In-line coupling of a reversed-phase column to cope with limited chemoselectivity of a quinine carbamate-based anion-exchange type chiral stationary phase

A chiral stationary phase based on tert-butylcarbamoyl quinine has shown remarkable enantiomer separation capability for the thyroid hormone thyroxine (T(4)) and its structural analogue triiodothyronine (T(3)) employing hydroorganic buffered mobile phases (typical RP conditions). To overcome the problem of a somehow limited chemoselectivity for the critical peak pair between adjacent L-thyroxine (L-T(4)) and D-thyroxine (D-T(4)) peaks on the chiral anion-exchanger CSP when all four compounds need to be analysed simultaneously like in impurity profiling of L-T(4 )drug products, an RP column (Gemini C18) was serially coupled with the chiral anion-exchanger column to add a hydrophobic selectivity increment and to improve thereby the critical resolution between L-T(3) and D-T(4). Various parameters such as organic modifier content, pH, buffer concentration and type, type of achiral column as well as sequence of achiral and chiral column have been investigated with individual and tandem columns. With the optimized conditions and use of the tandem column a significantly improved separation, as compared to the chiral anion-exchanger column alone, with a critical resolution as high as 3.7 and an almost equal band spacing of the four components of the test mixture could be obtained. The sequence of the columns (achiral-chiral or chiral-achiral) had no significant effect on the separation performance.     

Synthesis of Ni(OH)<Subscript>2</Subscript> in micellar environment: structural,spectroscopic, and electrochemical studies

This work describes the chemical synthesis of nickel hydroxide in the presence of cationic and anionic surfactants (dodecyl benzene sulfonate, DBS^?, and cetyltrimethylammonium, CTA⁺). The materials were characterized by X-ray diffraction, infrared spectroscopy, and thermogravimetric analysis. Our findings highlighted that the synthesis in the presence of anionic DBS^?, the α-Ni(OH)₂ structure was preferentially formed. This material showed a high structural disorder and a high amount of intercalated species, suggesting the presence of both micelles and individual surfactants. On the other hand, the synthesis performed in the presence of CTA⁺ has not showed any drastic change in the material structure compared with pure Ni(OH)₂; nevertheless, the intercalated cationic surfactant was identified by FTIR measurements. The enhanced electrochemical response found for the Ni(OH)₂/DBS^? over the Ni(OH)₂/CTA⁺ modified electrodes can be attributed to the enhancement of the ionic diffusion through the solid material as an effect of the high structural disorder and the presence of the excess of the negative electric charge in the Ni(OH)₂ sheets.     

Theoretical interpretation of X-rays photo-absorption in medium-Z elements plasmas measured at LULI2000 facility

We analyzed the spectra of X-ray transmission through radiatively heated medium-Z plasma (Fe, Ni, Cu and Ge) measured at LULI2000 facility in the wavelength range of 2p–nd transitions. The analysis was performed using the statistical superconfiguration code SCO, two line-by-line opacity codes based on the HULLAC and FAC packages and a new hybrid statistical-detailed code SCORCG. The temperature and mass density of the samples were estimated from hydrodynamic simulations based on the cavity radiative temperature measurements. The theory–experiment agreement is relatively good in the wavelength range corresponding to the 2p–3d transitions except in the germanium case. In the wavelength range of the 2p–2d, n > 3 transitions a relatively good theory–experiment agreement was found in the copper case. As predicted by calculations the separation of the characteristic spin-orbit-split 2p–3d structures, absent in the iron measured spectrum, appears in the nickel spectrum and is visible in the copper and germanium spectra. Comparisons of the experimental transmission with calculations confirm the importance of the relativistic configuration interaction. The absorption strength of the measured germanium 2p–3d transition is much larger than that obtained from the codes. Spatial temperature and density gradients, relatively high in the germanium sample, may be at the origin of this discrepancy.     

Development and validation of two methods based on high-performance liquid chromatography-tandem mass spectrometry for determining 1,2-benzopyrone, dihydrocoumarin, o-coumaric acid, syringaldehyde and kaurenoic acid in guaco extracts and pharmaceutical preparations

In this study, two HPLC-ESI-MS/MS methods were developed and validated for the determination of 1,2-benzopyrone (COU), o-coumaric acid (OCA), kaurenoic acid (KAU), syringaldehyde (SYR), and dihydrocoumarin (DIH) in guaco extracts and pharmaceutical preparations (syrup and oral solution). The chromatographic separation was achieved using a C18 XBridge 150×2.1-mm (5-μm particle size) column maintained at 25°C. The mobile phases consisted of a gradient of water and acetonitrile containing 0.05% formic acid or 5 mM ammonium formate for the positive and negative ion modes, respectively. All of the calibration curves showed excellent coefficients of correlation (r≥0.9970) over the ranges of 1.25-400 ng/mL for coumarin, 10-600 ng/mL for dihydrocoumarin, 5-250 ng/mL for KAU, and 25-500 ng/mL for o-coumaric acid and syringaldehyde. The range of recovery was 96.3-103% with an RSD% of <4.85% for intraday and interday precision. The results indicate that the developed methods are fast, efficient, and sensitive for the quantification of the guaco metabolites in extracts and pharmaceutical forms while avoiding purification and derivatization steps.     

