Effect of Chronic Administration of the Vinyl Chalcogenide 3-Methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on Oxidative Stress in Different Brain Areas of Rats

Selenium (Se) is an essential mineral for mammals. It is a nutrient related to the complex metabolic and enzymatic functions. Although Se has important physiological functions in the cells, organic compounds of Se can be extremely toxic, and may affect the central nervous system. This study aims to investigate the effect of the chronic treatment with the vinyl chalcogenide 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on some parameters of oxidative stress in the brain of rats. Animals received the vinyl chalcogenide (125, 250 or 500 μg/kg body weight) intraperitoneally once a day during 30 days. The cerebral cortex, the hippocampus, and the cerebellum were dissected and homogenized in KCl. Afterward, thiobarbituric acid reactive substances (TBARS), carbonyl, sulfhydryl, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in the brain. Results showed that the organoselenium enhanced TBARS in the cerebral cortex of rats but the compound was not able to change carbonyl levels. Furthermore, the organoselenium reduced thiol groups measured by the sulfhydryl assay in all tissues studied. The activity of the antioxidant enzyme CAT was increased by the organochalcogen in the cerebral cortex and in the cerebellum, and the activity of SOD was increased in the hippocampus. On the other hand, the activity of the antioxidant enzyme GPx was reduced in all brain structures. Our findings indicate that this organoselenium compound induces oxidative stress in different brain regions of rats, corroborating to the fact that this tissue is a potential target for organochalcogen action.     

Encapsulation of recombinant <Emphasis Type="Italic">E. coli</Emphasis> expressing cyclopentanone monooxygenase in polyelectrolyte complex capsules for Baeyer–Villiger biooxidation of 8-oxabicyclo[3.2.1]oct-6-en-3-one

Recombinant Escherichia coli cells, over-expressing cyclopentanone monooxygenase activity, were immobilized in polyelectrolyte complex capsules, made of sodium alginate, cellulose sulfate, poly(methylene-co-guanidine), CaCl₂ and NaCl. More than 90% of the cell viability was preserved during the encapsulation process. Moreover, the initial enzyme activity was fully maintained within encapsulated cells while it halved in free cells. Both encapsulated and free cells reached the end point of the Baeyer–Villiger biooxidation of 8-oxabicyclo[3.2.1]oct-6-en-3-one to 4,9-dioxabicyclo[4.2.1]non-7-en-3-one at the same time (48 h). Similarly, the enantiomeric excess above 94% was identical for encapsulated and free cells.     

Evaluating the impact of substrate and product concentration on a whole-cell biocatalyst during a Baeyer-Villiger reaction

The presence of high concentrations of substrate or product may impede the optimal functioning of a biocatalyst, more so in the case of whole cell biocatalysts where the metabolic status of the cells may be compromised. In this article we investigate these effects using as an example the Baeyer–Villiger oxidation of racemic bicyclo[3.2.0]hept-2-en-6-one to yield (?)-1(S),5(R)-2-oxabicyclo[3.3.0]oct-6-en-3-one and (?)-1(R),5(S)-3-oxabicyclo[3.3.0]oct-6-en-2-one by CHMO expressed in Escherichia coli TOP10. Multi parameter flow cytometry was used to illustrate that substrate (racemic bicyclo[3.2.0]hept-2-en-6-one) associated cell damage was concentration dependent. One of the two regio-isomeric products [(-)-1(S),5(R)-2-oxabicyclo[3.3.0]oct-6-en-3-one] was also used to identify that product associated cell damage was time dependent. In addition, both substrate and product concentrations affected the observed reaction rate.     

