Achiral and chiral analysis of duloxetine by chromatographic and electrophoretic methods,a review on the separation methodologies

Duloxetine (DLX) is a widely used antidepressant drug belonging to the class of selective serotonin and norepinephrine reuptake inhibitors (SNRIs); its efficacy has been demonstrated in the treatment of not only major depressive disorders but also diabetic neuropathic pain, generalized anxiety disorder, fibromyalgia or stress urinary incontinence. It is a chiral substance and is used in therapy in the form of the enantiopure S‐DLX, which is twice as active as R‐DLX. Several methods have been published for the achiral and chiral determination of DLX in pharmaceuticals, biological materials and environmental samples, the majority using liquid chromatography and capillary electrophoresis coupled with different detection techniques (UV detection, fluorescence, mass spectrometry). The aim of the current review is to provide a systematic survey of the analytical techniques used for the determination of DLX from different matrices.     

Optoelectronic,Aggregation, and Redox Properties of Double-Rotor Boron Difluoride Hydrazone Dyes

We develop the chemistry of boron difluoride hydrazone dyes (BODIHYs) bearing two aryl substituents and explore their properties. The low-energy absorption bands (λ_max=427–464 nm) of these dyes depend on the nature of the N-aryl groups appended to the BODIHY framework. Electron-donating and extended π-conjugated groups cause a redshift, whereas electron-withdrawing groups result in a blueshift. The title compounds were weakly photoluminescent in solution and strongly photoluminescent as thin films (λ_PL=525–578 nm) with quantum yields of up to 18 % and lifetimes of 1.1–1.7 ns, consistent with the dominant radiative decay through fluorescence. Addition of water to THF solutions of the BODIHYs studied causes molecular aggregation which restricts intramolecular motion and thereby enhances photoluminescence. The observed photoluminescence of BODIHY thin films is likely facilitated by a similar molecular packing effect. Finally, cyclic voltammetry studies confirmed that BODIHY derivatives bearing para-substituted N-aryl groups could be reversibly oxidized (E_ox1=0.62–1.02 V vs. Fc/Fc⁺) to their radical cation forms. Chemical oxidation studies confirmed that para-substituents at the N-aryl groups are required to circumvent radical decomposition pathways. Our findings provide new opportunities and guiding principles for the design of sought-after multifunctional boron difluoride complexes that are photoluminescent in the solid state.     

In Vivo Biological Behavior of Polymer Scaffolds of Natural Origin in the Bone Repair Process

Autologous bone grafts, used mainly in extensive bone loss, are considered the gold standard treatment in regenerative medicine, but still have limitations mainly in relation to the amount of bone available, donor area, morbidity and creation of additional surgical area. This fact encourages tissue engineering in relation to the need to develop new biomaterials, from sources other than the individual himself. Therefore, the present study aimed to investigate the effects of an elastin and collagen matrix on the bone repair process in critical size defects in rat calvaria. The animals (Wistar rats, n = 30) were submitted to a surgical procedure to create the bone defect and were divided into three groups: Control Group (CG, n = 10), defects filled with blood clot; E24/37 Group (E24/37, n = 10), defects filled with bovine elastin matrix hydrolyzed for 24 h at 37 °C and C24/25 Group (C24/25, n = 10), defects filled with porcine collagen matrix hydrolyzed for 24 h at 25 °C. Macroscopic and radiographic analyses demonstrated the absence of inflammatory signs and infection. Microtomographical 2D and 3D images showed centripetal bone growth and restricted margins of the bone defect. Histologically, the images confirmed the pattern of bone deposition at the margins of the remaining bone and without complete closure by bone tissue. In the morphometric analysis, the groups E24/37 and C24/25 (13.68 ± 1.44; 53.20 ± 4.47, respectively) showed statistically significant differences in relation to the CG (5.86 ± 2.87). It was concluded that the matrices used as scaffolds are biocompatible and increase the formation of new bone in a critical size defect, with greater formation in the polymer derived from the intestinal serous layer of porcine origin (C24/25).     

Optoelectronic Properties of Carbon-Bound Boron Difluoride Hydrazone Dimers

The creation of dimeric boron difluoride complexes of chelating N-donor ligands is a proven strategy for the enhancement of the optoelectronic properties of fluorescent dyes. We report dimers based on the boron difluoride hydrazone (BODIHY) framework, which offer unique and sometimes unexpected substituent-dependent absorption, emission, and electrochemical properties. BODIHY dimers have low-energy absorption bands (λ_max=421 to 479 nm, ϵ=17 200 to 39 900 m ⁻¹ cm⁻¹) that are red-shifted relative to monomeric analogues. THF solutions of these dimers exhibit aggregation-induced emission upon addition of water, with emission enhancement factors ranging from 5 to 18. Thin films of BODIHY dimers are weakly emissive as a result of the inner-filter effect, attributed to intermolecular π-type interactions. BODIHY dimers are redox-active and display two one-electron oxidation and two one-electron reduction waves that strongly depend on the N-aryl substituents. These properties are rationalized using density-functional theory calculations and X-ray crystallography experiments.     

