Coumarin-Resveratrol-Inspired Hybrids as Monoamine Oxidase B Inhibitors: 3-Phenylcoumarin versus trans-6-Styrylcoumarin.

Monoamine oxidases (MAOs) are attractive targets in drug design. The inhibition of one of the isoforms (A or B) is responsible for modulating the levels of different neurotransmitters in the central nervous system, as well as the production of reactive oxygen species. Molecules that act selectively on one of the MAO isoforms have been studied deeply, and coumarin has been described as a promising scaffold. In the current manuscript we describe a comparative study between 3-phenylcoumarin (endo coumarin-resveratrol-inspired hybrid) and trans-6-styrylcoumarin (exo coumarin-resveratrol-inspired hybrid). Crystallographic structures of both compounds were obtained and analyzed. 3D-QSAR models, in particular CoMFA and CoMSIA, docking simulations and molecular dynamics simulations have been performed to support and better understand the interaction of these molecules with both MAO isoforms. Both molecules proved to inhibit MAO-B, with trans-6-styrylcoumarin being 107 times more active than 3-phenylcoumarin, and 267 times more active than trans-resveratrol.

A styrylpyrone dimer isolated from Aniba heringeri causes apoptosis in MDA-MB-231 triple-negative breast cancer cells.

The styrylpyrone dehydrogoniothalamin (1) and two of its dimers (2 and 3) were isolated from the leaves of Aniba heringeri (Lauraceae). Compound 3 is new, while 1 and 2 are being reported for the first time in this species. Structures were determined by 1D- and 2D-NMR spectroscopy, mass spectrometry, and optical rotation data. Cytotoxic effects and selectivity indices were evaluated in five neoplastic cell lines-PC-3 (prostate), 786-0 (renal), HT-29 (colon), MCF-7, and MDA-MB-231 (breast)-and a non-neoplastic cell line, (NIH/3T3, murine fibroblast). Compound 1 inhibited cell growth by 50% (GI50) at concentrations in the 90.4-175.7 µM range, while 2 proved active against MCF-7 and MDA-MB-231 breast cells (GI50 = 12.24, and 34.22 µM, respectively). Compound 3 showed strong cytotoxicity (GI50 = 4.4 µM) against MDA-MB-231 (an established basal triple-negative breast carcinoma (TNBC) cell line), with a high selective index of 35. This compound was subsequently evaluated for apoptosis induction in MDA-MB-231 cells, using GI50 and 50% lethal concentrations (LC50). Flow cytometry analysis showed that at LC50 compound 3 induced cell death with phosphatidylserine externalization and caspase-3 activation. Apoptotic genes were measured by RT-qPCR, revealing an upregulation of BAX, with an increase in expression of the BAX/BCL2 ratio in treated cells. Fluorescence microscopy disclosed morphological changes related to apoptosis. Overall, these findings showed compound 3 to be a promising prototype against TNBC cells that tend to respond poorly to conventional therapies.

Anti-Inflammatory Potential of 1-Nitro-2-Phenylethylene.

Inflammation is a reaction of the host to infectious or sterile stimuli and has the physiological purpose of restoring tissue homeostasis. However, uncontrolled or unresolved inflammation can lead to tissue damage, giving rise to a plethora of chronic inflammatory diseases, including metabolic syndrome and autoimmunity pathologies with eventual loss of organ function. Beta-nitrostyrene and its derivatives are known to have several biological activities, including anti-edema, vasorelaxant, antiplatelet, anti-inflammatory, and anticancer. However, few studies have been carried out regarding the anti-inflammatory effects of this class of compounds. Thereby, the aim of this study was to evaluate the anti-inflammatory activity of 1-nitro-2-phenylethene (NPe) using in vitro and in vivo assays. Firstly, the potential anti-inflammatory activity of NPe was evaluated by measuring TNF-α produced by human macrophages stimulated with lipopolysaccharide (LPS). NPe at non-toxic doses opposed the inflammatory effects induced by LPS stimulation, namely production of the inflammatory cytokine TNF-α and activation of NF-κB and ERK pathways (evaluated by phosphorylation of inhibitor of kappa B-alpha [IκB-α] and extracellular signal-regulated kinase 1/2 [ERK1/2], respectively). In a well-established model of acute pleurisy, pretreatment of LPS-challenged mice with NPe reduced neutrophil accumulation in the pleural cavity. This anti-inflammatory effect was associated with reduced activation of NF-κB and ERK1/2 pathways in NPe treated mice as compared to untreated animals. Notably, NPe was as effective as dexamethasone in both, reducing neutrophil accumulation and inhibiting ERK1/2 and IκB-α phosphorylation. Taken together, the results suggest a potential anti-inflammatory activity for NPe via inhibition of ERK1/2 and NF-κB pathways on leukocytes.