Occurrence of Potential Brassinosteroid Precursor Steroids in Seeds of Wheat and Foxtail Millet

Triticum aestivum L.) and foxtail millet (Setaria italica Beauv.) were found by GC-MS to contain, in addition to bulk sterols, 4-en-3-one steroids including 24-ethylcholesta-4,24(28)Z- dien-3-one (a new steroid), 24-methylcholest-4-en-3-one, 24-ethylcholesta-4,22E-dien-3-one and 24-ethylcholest-4-en-3-one, as well as 5α-steroidal 3-one compounds including 24-methyl-5α-cholestan-3-one, 24-ethyl-5α-cholestan-3-one and 24-ethyl 5α-cholest-22E-en-3-one (in S. italica only). Analysis of free sterol and steryl ester fractions indicated that campestanol and sitostanol were present at high levels in both seeds. These results suggest that the seeds of T. aestivum and S. italica synthesize campestanol from campesterol via 24-methylcholest-4-en-3-one and 24-methyl-5α-cholestan-3-one as has already been demonstrated in Arabidopsis thaliana L., and also produce sitostanol from sitosterol via 24-ethylcholest-4-en-3-one and 24-ethyl-5α-chotestan-3-one. Biosynthetic relationships of campestanol and sitostanol with C₂₈ and C₂₉ brassinosteroids are discussed. Received 4 September 1998/ Accepted in revised form 26 November 1998     

Microbial and xanthine dehydrogenase inhibitory activity of some flavones

Xanthine dehydrogenase (XDH) is responsible for the pathological condition called Gout. In the present study different flavones synthesized from chalcone were evaluated in vitro for their inhibitory activity. Inhibitory activity of flavones on XDH was determined in terms of inhibition of uric acid synthesis from Xanthine. The enzymatic activity was found maximum at pH 7.5 and temperature 40°C. The flavones 6-chloro-2-[3-(4–hydroxy-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one (F₁) and 6-chloro-7methyl-2-[3-(4-chloro-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one(F₂),were noncompetitive and competitive inhibitor with Ki values 1.1 and 0.22 respectively. The flavones (F₁), (F₂), 6-chloro-2-[3-(4-chloro-phenyl)-1phenyl-1-H-pyrazol-4-yl]-chromen-4-one(F₃), 8-bromo-6-chloro-2-[3-(4-chloro-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one (F₄), 2-[3-(4-hydroxy-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one (F₅) and 6-methyl-2-[3-(4-hydroxy-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one (F₆) were also screened for their antimicrobial activity, measured in terms of zone of inhibition. A broad spectrum antifungal activity was obtained against Trichoderma viridae, Candida albicans, Microsporum cannis, Penicillium chrysogenum and Fusarium moniliformae. In case of Aspergillus niger and Aspergillus flavous only spore formation was affected, while antibacterial activity was observed against Staphylococcus aureus, Bacillus subtilis and Serratia marsecens only. The flavones were further analyzed for quantitative structural activity relationship study (QSAR) by using PASS, online software to determine their Pa value. Toxicity and drug relevant properties were revealed by PALLAS software in terms of their molecular weight. Log P values were also studied. The result showed both the F₁ and F₂ flavones as antigout and therefore supports the development of novel drugs for the treatment of gout.     

The organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one induces oxidative stress in heart, liver, and kidney of rats

The objective of this study was to investigate the in vitro effects of the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on some parameters of oxidative stress in liver, kidney, and heart of 10-day-old rats. The homogenates of liver, kidney, and heart were incubated for 1 h in the absence (control) or in the presence of 1, 10, or 30 μM of the organoselenium and thiobarbituric acid reactive substances, carbonyl, and the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were measured. First, we tested the influence of the compound on 1,1-diphenyl-2-picrylhydrazyl (DPPH(?)) radical scavenging and verified that the organochalcogen did not have any antioxidant properties. We observed an increase of lipid peroxidation in all concentrations tested in heart and kidney, while in liver only in the concentrations of 10 and 30 μM. Moreover, we also verified an enhance of protein oxidation in the concentrations of 10 and 30 μM in kidney. On the other hand, the compound caused a reduction on the activity of CAT in heart (10 and 30 μM), liver (30 μM), and kidney (30 μM). The activity of SOD was increased in heart (10 and 30 μM), while in liver (30 μM) and in kidney (10 and 30 μM) the activity was reduced. Our findings indicate that this organoselenium compound induces oxidative stress in liver, heart, and kidney of immature rats, collaborating to the fact that these tissues are potential targets for the organochalcogen action.     

