Microwave-assisted synthesis and bioevaluation of new sulfonamides

In this study, 4-[5-(4-hydroxyphenyl)-3-aryl-4,5-dihydro-1H-pyrazol-1-yl]benzenesulfonamide derivatives (8-14) were synthesized for the first time by microwave irradiation and their chemical structures were confirmed by ¹H NMR, ¹³C NMR and HRMS. Cytotoxic activities and inhibitory effects on carbonic anhydrase I and II isoenzymes of the compounds were investigated. The compounds 9 (PSE?=?4.2), 12 (PSE?=?4.1) and 13 (PSE?=?3.9) with the highest potency selectivity expression (PSE) values in cytotoxicity experiments and the compounds 13 (Ki?=?3.73?±?0.91?nM toward hCA I) and 14 (Ki?=?3.85?±?0.57?nM toward hCA II) with the lowest Ki values in CA inhibition studies can be considered as leader compounds for further studies.     

HPLC fluorescence method for the determination of nizatidine in human plasma and its application to pharmacokinetic study

A sensitive high‐performance liquid chromatographic (HPLC) method was developed for the determination of nizatidine in human plasma. Nizatidine was derivatized by 4‐fluoro‐7‐nitrobenzofurazan (NBD‐F). Chromatographic separation was performed on a Inertsil C₁₈ column (150 mm × 4.6 mm, 5 µm) using isocratic elution by a mobile phase consisting of methanol/water (55:45) at a flow rate of 1.2 mL/min. Amlodipine was used as the internal standard (IS). Fluorescence detector was used operated at 461 nm (excitation) and 517 nm (emission), respectively. The calibration curve was linear over the range of 50–2000 ng/mL. This method was successfully applied to a pharmacokinetic study after oral administration of a dose (150 mg) of nizatidine. Copyright © 2013 John Wiley & Sons, Ltd.     

Dietary Exposure to PCDD/Fs Through Animal Products in a Highly Polluted Area in Turkey

We present an estimation of dietary exposure to PCDD/Fs by animal products in Kocaeli, a highly polluted area in Turkey, based on current food data consumption. The calculation of the PCDD/F intakes by an exposure methodology concerning consumption habits of different receptor groups in Kocaeli was included. The data relate to the PCDD/F levels in food groups of animal origin (milk, egg, meat, chicken, and fish), food consumption rates, and the fractions of locally grown foods in total consumption were statistically assessed. Monte Carlo simulation was used to estimate the ranges of PCDD/F doses through the consumption of animal products. The PCDD/F intakes through the consumption of animal products were calculated to average between 0.4–1.8 pg WHO-TEQ.kg^?1 bodyweight (bw).day^?1. The results are within the range of 1–4 pg WHO-TEQ.kg^?1 bw.day^?1, proposed as the tolerable daily intake by the World Health Organization. On the other hand, contributions of the consumption of different foods to the total PCDD/F intake and the results of sensitivity analysis showed that the PCDD/F intake in semi-urban and rural settings was determined primarily by the consumption of milk products, while consumption of meat and fish had a greater importance in urban settings.     

Formate hydrogenlyase and formate secretion ameliorate H2 inhibition in the hyperthermophilic archaeon Thermococcus paralvinellae

Some hyperthermophilic heterotrophs in the genus Thermococcus produce H₂ in the absence of S° and have up to seven hydrogenases, but their combined physiological roles are unclear. Here, we show which hydrogenases in Thermococcus paralvinellae are affected by added H₂ during growth without S°. Growth rates and steady‐state cell concentrations decreased while formate production rates increased when T. paralvinallae was grown in a chemostat with 65 µM of added H_2(aq). Differential gene expression analysis using RNA‐Seq showed consistent expression of six hydrogenase operons with and without added H₂. In contrast, expression of the formate hydrogenlyase 1 (fhl1) operon increased with added H₂. Flux balance analysis showed H₂ oxidation and formate production using FHL became an alternate route for electron disposal during H₂ inhibition with a concomitant increase in growth rate relative to cells without FHL. T. paralvinellae also grew on formate with an increase in H₂ production rate relative to growth on maltose or tryptone. Growth on formate increased fhl1 expression but decreased expression of all other hydrogenases. Therefore, Thermococcus that possess fhl1 have a competitive advantage over other Thermococcus species in hot subsurface environments where organic substrates are present, S° is absent and slow H₂ efflux causes growth inhibition.     