Mechanism of the vasorelaxant effect induced by trans-4-methyl-ß-nitrostyrene, a synthetic nitroderivative, in rat thoracic aorta.

Mechanisms underlying the vasorelaxant effects of trans-4-methyl-ß-nitrostyrene (T4MeN) were studied in rat aortic rings. In endothelium-intact preparations, T4MeN fully and similarly relaxed contractions induced by phenylephrine (PHE) (IC50  = 61.41 [35.40-87.42] µmol/L) and KCl (IC50  = 83.50 [56.63-110.50] µmol/L). The vasorelaxant effect of T4MeN was unchanged by endothelium removal, pretreatment with L-NAME, indomethacin, tetraethylammonium, ODQ or MDL-12,330A. Under Ca2+ -free conditions, T4MeN significantly reduced with a similar potency: (i) phasic contractions induced by PHE, but not by caffeine; (ii) contractions due to CaCl2 in aortic preparations stimulated with PHE (in the presence of verapamil) or high KCl; (iii) contractions evoked by the restoration of external Ca2+ levels after depletion of intracellular Ca2+ stores in the presence of thapsigargin. In contrast, T4MeN was more potent at inhibiting contractions evoked by the tyrosine phosphatase inhibitor, sodium orthovanadate, than those induced by the activator of PKC, phorbol-12,13-dibutyrate. These results suggest that T4MeN induces an endothelium- independent vasorelaxation that appears to occur intracellularly through the inhibition of contractions that are independent of Ca2+ influx from the extracellular milieu but involve phosphorylation of tyrosine residues.

Retro-Curcuminoids as Mimics of Dehydrozingerone and Curcumin: Synthesis, NMR, X-ray, and Cytotoxic Activity.

Curcumin and its derivatives have been extensively studied for their remarkable medicinal properties, and their chemical synthesis has been an important step in the optimization of well-controlled laboratory production. A family of new compounds that mimic the structure of curcumin and curcuminoids, here named retro-curcuminoids (7-14), was synthesized and characterized using 1D ¹H- and 13C-NMR, IR, and mass spectrometry; the X-ray structure of 7, 8, 9, 10, 12, 13, and 14 are reported here for the first time. The main structural feature of these compounds is the reverse linkage of the two aromatic moieties, where the acid chloride moiety is linked to the phenolic group while preserving α, ß-unsaturated ketone functionality. The cytotoxic screening of 7, 8, 9, and 10 at 50 and 10 µg/mL was carried out with human cancer cell lines K562, MCF-7, and SKLU-1. Lipid peroxidation on rat brain was also tested for compounds 7 and 10. Compounds 7, 8, and 10 showed relevant cytotoxic activity against these cancer cell lines, and 10 showed a protective effect against lipid peroxidation. The molecular resemblance to curcuminoids and analogs with ortho substituents suggests a potential source of useful bioactive compounds.

Synthesis, characterization and evaluation of two crosslinked polymeric resins and their comparison with walnut shell in oil removal from water.

The aim of this paper was to compare two kinds of adsorbents (walnut shell and polymeric resins) in terms of their efficiency to remove oil from water, since walnut shell losses weight during the process requiring interruption, while polymeric resins do not. Polymeric resins based on glycidyl methacrylate and divinylbenzene (GMA-DVB) and styrene and divinylbenzene (STY-DVB) were synthesized and characterized. All adsorbents were tested by continuous flow process, eluting 3,000 bed volumes of synthetic oily water, and the oil content was monitored by fluorescence spectroscopy. Although the walnut shell presented high efficiency (∼94%), STY-DVB was even better (∼100%) besides presenting better mechanical resistance. Moreover, polymeric resins, mainly when based on GMA, can be chemically modified to remove specific contaminants still remaining in water after conventional treatment.

Dihydrogoniothalamin, an Endothelium and NO-Dependent Vasodilator Drug Isolated from Aniba panurensis.