Enantioselective Baeyer–Villiger Oxidation of Bicyclo[3.2.0]hept-2-en-6-One with Fungi: Optimization of Biotransformation and Use of TiO2 as Support of Cell Growth

Fungi from Amazonian forest soil (Ecuador) and an Italian factory were screened for Baeyer–Villiger (BV) oxidation of bicyclo [3.2.0]hept-2-en-6-one to 2-oxabicyclo[3.3.0]oct-6-en-3-one (Corey’s lactone). Isolates of Fusarium sp. and F. solani produced the (+)-(1R,5S)-lactone while isolates of Aspergillus terricola and A. amazonicus afforded the (−)-(1S,5R)-lactone. Highest conversions (85% yield and 70% enantiomeric excess) were obtained with A. amazonicus grown in presence of 2.7 mM titanium dioxide.     

Acute administration of the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one induces biochemical and hematological disorders in male rats

Organochalcogens are extensively produced and employed by industry and agriculture, and the risk of occupational and environmental toxicity to them has been poorly understood. Here, we investigated the acute effect of a new organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on biochemical and hematological parameters in male Wistar rats. The animals were treated with a single intraperitoneal injection of the organochalcogen at doses of 125, 250 or 500 μg·kg(-1). After 60 min, the animals were sacrificed by decapitation, and the trunk blood was collected for determination of glucose, triglycerides, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase, lactate dehydrogenase, urea, creatinine, C-reactive protein, red blood cells, hematocrit, hemoglobin and white blood cells (WBC). Our results showed a reduction in cholesterol levels in all treated groups, an increase in ALT activity at doses of 250 and 500 μg·kg(-1), a decrease of hemoglobin and an increase in WBC in animals that received 250 and 500 μg·kg(-1) of the organoselenium. In addition, we observed an increase in neutrophil counts at 125 μg·kg(-1) dose and a decrease at 500 μg·kg(-1) dose. We also verified an increase in lymphocyte counts at the dose of 500 μg·kg(-1). Thus, the present study shows that the acute treatment with this new organochalcogen causes biochemical changes and hematological disorders in male rats.     

Regulation of sulphur assimilation in lettuce plants in the presence of selenium

Selenium (Se) is considered an essential trace element for animals because of its nutritional and clinical value, including its special relevance in cancer prevention, and thus Se is at present used in biofortification programmes. However, possible effects of Se application on S metabolism and plant growth are still not clear. Thus, we analysed the effect that Se application in two different forms (selenate versus selenite) exerts on the S metabolism in lettuce plants grown for 66 days. Our results indicate that the application of selenite as opposed to selenate does not affect the foliar concentration of S. With respect to different enzymes in charge of sulphate (SO₄²⁻) assimilation, the ATP-sulphurylase activity varies only with the application of different rates of selenate, while the activity of O-acetylserine(thiol)lyase (OAS-TL) and serine-acetyltransferase (SAT) increase in activity mainly when selenite is applied. Finally, the concentration of cysteine (Cys) and total thiols (SH-total), fundamentally in the selenate treatments, increased with shoot biomass. In conclusion, this study confirms that the form and application rate of Se affects S assimilation, selenate being the more suitable form to improve effectiveness of the biofortification programme with this trace element.     

Synthesis,characterization, antiamoebic activity and cytotoxicity of new pyrazolo[3, 4-d]pyrimidine-6-one derivatives

A new series of pyrazolo[3,4-d]pyrimidine-6-one derivatives (2a–2j) were prepared by using the Biginelli multicomponent cyclocondensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1a), different aromatic aldehydes, and urea with a catalytic amount of HCl at reflux temperature. These compounds were characterized by IR, ¹H NMR, ¹³C NMR, and Mass spectral data. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica. The results showed that the compounds 2b, 2i, and 2j with IC₅₀ values of 0.37 µM, 0.04 µM, and 0.06 µM, respectively, exhibited better antiamoebic activity than the standard drug metronidazole (IC₅₀?=?1.33 µM). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that the compounds 2b, 2i, and 2j exhibited >80% viability at the concentration range of 1.56–50 µM.     

