Unveiling a New Selenocyanate as a Multitarget Candidate with Anticancer,Antileishmanial and Antibacterial Potential

Currently, cancer, leishmaniasis and bacterial infections represent a serious public health burden worldwide. Six cinnamyl and benzodioxyl derivatives incorporating selenium (Se) as selenocyanate, diselenide, or selenide were designed and synthesized through a nucleophilic substitution and/or a reduction using hydrides. Ferrocene was also incorporated by a Friedel–Crafts acylation. All the compounds were screened in vitro for their antiproliferative, antileishmanial, and antibacterial properties. Their capacity to scavenge free radicals was also assessed as a first approach to test their antioxidant activity. Benzodioxyl derivatives 2a–b showed cytotoxicity against colon (HT-29) and lung (H1299) cancer cell lines, with IC₅₀ values below 12 µM, and were also fairly selective when tested in nonmalignant cells. Selenocyanate compounds 1–2a displayed potent antileishmanial activity in L. major and L. infantum, with IC₅₀ values below 5 µM. They also exhibited antibacterial activity in six bacterial strains, notably in S. epidermidis with MIC and MBC values of 12.5 µg/mL. Ferrocene-containing selenide 2c was also identified as a potent antileishmanial agent with radical scavenging activity. Remarkably, derivative 2a with a selenocyanate moiety was found to act as a multitarget compound with antiproliferative, leishmanicidal, and antibacterial activities. Thus, the current work showed that 2a could be an appealing scaffold to design potential therapeutic drugs for multiple pathologies.     

pH‐Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases

A general approach is reported for the design of small‐molecule competitive inhibitors of lysosomal glycosidases programmed to 1) promote correct folding of mutant enzymes at the endoplasmic reticulum, 2) facilitate trafficking, and 3) undergo dissociation and self‐inactivation at the lysosome. The strategy is based on the incorporation of an orthoester segment into iminosugar conjugates to switch the nature of the aglycone moiety from hydrophobic to hydrophilic in the pH 7 to pH 5 window, which has a dramatic effect on the enzyme binding affinity. As a proof of concept, new highly pH‐responsive glycomimetics targeting human glucocerebrosidase or α‐galactosidase with strong potential as pharmacological chaperones for Gaucher or Fabry disease, respectively, were developed.     

Importance of weak interactions in developing 1,3-bis(4,6-dimethyl-1H-nicotinonitrile-1-yl)1,3-dioxy propane polymorphs

The structure of 1,3-bis(4,6-dimethyl-1H-nicotinonitrile-1-yl)1,3-dioxy propane polymorphs has been characterized by X-ray diffraction, FT-IR, 1H and 13C NMR spectroscopies. The influence of intra and intermolecular weak interactions is thoroughly studied in solid state using single crystal X-ray diffraction and FT-IR. These polymorphs belong to monoclinic space group 'P2(1/n)' and 'P2(1/c)'. These polymorphs have C-H?n (lone pair), hydrogen bonds, C-N?π, C-H?π and π?π intermolecular non-covalent interactions. These polymorphs are the result of weak interactions and solvent used in crystallization. The FT-IR spectra have been recorded in the solid phase and NMR has been recorded in solvent. The optimized geometry has been calculated by B3LYP methods using different basis sets. The FT-IR and NMR spectra of 1st polymorphs has been calculated at B3LYP/6-31G (d) level. The scaled theoretical wave number showed good agreement with the experimental values. These two polymorphs as well as other stereomers are studied by DFT calculations.     

Heterometallic platinum(II) compounds with β-aminoethylferrocenes: synthesis, electrochemical behaviour and anticancer activity