Discovery of New Hits as Antitrypanosomal Agents by In Silico and In Vitro Assays Using Neolignan-Inspired Natural Products from Nectandra leucantha

In the present study, the phytochemical study of the n-hexane extract from flowers of Nectandra leucantha (Lauraceae) afforded six known neolignans (1–6) as well as one new metabolite (7), which were characterized by analysis of NMR, IR, UV, and ESI-HRMS data. The new compound 7 exhibited potent activity against the clinically relevant intracellular forms of T. cruzi (amastigotes), with an IC₅₀ value of 4.3 μM and no observed mammalian cytotoxicity in fibroblasts (CC₅₀ > 200 μM). Based on the results obtained and our previous antitrypanosomal data of 50 natural and semi-synthetic related neolignans, 2D and 3D molecular modeling techniques were employed to help the design of new neolignan-based compounds with higher activity. The results obtained from the models were important to understand the main structural features related to the biological response of the neolignans and to aid in the design of new neolignan-based compounds with better biological activity. Therefore, the results acquired from phytochemical, biological, and in silico studies showed that the integration of experimental and computational techniques consists of a powerful tool for the discovery of new prototypes for development of new drugs to treat CD.     

A Double-ended Queue with Catastrophes and Repairs, and a Jump-diffusion Approximation

Consider a system performing a continuous-time random walk on the integers, subject to catastrophes occurring at constant rate, and followed by exponentially-distributed repair times. After any repair the system starts anew from state zero. We study both the transient and steady-state probability laws of the stochastic process that describes the state of the system. We then derive a heavy-traffic approximation to the model that yields a jump-diffusion process. The latter is equivalent to a Wiener process subject to randomly occurring jumps, whose probability law is obtained. The goodness of the approximation is finally discussed.     

Synthesis and chromatographic resolution of conformationally constrained analogues of homotaurine

The first series of conformationally constrained analogues of homotaurine is reported. The partial constriction of the skeleton was realized through the insertion of a cyclopropyl ring, between the α,β- and β,γ-positions, thus affording, respectively, trans- and cis-2-aminomethylcyclopropane-1-sulfonic acids and trans- and cis-(2-aminocyclopropyl)methanesulfonic acids. The resolution of all four racemic mixtures was accomplished using HPLC system carrying the polysaccharide-based Chiralpak^® IB^® column as the chiral stationary phase. The coupling with an ‘Evaporative Light Scattering Detector (ELSD)’ has been particularly valuable during the chromatographic study.     

Interaction Study between ESIPT Fluorescent Lipophile-Based Benzazoles and BSA

In this study, the interactions of ESIPT fluorescent lipophile-based benzazoles with bovine serum albumin (BSA) were studied and their binding affinity was evaluated. In phosphate-buffered saline (PBS) solution these compounds produce absorption maxima in the UV region and a main fluorescence emission with a large Stokes shift in the blue–green regions due to a proton transfer process in the excited state. The interactions of the benzazoles with BSA were studied using UV-Vis absorption and steady-state fluorescence spectroscopy. The observed spectral quenching of BSA indicates that these compounds could bind to BSA through a strong binding affinity afforded by a static quenching mechanism (K_q~10¹² L·mol⁻¹·s⁻¹). The docking simulations indicate that compounds 13 and 16 bind closely to Trp134 in domain I, adopting similar binding poses and interactions. On the other hand, compounds 12, 14, 15, and 17 were bound between domains I and III and did not directly interact with Trp134.     

Antileishmanial Effects of Acetylene Acetogenins from Seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae) and Semisynthetic Derivatives