Dihydrogoniothalamin is a styrylpyrone isolated from the leaves of Aniba panurensis. The present work aimed at investigating the vasorelaxant activity of dihydrogoniothalamin and its underlying mechanism of action in the rat aorta. Dihydrogoniothalamin (0.01-100 µM) induced a concentration-dependent vasodilatation of aortas precontracted with phenylephrine. Endothelium removal or pretreatment of the preparation with NG nitro-L-arginine-methyl-ester abolished the vasodilator response for dihydrogoniothalamin. Pretreatment with calmidazolium did not affect the vasodilator response of dihydrogoniothalamin. On the other hand, wortmannin, a nonselective inhibitor of phosphatidylinositol 3-kinases, and protein kinase B inhibitor IV significantly shifted the concentration-response curve of dihydrogoniothalamin to the right and reduced its maximal effect. A nonselective antagonist of estrogen receptors, ICI 182,780, and a selective antagonist of estrogen receptor α, methyl-piperidino-pyrazole, were able to reduce the relaxation induced by dihydrogoniothalamin, but no effect was observed in the presence of the selective antagonists of estrogen receptor ß and G protein-coupled receptor 30, 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), and G-15, respectively. Dihydrogoniothalamin also increased the phosphorylation of the activation sites of endothelial nitric oxide synthase and protein kinase B. The present results led us to conclude that dihydrogoniothalamin is a vasodilator drug acting in an endothelium- and nitric oxide-dependent manner through a mechanism involving the activation of nitric oxide synthase via the phosphatidylinositol 3-kinase/protein kinase B pathway, partially by stimulation of estrogen receptor α.

Removal of naphthalene from aqueous systems by poly(divinylbenzene) and poly(methyl methacrylate-divinylbenzene) resins.

Treatment of the oily wastewater from crude oil extraction is a growing challenge due to rising concern for the environment. Polyaromatic hydrocarbons (PAHs) deserve special attention because of their high toxicity. There is a need to develop processes able to minimize the discharge of these compounds and analytic techniques to monitor the levels of PAHs in aqueous media. In this study poly(methyl methacrylate-divinylbenzene) (MMA-DVB) and poly(divinylbenzene) (DVB) were assessed with respect to their capacity to retain naphthalene (NAF) in continuous flow and batch processes (adsorption equilibrium and kinetics). The analytic techniques applied were gas chromatography and spectrofluorimetry, which was adapted for quantification of NAF. The batch adsorption studies showed that DVB is more efficient in adsorption than MMA-DVB, and the Freundlich model and pseudo-second-order model better fitted the equilibrium data and adsorption kinetics, respectively. The elution results showed that both resins are highly efficient in removing NAF, with DVB outperforming MMA-DVB. However, MMA is cheaper raw material, making MMA-DVB more competitive for treatment of oily wastewater. The resins were regenerated by eluting about 7.2 and 2.5 L of methanol:water (70:30 v/v), respectively for DVB and MMA-DVB. Regarding to the useful life after regeneration, the resins presented a reduction about 30%, relating to zero concentration of NAF.

Catalytic chalcogenylation under greener conditions: a solvent-free sulfur- and seleno-functionalization of olefins via I2/DMSO oxidant system.

Herein, we report a solvent- and metal-free methodology for the alkoxy-chalcogenylation of styrenes, using molecular iodine as a catalyst, DMSO as a stoichiometric oxidant, and different nucleophiles under microwave irradiation. This eco-friendly approach afforded the desired products in good to excellent yields in only 10 min. In addition, using the same protocol, we carried out the cyclization reaction of relevant molecules, such as lapachol derivatives.

Copper-catalyzed intermolecular and regioselective aminofluorination of styrenes: facile access to ß-fluoro-N-protected phenethylamines.

A copper-catalyzed regio- and intermolecular aminofluorination of styrenes has been developed. In this reaction Ph-I=N-Ts and Et3N·3HF act as nitrogen and fluorine sources, respectively. The obtained ß-fluoro-N-Ts-phenethylamines can be N-alkylated with subsequent deprotection affording the corresponding ß-fluoro-N-alkylated phenethylamines, which are interesting building blocks for compounds acting on neuronal targets.

[Styrylquinolines-type synthetic compounds with leishmanicidal and cytotoxic activities]. / Compuestos sintéticos del tipo de estirilquinolinas con actividades leishmanicida y citotóxica.