Structure and biological evaluation of novel cytotoxic sterol glycosides from the marine red alga Peyssonnelia sp

Bioactivity-guided fractionation of the extract from a Fijian red alga Peyssonnelia sp. led to the isolation of two novel sterol glycosides 19-O-β-d-glucopyranosyl-19-hydroxy-cholest-4-en-3-one (1) and 19-O-β-d-N-acetyl-2-aminoglucopyranosyl-19-hydroxy-cholest-4-en-3-one (2), and two known alkaloids indole-3-carboxaldehyde (3) and 3-(hydroxyacetyl)indole (4). Their structures were characterized by 1D and 2D NMR and mass spectral analysis. The sterol glycosides inhibited cancer cell growth with mean IC₅₀ values (for 11 human cancer cell lines) of 1.63 and 1.41 μM for 1 and 2, respectively. The most sensitive cancer cell lines were MDA-MB-468 (breast) and A549 (lung), with IC₅₀’s in of 0.71–0.97 μM for 1 and 2. Modification of the sterol glycoside structures revealed that the α,β-unsaturated ketone at C-3 and oxygenation at C-19 of 1 and 2 are crucial for anticancer activity, whereas the glucosidic group was not essential but contributed to enhanced activity against the most sensitive cell lines.     

Reduction screening with endophytic fungi: Synthesis of homochiral secondary alcohols

Twelve strains of endophytic fungi, isolated from various plants (i.e. Eugenia hallii, Schinus molle, Crataegus monogyna, Juniperus communis and Sambucus nigra) sampled in Amazonian forest and in Italy, were screened for their reduction activity with a cocktail of ketones 1–4. The four most active strains [i.e. Phomopsis (FE86 and FE290), Pestalotia and Epicoccum] were chosen for the reduction of 5-hexen-2-one 1, acetophenone 2, cis-bicyclo[3.2.0]hept-2-en-6-one 3, 2-methylcyclohexanone 4, 6-methyl-5-hepten-2-one 5, 2-furyl methyl ketone 6, 1-indanone 7, and 2,4,4-trimethyl-2-cyclohexen-1-one 8 and in all cases the S-alcohols were obtained with variable yields and enantiomeric excesses depending on the strains.     

Steroidal constituents of Solanum xanthocarpum

From the extract of the fruits of Solanum xanthocarpum (Solanaceae), five new steroidal compounds were isolated and characterized: 4α-methyl-24ξ-ethyl-5α-cholest-7-en-3β,22ξ-diol (1), 3β,22ξ-dihydroxy-4α-methyl-24ξ-ethyl-5α-cholest-7-en-6-one (2), 3β-benzoxy-14β,22ξ-dihydroxy-4α-methyl-24ξ-ethyl-5α-cholest-7-en-6-one (3), 3β-benzoxy-14α,22ξ-dihydroxy-4α-methyl-24ξ-ethyl-5α-cholest-7-en-6-one (4) and 3β-(p-hydroxy)-benzoxy-22ξ-hydroxy-4α-methyl-24ξ-ethyl-5α-cholest-7-en-6-one (5).     

3-(4-Piperidinyl)- and 3-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indoles as bioavailable h5-HT2A antagonists

A series of 3-(4-piperidinyl)- and 3-(8-aza-bicyclo[3.2.l]oct-3-yl)-2-phenyl-1H-indoles have been prepared and evaluated as ligands for the h5-HT_2A receptor. 3-(8-Phenethyl-8-aza-bicyclo[3.2.l]oct-3-yI)-2-phenyl-1H-indole is a high-affinity (1.2 nM), selective (>800 fold over h5-HT_2C and hD₂ receptors) antagonist at the h5-HT_2A receptor with oral bioavailability in rats.     