A new family of heterometallic compounds 3-6 containing ferrocenyl and platinum(II) centers has been synthesized by reaction of 1-β-aminoethylferrocene (1) and 1,1'-bis(β-aminoethyl)ferrocene (2) with Pt(II) precursors. Using K(2)[PtCl(4)] as the Pt(II) source, the cis-square-planar neutral compounds [Fe{η(5)-C(5)H(4)(CH(2))(2)NH(2)}(2)PtCl(2)] (3) and [{Fe(η(5)-C(5)H(4)(CH(2))(2)NH(2))(η(5)-C(5)H(5))}(2)PtCl(2)] (5) were obtained. Reaction of cis-[PtCl(2)(dmso)(2)] with 1 and 2 resulted in the displacement of dmso and chloride ligands from the platinum coordination sphere, affording the cationic and neutral compounds [Fe{η(5)-C(5)H(4)(CH(2))(2)NH(2)}(2)Pt(dmso)Cl]Cl (4) and [Fe(η(5)-C(5)H(4)(CH(2))(2)NH(2))(η(5)-C(5)H(5))Pt(dmso)Cl(2)] (6). Compounds 3-6 were thoroughly characterized using multinuclear ((1)H, (13)C, (195)Pt) NMR, IR spectroscopy, ESI mass spectrometry and elemental analysis. Single-crystal X-ray analysis of heterometallic 6 confirmed the cis geometry of the molecule and revealed that the platinum atom is held in a perfect square-planar geometry. The electrochemical behaviour of the heterometallic compounds 3-6, which has been examined by cyclic (CV) and square wave (SWV) voltammetries in dichloromethane and dmso solution, is characterized by the reversible one-electron oxidation of the ferrocene moieties. The results of the biological activity studies revealed that the organometallic complex 5 is active against all cell lines with GI(50) values in the range 1.7-2.3 μM. When compared to the standard anticancer drug cisplatin, heterotrimetallic 5, possessing two aminoethylferrocenyl units coordinated to the Pt(II) center, showed a greater activity profile in the colon cancer cell line. Cell cycle studies revealed that the new mixed compound exhibits a mechanism of action different to cisplatin.     

Study of tungstate–protein interaction in human serum by LC–ICP-MS and MALDI-TOF

Oral administration of sodium tungstate is an effective treatment for type 1 and 2 diabetes in animal models; it does not incur significant side effects, and it may constitute an alternative to insulin. However, the mechanism by which tungstate exerts its observed metabolic effects in vivo is still not completely understood. In this work, serum-containing proteins which bind tungstate have been characterized. Size exclusion chromatography (SEC) coupled to inductively coupled plasma mass spectrometry (ICP-MS) with a Phenomenex Bio-Sep-S 2000 column and 20 mM HEPES and 150 mM NaCl at pH 7.4 as the mobile phase was chosen as the most appropriate methodology to screen for tungsten–protein complexes. When human serum was incubated with tungstate, three analytical peaks were observed, one related to tungstate–albumin binding, one to free tungstate, and one to an unknown protein binding (MW higher than 300 kDa). Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometric analysis of the tungsten-containing fractions collected from SEC–ICP-MS chromatograms, after desalting and preconcentration processes, confirmed the association of tungstate with albumin and the other unknown protein. Figure SEC-ICP-MS // MALDI-TOF     

Simultaneous determination of p-hydroxybenzoic acid and parabens by capillary electrophoresis with improved sensitivity in nonaqueous media

New methods based on nonaqueous capillary electrophoresis (NACE) were developed as promising alternatives for the simultaneous separation and determination of p-hydroxybenzoic acid (PHBA) and a group of parabens (methyl, ethyl, propyl, butyl and benzyl p-hydroxybenzoates), with good resolution and excellent sensitivity. As an effective on-line preconcentration technique, large-volume sample stacking (LVSS) was successfully combined with NACE allowing significant sensitivity enhancement. Identification and quantification of the analytes were performed by diode array detection (DAD). The influence of different parameters, such as buffer apparent pH, concentration of electrolyte, temperature, applied voltage and sample volume, on the efficiency, resolution and sensitivity of the electrophoretic separation was studied. The analytical performance was evaluated, and both NACE-DAD and LVSS-NACE-DAD methods showed good linearity, precision and instrumental LODs at low ng/mL levels. These LODs were compared with those described in the literature, and it was found that NACE-DAD method was comparable to GC-MS, while LVSS-NACE-DAD procedure achieved sensitivity similar to LC-MS, LC-MS/MS and GC-MS/MS, even using conventional ultraviolet-visible absorption detection. To test their suitability, proposed methods were evaluated for the analysis of PHBA and parabens at low and sub-ng/mL levels in environmental water samples.     