INTRODUCTION: Leishmaniasis is a major public health problem faced by many countries, including Colombia. Its treatment has limitations such as the toxicity of the drugs used, the emergence of resistant strains, and prolonged and expensive treatments. Thus, there is an urgent need to find alternative solutions. OBJECTIVE: To evaluate the leishmanicidal and cytotoxic activities of three 2-styrylquinolines type compounds: 2-[(E)-2-(2,3-diacetyloxyphenyl)ethenyl]quinolin-8-yl-acetate, E1; 2-[(E)-2-(4-acetyloxy-3-methoxyphenyl)ethenyl] quinoline, E2, and 2-[(E)-2-(2,3-diacetyloxyphenyl)ethenyl] quinoline, E3. MATERIALS AND METHODS: The 2-styrylquinolines were obtained by organic synthesis using Perkin-type condensation reaction from 8-hydroxy quinaldine or quinaldine and aromatic aldehydes. The leishmanicidal activity was evaluated on intracellular amastigotes of Leishmania (Viannia) panamensis by flow cytometry. The results were expressed as lethal concentration 50 (LC 50 ) for cytotoxicity and effective concentration 50 (EC 50 ) for leishmanicidal activity, calculated by the Probit method. RESULTS: E3 showed high activity against L. (V) panamensis with a calculated EC 50 value of 1.4 µg/ml, and a selectivity index of 3.9; E1 and E2 showed higher EC 50 values of 5.6 and 68.1 µg/ml, respectively. For cytotoxicity, LC 50 values ranging from 5.4 to 68.1 µg/ml were calculated. E2 was moderately toxic, showing an LC 50 very similar to that of amphotericin B, a substance used as cytotoxic control. CONCLUSION: The styrylquinoline E3 is a promising compound against L. (V) panamensis , as it was able to significantly inhibit amastigotes inside the cell, reducing infection despite its toxicity.

Compuestos sintéticos del tipo de estirilquinolinas con actividades leishmanicida y citotóxica / Styrylquinolines-type synthetic compounds with leishmanicidal and cytotoxic activities

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Protective effect of ((4-tert-butylcyclohexylidene) methyl) (4-methoxystyryl) sulfide, a novel unsymmetrical divinyl sulfide, on an oxidative stress model induced by sodium nitroprusside in mouse brain: involvement of glutathione peroxidase activity.

OBJECTIVES: In this study, the antioxidant action of ((4-tert-butylcyclohexylidene) methyl) (4-methoxystyryl) sulfide, a novel unsymmetrical divinyl sulfide, against oxidative damage induced by sodium nitroprusside (SNP) in brains of mice was investigated. METHODS: Mice received SNP (0.335 µmol/site, intracerebroventricular) 30 min after administration of sulfide (10 mg/kg, intragastrically). After 1 h, animals were sacrificed and the brains were removed to biochemistry analysis. Thiobarbituric acid reactive species (TBARS), protein carbonyl (PC) and non-protein thiol (NPSH) levels, as well as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) activities were determined. KEY FINDINGS: SNP increased TBARS and PC levels, CAT, GPx, GR and GST activities and reduced NPSH levels. Administration of the sulfide attenuated the changes produced by SNP and increased per se GPx activity in brains of mice. Toxicological parameters revealed that this compound did not cause acute renal or hepatic damage. CONCLUSIONS: In conclusion, ((4-tert-butylcyclohexylidene) methyl) (4-methoxystyryl) sulfide protected against oxidative damage caused by SNP in mouse brain. GPx activity is involved, at least in part, in the cerebral antioxidant action of this compound.

A facile and convenient sequential homobimetallic catalytic approach towards ß-methylstyrenes. A one-pot Stille cross-coupling/isomerization strategy.

An efficient one-pot synthetic approach towards ß-methylstyrenes is reported. The transformation, based on sequential homobimetallic catalysis, involves a Stille cross-coupling reaction between aryl halides and allyltributylstannane, followed by an in situ palladium-catalyzed conjugative isomerization. The reaction was optimized, and the best results were obtained with 10 mol% Pd(PPh3)2Cl2, 8.0 equiv. LiCl, and 0.5 equiv. PPh3 in diglyme at 130 °C for 12 h. It was demonstrated that the reaction tolerates a wide variety of functional groups.

Basic-functionalized recyclable ionic liquid catalyst: A solvent-free approach for Michael addition of 1,3-dicarbonyl compounds to nitroalkenes under ultrasound irradiation.

A task-specific ionic liquid (TSIL) has been introduced as a recyclable catalyst in Michael addition. A series of nitroalkenes and various C-based nucleophiles were reacted in the presence of 30mol% of recyclable basic-functionalized ionic liquid. Good to excellent yields were obtained in 30min under ultrasound irradiation.

Protecting groups transfer: unusual method of removal of tr and tbdms groups by transetherification.