New Δ8(14)-15-Ketosterols with an Oxygenated Side Chain

New analogues of 3β-hydroxy-5α-cholest-8(14)-en-15-one (15-ketosterol) with modified 17-chains [(22S,23S,24S)- and (22R,23R,24S)-3β-hydroxy-24-methyl-22,23-oxido-5α -cholest-8(14)-en-15- ones and (22RS,23ξ,24S)-24-methyl-5α-cholesta-8(14)-ene-3β, 22,23-triol-15-one] were synthesized from (22E,24S)-3β-acetoxy-24-methyl-5α-cholesta-8(14), 22-dien-15-one. The chiralities of their 22 and 23 centers were determined by NMR spectroscopy. The isomeric 22,23-epoxides effectively inhibited cholesterol biosynthesis in hepatoma Hep G2 cells (IC₅₀ 0.9±0.2 and 0.7±0.2 μM, respectively), and their activities significantly exceeded those of 15-ketosterol (IC₅₀ 4.0±0.5 μM), (22E,24S)-3β-hydroxy-24-methyl-5α-cholesta-8(14),22- dien-15-one (IC₅₀ 3.1±0.4 μM), and the 3β,22,23-triol synthesized (IC₅₀ 6.0±1.0 μM).__________Translated from Bioorganicheskaya Khimiya, Vol. 31, No. 3, 2005, pp. 312–319.Original Russian Text Copyright © 2005 by Flegentov, Piir, Medvedeva, Tkachev, Timofeev, Misharin.     

A novel copper(II) complex with a pendant Schiff base: An unprecedented monodentate bonding mode of the potentially tridentate ligand

The 1:1 condensation of 1-benzoylacetone and 1,2-diaminopropane yields 6-amino-3-methyl-1-phenyl-4-azahept-2-en-1-one (HL). When copper(II) perchlorate is added to the methanolic solution of HL, followed by triethylamine in 1:2:1 molar ratio, an unusual copper(II) complex, [Cu(L)(HL)]ClO₄, is separated out where the deprotonated ligand, L, is coordinated in the usual chelating tridentate manner but HL is coordinated to Cu(II) only through the amine N, i.e. it acts as a pendant ligand. The complex is characterized by X-ray crystal structure analysis.     

DABCO-based chiral ionic liquids as recoverable and reusable organocatalyst for asymmetric Diels–Alder reaction

New DABCO-based chiral ionic liquids were synthesized and evaluated in asymmetric Diels–Alder reaction of cyclopentadiene with α,β-unsaturated aldehydes or 4-phenyl-3-buten-2-one. Chiral ionic liquid of modified MacMillan catalyst having a DABCO cation and hexafluorophosphate anion acts as organocatalyst (5 mol%) for the Diels–Alder reaction of crotonaldehyde and cyclopentadiene producing 98% of the product and 87% ee (endo) in CH₃CN/H₂O (95/5) at 25°C in 2 h. The scope and limitations of the catalysis were also studied by using cyclopentadiene and α,β-unsaturated aldehydes, and the Diels–Alder products were obtained in 18%–92% yields with 68%–93% ee. The catalyst was recycled and reused up to 6 cycles with a slight drop in ee and conversion of the product.     

Synthesis and evaluation of modified chalcone based p53 stabilizing agents

Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (CAL-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI₅₀ values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI₅₀ of 0.473 ± 0.043 µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-h post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities.     

Stereoselective Synthesis of Carbocyclic α-L-Homonucleosides

Abstract

The synthesis of several optically pure carbocyclic α-L-isomeric homonucleosides [3a-e, 6a,b, 7a,b, 10a-d] is reported. The (1R, 5S)-2-oxabicyclo[3.3.0]oct-6-en-3-one 1 was used as a chiral starting material.