As part of our continuous studies involving the prospection of natural products from Brazilian flora aiming at the discovery of prototypes for the development of new antiparasitic drugs, the present study describes the isolation of two natural acetylene acetogenins, (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11′-yn-19′-enyl)butanolide (1) and (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11′-ynyl)butanolide (2), from the seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae). Using an ex-vivo assay, compound 1 showed an IC₅₀ value of 29.9 μM against the intracellular amastigote forms of Leishmania (L.) infantum, whereas compound 2 was inactive. These results suggested that the terminal double bond plays an important role in the activity. This effect was also observed for the semisynthetic acetylated (1a and 2a) and eliminated (1b and 2b) derivatives, since only compounds containing a double bond at C-19 displayed activity, resulting in IC₅₀ values of 43.3 μM (1a) and 23.1 μM (1b). In order to evaluate the effect of the triple bond in the antileishmanial potential, the mixture of compounds 1 + 2 was subjected to catalytic hydrogenation to afford a compound 3 containing a saturated side chain. The antiparasitic assays performed with compound 3, acetylated (3a), and eliminated (3b) derivatives confirmed the lack of activity. Furthermore, an in-silico study using the SwissADME online platform was performed to bioactive compounds 1, 1a, and 1b in order to investigate their physicochemical parameters, pharmacokinetics, and drug-likeness. Despite the reduced effect against amastigote forms of the parasite to the purified compounds, different mixtures of compounds 1 + 2, 1a + 2a, and 1b + 2b were prepared and exhibited IC₅₀ values ranging from 7.9 to 38.4 μM, with no toxicity for NCTC mammalian cells (CC₅₀ > 200 μM). Selectivity indexes to these mixtures ranged from >5.2 to >25.3. The obtained results indicate that seeds of Porcelia macrocarpa are a promising source of interesting prototypes for further modifications aiming at the discovery of new antileishmanial drugs.     

One-electron bonds in copper–aluminum and copper–gallium complexes

Odd-electron bonds have unique electronic structures and are often encountered as transiently stable, homonuclear species. In this study, a pair of copper complexes supported by Group 13 metalloligands, M[N((o-C₆H₄)NCH₂PⁱPr₂)₃] (M = Al or Ga), featuring two-center/one-electron (2c/1e) σ-bonds were synthesized by one-electron reduction of the corresponding Cu(i) ⇢ M(III) counterparts. The copper bimetallic complexes were investigated by X-ray diffraction, cyclic voltammetry, electron paramagnetic spectroscopy, and density functional theory calculations. The combined experimental and theoretical data corroborate that the unpaired spin is delocalized across Cu, M, and ancillary atoms, and the singly occupied molecular orbital (SOMO) corresponds to a σ-(Cu–M) bond involving the Cu 4p_z and M ns/np_z atomic orbitals. Collectively, the data suggest the covalent nature of these interactions, which represent the first examples of odd-electron σ-bonds for the heavier Group 13 elements Al and Ga.

Hanging on by a thread. Formally zerovalent copper complexes with an Al(iii) or Ga(iii) support were investigated. The combined experimental and theoretical data corroborate the presence of an odd-electron σ-bond between Cu and the Group 13 center.

Odd-electron σ-bonds, where the electrons are delocalized between two atoms, can occur as two-center/one-electron (2c/1e) or two-center/three-electron (2c/3e) interactions. Proposed by Pauling in 1931,¹ odd-electron σ-bonds have garnered attention because of their fundamental importance to chemical bonding and their relationship to radical species generated during oxidative stress in biological systems.^2–14 Examples of compounds exhibiting odd-electron bonding are typically homonuclear (like H₂⁺, He₂⁺, and alkali metal dimers) and transiently stable, limiting them to spectroscopic characterization.^1,11,15–18The first solid-state structure of a formally one-electron σ-bond was a tetraphosphabenzene species (Fig. 1a) which was formed by the coupling of two diphosphirenyl radicals.¹⁹ Following this discovery, the formation of discrete 2c/1e σ-bonds, where the odd-electron is delocalized between two homonuclear main group centers, was reported for B·B and then extended to P·P.^8,17,20 Of note, the first solid-state structure of a B·B compound was reported in only 2014 (Fig. 1b).²¹ Examples of 2c/1e σ-bonds between the heavier Group 13 congeners are even more lacking because of the greater propensity for their unpaired spins to couple, forming larger more stable clusters.⁸ To our knowledge, there are only three structurally characterized examples of odd-electron bonds for the heavy Group 13 atoms,²² and these examples are all homonuclear π-radicals (Fig. 1c).^23–26Open in a separate windowFig. 1Select examples of structurally characterized molecules (a–d) featuring odd-electron bonds.Heteronuclear odd-electron σ-bonds are also rare. The Cu(TPB) complex, where TPB is a trisphosphinoborane, is the single structural example of a 2c/1e bond between heteroatoms (Fig. 1d).²⁷ The authors described the bonding as Cu·B, where the unpaired electron is heavily polarized toward B. A theoretical study predicted that such a bond would also exist between Cu and Al, but no heavier analogues of Cu(TPB) have been synthesized to date.²⁸ Furthermore, the heavier Group 13 elements by virtue of their lower electronegativity compared to B should facilitate greater covalent interactions with the Cu center.Hence, we sought to target formally zerovalent Cu complexes supported by Al(III) or Ga(III) as an extension of the previously reported isoelectronic nickelate species and Cu(TPB).²⁹ Herein, we describe the synthesis, structure, spectroscopic characterization, and DFT calculations of cationic [CuML]⁺ complexes (L = [N((o-C₆H₄)NCH₂PⁱPr₂)₃]³⁻; M = Al and Ga) as well as their one-electron reduced metalloradical counterparts that feature discrete 2c/1e bonds.