The triphenylmethyl (Tr) group undergoes a transfer (transetherification or disproportionation) between the molecules of 5'-O-Tr-2'-deoxynucleosides in a process mediated by anhydrous sulfates of Cu(+2), Fe(+2), or Ni(+2) to yield mixtures of 3',5'-bis-O-Tr and 3'-O-Tr products. If phenylmethanol is present in a reaction medium, detritylation results with concomitant formation of phenylmethyl triphenylmethyl ether. The behavior of t-butyldimethylsilyl (TBDMS) group in 5'-O-TBDMS-2'-deoxynucleosides is exactly the same. Such type of transetherifications was not observed before for the O-Tr and O-TBDMS groups.

Synthesis and evaluation of nitrostyrene derivative compounds, new snake venom phospholipase A2 inhibitors.

Several nitrostyrene derivatives were synthesized and their inhibitive activities on phospholipase A(2) (PLA(2)) from Bothrops jararacussu venom were evaluated. Some compounds were very efficient as inhibition agents against edema-inducing, enzymatic and myotoxic activities. Data revealed that the size of the substitute and substitution position in the nitrostyrene moiety had important influence on the inhibition capacities. The enzymatic kinetic studies show that the nitrostyrene derivatives compounds inhibit PLA(2) in a non-competitive manner. The electronic, molecular and topologic parameters were calculated using ab initio quantum calculations (density functional theory-DFT) and analyzed by chemometric methods (principal component analysis (PCA) and hierarchical cluster analysis (HCA)) in order to build models able to establish relationships between the electronic features and the structure-activity presented by the target compound. Compounds with the nitro group in the ortho, meta and para position (compounds 2-4) on the aromatic ring were more efficient in the inhibition of PLA(2) activity in all tests. These results indicate that the influence of the nitro group in the aromatic ring is, in fact, important. In addition, quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA(2) present lower values of highest occupied molecular orbital (HOMO) energy and polarizability, suggesting the formation of a charge-transferring complex between the nitrostyrene compounds and PLA(2).

Participation of dihydrostyryl-2-pyrones and styryl-2-pyrones in the central effects of Polygala sabulosa (Polygalaceae), a folk medicine topical anesthetic.

This study was undertaken to evaluate the psychopharmacological effects in mice of the hydroethanolic extract (HE), aqueous, hexane and ethyl acetate (EA) fractions, and 6-methoxy-7-prenyloxycoumarin, three dihydrostyryl-2-pyrones and three styryl-2-pyrones isolated from Polygala sabulosa (Polygalaceae), a folk medicine used as a topical anesthetic. In the elevated plus-maze test (EPM), the HE of P. sabulosa and its EA induced an increase in the percentage of time spent on, and in the frequency of entries into the open arms, as well as in the number of unprotected head-dipping, besides a reduction in protected stretch-attend postures, thus indicating an anxiolytic-like profile of action for this plant species. In the hypnosis test, HE and EA enhanced the duration of pentobarbital-induced sleep, a hypnosedative effect confirmed in ethyl ether-induced hypnosis. Moreover, both preparations reduced the duration of the first convulsion induced by pentylenetetrazol, besides decreasing the severity of the seizures. The dihydrostyryl-2-pyrones (1) and (3) as well as styryl-2-pyrones (4) and (7), centrally administered, showed a similar anxiolytic-like effect in the EPM test, while the dihydrostyryl-2-pyrone (2) and styryl-2-pyrone (5) were inactive at the doses used here. These results suggest that P. sabulosa is a herbal medicine which possesses anxiolytic-like, hypnosedative and anticonvulsant effects, and these central effects can be attributed to the presence of the dihydrostyryl-2-pyrone and styryl-2-pyrone compounds.

A resonance Raman investigation on the interaction of styrene and 4-methyl styrene oligomers on sulphated titanium oxide.

In order to understand the nature of the interaction that gives rise to the yellow-orange colour observed when styrene or 4-methyl styrene are put in contact with sulphated TiO2, the resonance Raman spectra of such systems, including deuterated styrene (ring-deuterated d5 and perdeuterated d8) and allylbenzene were investigated. In all cases a substantial enhancement of the ring v(CC) stretching mode was observed. A charge transfer process involving a transition from the ring pi-electrons to the empty d-pi orbitals of titanium was ascribed responsible for the absorption in the visible. Two types of resonance Raman spectra were observed depending on the excitation wavelength, which can be explained by the presence of two kinds of oligomers, saturated and unsaturated, on the surface of the oxide with the former giving rise to a Raman enhancement at a higher excitation energy.