Development of a method for quantitative determination of the cytotoxic agent piplartine (piperlongumine) in multiple skin layers

This study reports the development of a simple and reproducible method, with high rates of recovery, to extract the cytotoxic agent piplartine from skin layers, and a sensitive and rapid UV‐HPLC method for its quantification. Considering the potential of piplartine for topical treatment of skin cancer, this method may find application for formulation development and pharmacokinetics studies to assess cutaneous bioavailability. Porcine skin was employed as a model for human tissue. Piplartine was extracted from the stratum corneum (SC) and remaining viable skin layers (VS) using methanol, vortex homogenization and bath sonication, and subsequently assayed by HPLC using a C₁₈ column, and 1:1 (v/v) acetonitrile–water (adjusted to pH 4.0 with acetic acid 0.1%) as mobile phase. The quantification limit of piplartine was 0.2 μg/mL (0.6 μm ), and the assay was linear up to 5 μg/mL (15.8 μm ), with within‐day and between‐days assay coefficients of variation and relative errors <15%. Piplartine recovery from SC and VS varied from 86 to 96%. The method was suitable to assay samples from skin penetration studies, enabling detection of differences in cutaneous delivery in different skin compartments resulting from treatment with various formulations and time periods.     

Enantioselective analysis of venlafaxine and its active metabolites: A review on the separation methodologies

Venlafaxine (VFX) is a serotonin and norepinephrine reuptake inhibitor chiral drug used in therapy as an antidepressant in the form of a racemate consisting of R‐ and S‐VFX. The two enantiomers of VFX exhibit different pharmacological activities: R‐VFX inhibits both norepinephrine and serotonin synaptic reuptake, whereas S‐VFX inhibits only the serotonin one. R‐ and S‐VFX are metabolized in the liver to the respective R‐ and S‐O‐desmethylvenlafaxine (ODVFX), R‐ and S‐N‐desmethylvenlafaxine (NDVFX), and R‐ and S‐N,O‐didesmethylvenlafaxine (NODVFX). The pharmacological profile of ODVFX is close to that of VFX, whereas the other two chiral metabolites (NDVFX and NODVFX) have lower affinity for the receptor sites. The pharmacokinetics of the VFX enantiomers appear stereoselective, including the metabolism process. In the past 20 years, several studies describing the enantioselective analysis of R‐ and S‐VFX in pharmaceutical formulations and its chiral metabolites in biological matrices were published. These methods encompass liquid chromatography coupled with UV detection, mass spectrometry, or tandem mass spectrometry, and capillary electrophoresis. This paper reviews the published methods used for the determination of the individual enantiomers of VFX and its chiral metabolites in different matrices.     

Phosphono Bisbenzguanidines as Irreversible Dipeptidomimetic Inhibitors and Activity‐Based Probes of Matriptase‐2

Matriptase‐2, a type II transmembrane serine protease, plays a key role in human iron homeostasis. Inhibition of matriptase‐2 is considered as an attractive strategy for the treatment of iron‐overload diseases, such as hemochromatosis and β‐thalassemia. In the present study, synthetic routes to nine dipeptidomimetic inactivators were developed. Five active compounds ( 41 – 45 ) were identified and characterized kinetically as irreversible inhibitors of matriptase‐2. In addition to a phosphonate warhead, these dipeptides possess two benzguanidine moieties as arginine mimetics to provide affinity for matriptase‐2 by binding to the S1 and S3/S4 subpockets, respectively. This binding mode was strongly supported by covalent docking analysis. Compounds 41 – 45 were obtained as mixtures of two diastereomers and were therefore separated into the single epimers. Compound 45 A , with S configuration at the N‐terminal amino acid and R configuration at the phosphonate carbon atom, was the most potent matriptase‐2 inactivator with a rate constant of inactivation of 2790 m ^?1 s^?1 and abolished the activity of membrane‐bound matriptase‐2 on the surface of intact cells. Based on the chemotyp of phosphono bisbenzguanidines, the design and synthesis of a fluorescent probe ( 51 A ) by insertion of a coumarin label is described. The in‐gel fluorescence detection of matriptase‐2 was demonstrated by applying 51 A as the first activity‐based probe for this enzyme.     

Redox‐Active Tetraruthenium Macrocycles Built from 1,4‐Divinylphenylene‐Bridged Diruthenium Complexes

Metallamacrocylic tetraruthenium complexes were generated by treatment of 1,4‐divinylphenylene‐bridged diruthenium complexes with functionalized 1,3‐benzene dicarboxylic acids and characterized by HR ESI‐MS and multinuclear NMR spectroscopy. Every divinylphenylene diruthenium subunit is oxidized in two consecutive one‐electron steps with half‐wave potential splittings in the range of 250 to 330 mV. Additional, smaller redox‐splittings between the +/2+ and 0/+ and the 3+/4+ and 2+/3+ redox processes, corresponding to the first and the second oxidations of every divinylphenylene diruthenium entity, are due to electrostatic effects. The lack of electronic coupling through bond or through space is explained by the nodal properties of the relevant molecular orbitals and the lateral side‐by‐side arrangement of the divinylphenylene linkers. The polyelectrochromic behavior of the divinylphenylene diruthenium precursors is retained and even amplified in these metallamacrocyclic structures. EPR studies down to T=4 K indicate that the dications 1‐H²⁺ and 1‐OBu²⁺ are paramagnetic. The dications and the tetracation of macrocycle 3‐H display intense (dications) or weak ( 3‐H⁴⁺ ) EPR signals. Quantum chemical calculations indicate that the four most stable conformers of the macrocycles are largely devoid of strain. Bond parameters, energies as well as charge and spin density distributions of model macrocycle 5‐H^Me were calculated for the different charge and spin states.