Ultrafast Deactivation Mechanism of the Excited Singlet in the Light‐Induced Spin Crossover of [Fe(2,2′‐bipyridine)3]2+

The mechanism of the light‐induced spin crossover of the [Fe(bpy)₃]²⁺ complex (bpy=2,2′‐bipyridine) has been studied by combining accurate electronic‐structure calculations and time‐dependent approaches to calculate intersystem‐crossing rates. We investigate how the initially excited metal‐to‐ligand charge transfer (MLCT) singlet state deactivates to the final metastable high‐spin state. Although ultrafast X‐ray free‐electron spectroscopy has established that the total timescale of this process is on the order of a few tenths of a picosecond, the details of the mechanisms still remain unclear. We determine all the intermediate electronic states along the pathway from low spin to high spin and give estimates for the deactivation times of the different stages. The calculations result in a total deactivation time on the same order of magnitude as the experimentally determined rate and indicate that the complex can reach the final high‐spin state by means of different deactivation channels. The optically populated excited singlet state rapidly decays to a triplet state with an Fe d⁶(${{\rm t}{{5\hfill \atop {\rm 2g}\hfill}}}$ ${{\rm e}{{1\hfill \atop {\rm g}\hfill}}}$ ) configuration either directly or by means of a triplet MLCT state. This triplet ligand‐field state could in principle decay directly to the final quintet state, but a much faster channel is provided by internal conversion to a lower‐lying triplet state and subsequent intersystem crossing to the high‐spin state. The deactivation rate to the low‐spin ground state is much smaller, which is in line with the large quantum yield reported for the process.     

Guest Modulation of Spin‐Crossover Transition Temperature in a Porous Iron(II) Metal–Organic Framework: Experimental and Periodic DFT Studies

The synthesis, structure, and magnetic properties of three clathrate derivatives of the spin‐crossover porous coordination polymer {Fe(pyrazine)[Pt(CN)₄]} ( 1 ) with five‐membered aromatic molecules furan, pyrrole, and thiophene is reported. The three derivatives have a cooperative spin‐crossover transition with hysteresis loops 14–29 K wide and average critical temperatures T_c=201 K ( 1?fur ), 167 K ( 1?pyr ), and 114.6 K ( 1?thio ) well below that of the parent compound 1 (T_c=295 K), confirming stabilization of the HS state. The transition is complete and takes place in two steps for 1?fur , while 1?pyr and 1?thio show 50 % spin transition. For 1?fur the transformation between the HS and IS (middle of the plateau) phases occurs concomitantly with a crystallographic phase transition between the tetragonal space groups P4/mmm and I4/mmm, respectively. The latter space group is retained in the subsequent transformation involving the IS and the LS phases. 1?pyr and 1?thio display the tetragonal P4/mmm and orthorhombic Fmmm space groups, respectively, in both HS and IM phases. Periodic calculations using density functional methods for 1?fur , 1?pyr , 1?thio , and previously reported derivatives 1?CS₂ , 1?I, 1?bz (benzene), and 1?pz (pyrazine) have been carried out to investigate the electronic structure and nature of the host–guest interactions as well as their relationship with the changes in the LS–HS transition temperatures of 1?Guest . Geometry‐optimized lattice parameters and bond distances in the empty host 1 and 1?Guest clathrates are in general agreement with the X‐ray diffraction data. The concordance between the theoretical results and the experimental data also comprises the guest molecule orientation inside the host and intermolecular distances. Furthermore, a general correlation between experimental T_c and calculated LS–HS electronic energy gap was observed. Finally, specific host–guest interactions were studied through interaction energy calculations and crystal orbital displacement (COD) curve analysis.     

Efficient Synthetic Approach to Substituted Benzo[b]furans and Benzo[b]thiophenes by Iodine‐Promoted Cyclization of Enaminones

An efficient synthetic approach to the substituted benzo[b]furan and benzo[b]thiophene scaffolds by iodine‐mediated cyclization of the corresponding enaminones is described. This protocol was applied to a large series of these latter precursors to afford the respective benzoheterocycles substituted at the C‐2 position by a carbonyl group functionality. A study of the factors that control this process reveals that the reactivity depends on the presence of electron‐donor groups in the aryl ring of the aryloxycarbonylic and arylthiocarbonylic moieties.