Evaluation of Montandoniola confusa Streito and Matocq sp. nov. and Orius insidiosus Say (Heteroptera: Anthocoridae), for control of Gynaikothrips uzeli Zimmerman (Thysanoptera: Phlaeothripidae) on Ficus benjamina

Since its discovery in Florida in 2003, the weeping fig thrips, Gynaikothrips uzeli Zimmerman has spread rapidly throughout the southeastern United States in shipments of ornamental Ficus benjamina L. Concurrently, there have been reports of an invasive anthocorid, Montandoniola confusa (=moraguesi) Streito and Matocq sp. nov., widely associated with G. uzeli populations in landscape plantings of ornamental Ficus spp. We evaluated M. confusa and a commercially available anthocorid, Orius insidiosus Say, as biological control agents of G. uzeli. Prey preference studies revealed that eggs were the numerically preferred host stage for both predator species (representing 92% and 94% of all prey taken in ‘no choice’ and ‘choice’ tests, respectively). Females of both predator species consumed significantly more eggs than males (83–91 versus 25–35 per 48 h period, respectively), and (in the absence of eggs) also more larvae (4.1–5.5 versus 2.1–2.5). Fecundity of M. confusa was significantly higher than for O. insidious, 10.6 ± 1.5 eggs per 48 h versus 5.0 ± 1.4, respectively. Greenhouse tests on heavily infested F. benjamina revealed that M. confusa was a highly effective predator of G. uzeli. Evaluations with three F. benjamina cultivars showed that M. confusa reproduced throughout the year and reduced thrips populations ⩾95% and leaf galls by up to 77% within 5 weeks. By contrast O. insidiosus did not establish or significantly reduce populations of G. uzeli inside leaf galls. Methods to monitor and protect M. confusa in urban landscapes are discussed.     

Enhanced G2/M Arrest,Caspase Related Apoptosis and Reduced E-Cadherin Dependent Intercellular Adhesion by Trabectedin in Prostate Cancer Stem Cells

Trabectedin (Yondelis, ET-743) is a marine-derived tetrahydroisoquinoline alkaloid. It is originally derived from the Caribbean marine tunicate Ecteinascidia turbinata and currently produced synthetically. Trabectedin is active against a variety of tumor cell lines growing in culture. The present study focused on the effect of trabectedin in cell proliferation, cell cycle progression, apoptosis and spheroid formation in prostate cancer stem cells (CSCs). Cluster of differentiation (CD) 133^+high/CD44^+high prostate CSCs were isolated from the DU145 and PC-3 human prostate cancer cell line through flow cytometry. We studied the growth-inhibitory effects of trabectedin and its molecular mechanisms on human prostate CSCs and non-CSCs. DU-145 and PC-3 CSCs were treated with 0.1, 1, 10 and 100 nM trabectedin for 24, 48 and 72 h and the growth inhibition rates were examined using the sphere-forming assay. Annexin-V assay and immunofluorescence analyses were performed for the detection of the cell death. Concentration-dependent effects of trabectedin on the cell cycle were also evaluated. The cells were exposed to the different doses of trabectedin for 24, 48 and 72 h to evaluate the effect of trabectedin on the number and diameter of spheroids. According to the results, trabectedin induced cytotoxicity and apoptosis at the IC₅₀ dose, resulting in a significant increase expression of caspase-3, caspase-8, caspase-9, p53 and decrease expression of bcl-2 in dose-dependent manner. Cell cycle analyses revealed that trabectedin induces dose-dependent G2/M-phase cell cycle arrest, particularly at high-dose treatments. Three-dimensional culture studies showed that trabectedin reduced the number and diameter of spheroids of DU145 and PC3 CSCs. Furthermore, we have found that trabectedin disrupted cell-cell interactions via E-cadherin in prostasphere of DU-145 and PC-3 CSCs. Our results showed that trabectedin inhibits cellular proliferation and accelerates apoptotic events in prostate CSCs; and may be a potential effective therapeutic agent against prostate cancer.     

Designing,synthesis and bioactivities of 4-[3-(4-hydroxyphenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]benzenesulfonamides

In this study, 4-[3-(4-hydroxyphenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]benzenesulfonamide (1–9) types compounds were synthesized and their chemical structures were confirmed by ¹H NMR, ¹³C NMR and HRMS spectra. Cytotoxic and carbonic anhydrase (CA) inhibitory effects of the compounds were investigated. Cytotoxicity experiments pointed out that compound 4, (4-[5-(4-chlorophenyl)-3-(4-hydroxyphenyl)-4,5-dihydro-pyrazol-1-yl]benzenesulfonamide), exerting the highest tumor selectivity (TS) and potency selectivity expression (PSE) values, can be considered as a lead compound of this study in terms of development of novel anticancer agents. All synthesized sulfonamides showed a good inhibition profile on hCA IX and XII in the range of 53.5–923?nM and 6.2–95?nM, respectively. These compounds were 2.5–13.4 times more selective for the inhibition of hCA XII versus hCA IX, except compound 2 which had similar inhibitory action towards both isoenzymes.     

Inhibitory effects of isatin Mannich bases on carbonic anhydrases,acetylcholinesterase, and butyrylcholinesterase

The effects of isatin Mannich bases incorporating (1-[piperidin-1-yl (P1)/morpholin-4-yl (P2)/N-methylpiperazin-1-yl (P3)]methyl)-1H-indole-2,3-dione) moieties against human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoenzymes hCA I and hCA II, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes were evaluated. P1–P3 demonstrated impressive inhibition profiles against AChE and BChE and also inhibited both CAs at nanomolar level. These inhibitory effects were more powerful in all cases than the reference compounds used for all these enzymes. This study suggests that isatin Mannich bases P1–P3 are good candidate compounds especially for the development of new cholinesterase inhibitors since they were 2.2–5.9 times better inhibitors than clinically used drug Tacrine.