLC method with UV detection at 260 nm. The third method is an HPLC method coupled to amperometric detection which is carried out at an oxidation potential of +0.8 V. In both HPLC systems, the chromatographic separation is obtained on an RP C18 column using a mixture of ACN and an acidic phosphate buffer (25:75 v/v) as the mobile phase. A feasible pretreatment procedure with a methanol/water mixture has been implemented to achieve the quantitative extraction of the main soy isoflavones and of melatonin from the capsules. The results obtained with the three methods are in good agreement with each other and satisfactory in terms of linearity (r(2) >0.9996), precision (RSD <5.4%) and accuracy (recovery >97%). Thus, each of the three analytical methods seems to be suitable for the simultaneous analysis of the main soy isoflavones and melatonin in the new commercial formulation.     

Time-dependent observables and diabatic curve crossing: a model study

We study the diabatic crossing of two electronic surfaces from the time-dependent point of view, looking at the time and frequency-resolved spontaneous emission spectra and to the total population of the excited state, which for a pump and-probe experiment with two δ-like pulses, is proportional to the total emission. The results of some computations on a model case are presented and discussed.     

Cascade Mi (i = 1–5) subshell X‐ray emission at incident photon energies across the Lj (j = 1–3) subshell absorption edges of 66Dy

The total M shell and the M_k (k = ξ, αβ, γ, m) X‐ray production cross sections for ₆₆Dy have been measured at incident photon energies across its L_j (j = 1–3) subshell absorption edge energies, ranging 7.8–9.2 keV. This study aims to investigate the evolution of the probability for cascade decay of L_j subshell vacancies as the tunable incident energy ionizes progressively different ₆₆Dy L_j subshells. The experimental X‐ray production cross sections have been compared with theoretical ones calculated using the nonrelativistic Hartree–Fock–Slater (HFS) model‐based photoionization cross sections; three sets of the X‐ray emission rates, fluorescence and Coster–Kronig yield based on the nonrelativistic Hartree–Slater (NRHS) model, Dirac–Hartree–Slater (DHS) model and Dirac–Fock (DF) model; the L_j (j = 1–3) subshell to the M_i (i = 1–5) subshell vacancy transfer probabilities evaluated in the present work. Presently measured total M shell and the M_αβ X‐ray production cross sections are found to be significantly lower than the theoretical ones evaluated using physical parameters based on the relativistic Dirac–Fock/Dirac–Hartree–Slater model calculations, whereas a much better agreement is observed with respect to the NRHS model‐based calculations; however, the measured X‐ray production cross sections are still systematically lower than the NRHS values.     

Multiple periodic solutions of scalar second order differential equations

We prove multiplicity of periodic solutions for a scalar second order differential equation with an asymmetric nonlinearity, thus generalizing previous results by Lazer and McKenna (1987) [1] and Del Pino, Manasevich and Murua (1992) [2]. The main improvement lies in the fact that we do not require any differentiability condition on the nonlinearity. The proof is based on the use of the Poincaré-Birkhoff Fixed Point Theorem.     

A semi-analytical finite element formulation for modeling stress wave propagation in axisymmetric damped waveguides

A semi-analytical finite element (SAFE) method is presented for analyzing the wave propagation in viscoelastic axisymmetric waveguides. The approach extends a recent study presented by the authors, in which the general SAFE method was extended to account for material damping. The formulation presented in this paper uses the cylindrical coordinates to reduce the finite element discretization over the waveguide cross-section to a mono-dimensional mesh. The algorithm is validated by comparing the dispersion results with viscoelastic cases for which a Superposition of Partial Bulk Waves solution is known. The formulation accurately predicts dispersion properties and does not show any missing root. Applications to viscoelastic axisymmetric waveguides with varying mechanical and geometrical properties are presented.     

Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp3)−H Activation Strategy

This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (−)-epicoccin G and (−)-rostratin A using a double C(sp³)−H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8’ alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis-triflate substrate. This bis-triflate served as the functional handles for the key transformation of the synthesis: a double C(sp³)−H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (−)-epicoccin G and to the more challenging (−)-rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (−)-epicoccin G and (−)-rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue.     

Retracted: The Manganese(I)-Catalyzed Asymmetric Transfer Hydrogenation of Ketones: Disclosing the Macrocylic Privilege

The bis(carbonyl) manganese(I) complex [Mn(CO)₂( 1 )]Br ( 2 ) with a chiral (NH)₂P₂ macrocyclic ligand ( 1 ) catalyzes the asymmetric transfer hydrogenation of polar double bonds with 2-propanol as the hydrogen source. Ketones (43 substrates) are reduced to alcohols in high yields (up to >99 %) and with excellent enantioselectivities (90–99 % ee). A stereochemical model based on attractive CH–π interactions is proposed.     

Product measures and convergence theorems for product integrals in integration theory for semigroup valued functions

In [11] Sion has investigated measures and integrals having values in uniform semigroups. In this paper a result which gives sufficient conditions for the existence of a unique product of semigroup valued measures is established. Moreover a convergence theorem for product integrals of semigroup valued functions is proved.