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Poly(ADP-ribose) polymerase 1 (PARP1), a widely explored anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of a Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide co-crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC 50  = 12 μM), 4 (IC 50  = 5.8 μM), and 10 (IC 50  = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC 50  = 0.082 μM) as the most potent inhibitor of PARP1 from the series., Competing Interests: Declaration of Competing Interest TTT is a co-founder of Hysplex, LLC, with interests in PARP inhibitor development. The other authors declare no competing financial interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Polybrominated dibenzo-p-dioxins (PBDDs) and mixed bromo/chloro dibenzo-p-dioxins (PXDDs) are persistent organic pollutants that can possess the same toxicity as their fully chlorinated analogs (PCDDs) and have been identified in the same matrices. Herein a general synthetic methodology is described to produce multiple congeners of PBDDs and PXDDs with varying degrees of halogenation and substitution patterns for use as analytical and/or internal standards, and for absorption, disposition, metabolism, and excretion (ADME) studies. The syntheses of PBDDs and PXDDs were accomplished by condensing a common precursor, 4,5-dibromo catechol, with variable precursors, i.e., polychlorinated 1-chloro-2-nitrobenzenes or polybrominated 1-fluoro-2-nitrobenzenes, to introduce a desired number of halogens and specific substitution patterns. Initial attempts to synthesize PBDDs and PXDDs were performed in potassium carbonate with DMSO at 145-150 °C. PXDDs syntheses resulted in formation of the desired products at >90% purity but attempts at higher brominated PBDDs syntheses resulted in dehalogenated by-products. To preclude by-product formation, additional syntheses for some PBDDs were conducted by refluxing the precursors in acetonitrile, which resulted in pure products at higher yield. Six PXDDs ranging from four to six halogens were synthesized (20-84% yield), of which three contained the halogen substitution pattern of 2,3,7,8. Five PBDDs ranging from four to six bromines were produced in 23-83% yield, three of which were toxic. Using the initial DMSO method, [ 14 C]-1,3,7,8-tetrabromodibenzo-p-dioxin (0.26 μCi/μmol; 11% overall yield) was synthesized from commercially available [ 14 C]-phenol to allow an ADME study to be conducted., (Published by Elsevier Ltd.)

A series of novel 1,4-benzodioxane thiazolidinedione piperazine derivatives targeting FabH were designed and synthesized. The compounds exhibited better inhibitory activity against Gram-negative bacteria by computer-assisted screening, antibacterial activity test and E. coli FabH inhibitory activity test, wherein compound 6j exhibited the most significant inhibitory activity (MIC = 1.80 μΜ for P. aeruginosa, MIC = 1.56 μΜ for E. coli). Besides, compound 6j still showed the best E. coli FabH inhibitory activity (IC 50  = 0.06 μΜ). Moreover, the antibacterial activities of all compounds were strongly correlated with the inhibitory ability of FabH, with a correlation coefficient of 0.954. Computational docking studies also showed that compound 6j has interacting with FabH key residues in the active site., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A selective aziridinium ring-opening was used to etherify an α-aryl-β-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-β-amino alcohol in this system. Process analytical techniques were used to establish reaction understanding, and mixing on large scale was modeled in silico. The process provided a selective and efficient method of preparing the nonsteroidal, inhaled selective glucocorticoid receptor modulator AZD7594.

1,4-Dicyanodibenzodioxins bearing carboxy methyl ester groups were synthesized using our established one-step SNAr coupling reaction between ortho- and meta-ester substituted catechols and perfluorinated terephthalonitrile. These are the first examples of 1,4-dicyanodibenzodioxins substituted at both the benzene moieties. Optical spectra were similar to the earlier examples reported, with a marginal blue shift for the ester dibenzodioxins. Theoretical analysis of the molecular orbitals reveals modest destabilization of the frontier molecular orbitals of one carboxy methyl ester isomer over the other and overall higher HOMO-LUMO gap for both isomers when compared to the earlier published 1,4-dicyanodibenzodioxins. In vitro cytotoxicity against human cervical cancer HeLa cell line was evaluated for these two compounds and all other previously published dibenzodioxins from our laboratory (1,4-dicyano, 1,2-dicyano and 2,3-dicyano variants). A number of derivatives showed anti-tumor activity in μM ranges and also exhibited no cytotoxicity against normal HEK 293 cell line. Mechanistic investigation of cell death pathways indicated high levels of reactive oxygen species (ROS) in the dibenzodioxin treated tumor cell lines along with cellular nuclear fragmentation, both of which are markers of the apoptotic cell death pathway., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Fractionation of the bioactive CHCl 3 -MeOH (1:1) extracts obtained from two collections of the sponge consortium Plakortis symbiotica-Xestospongia deweerdtae from Puerto Rico provided two new plakinidone analogues, designated as plakinidone B (2) and plakinidone C (3), as well as the known plakinidone (1), plakortolide F (4), and smenothiazole A (5). The structures of 1-5 were characterized on the basis of 1D and 2D NMR spectroscopic, IR, UV, and HRMS analysis. The absolute configurations of plakinidones 2 and 3 were established through chemical correlation methods, VCD/ECD experiments, and spectroscopic data comparisons. When assayed in vitro against Mycobacterium tuberculosis H 37 Rv, none of the plakinidones 1-3 displayed significant activity, whereas smenothiazole A (5) was the most active compound, exhibiting an MIC value of 4.1 μg/mL. Synthesis and subsequent biological screening of 8, a dechlorinated version of smenothiazole A, revealed that the chlorine atom in 5 is indispensable for anti-TB activity.

A series of novel dioxin-containing triaryl pyrazoline derivatives C1-C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B-Raf(V600E) and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04μM and GI50 value of 0.87μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-Raf(V600E) from B-Raf(WT), C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.

In connection with its first synthesis, plakinidone was structurally revised to a five-membered lactone. The key evidence for the previous assignment of this natural product as a perlactone was proven to be a misinterpretation of the MS data because of unawareness of a facile air oxidation. The synthetic samples also allowed for detection of differences in (13)C NMR for diastereomers of remote stereogenic centers, along with the influence of the air oxidation on the optical rotation.

Employing a chiral spirodiphosphine monoxide ligand with 1,1'-spirobiindane backbone (SDP(O)), a desymmetrization strategy of Pd-catalyzed intramolecular asymmetric aryl C-O coupling of 2-(2-halophenoxy)propane-1,3-diols, was developed. The SDP(O) ligand shows much better results than its SDP counterpart. The protocol provides an efficient and highly enantioselective method for the synthesis of 2-hydroxymethyl-1,4-benzodioxanes. Density functional theory studies provide a model that accounts for the origin of the enantioselectivity.

Dibenzodioxins bearing multiple electron withdrawing groups were synthesized using a simple one-step methodology including examples of molecules possessing electron acceptor groups in both ends. As a consequence internal charge delocalization occurs and the optical spectra are found to be bathochromically shifted compared to similar examples known thus far. A theoretical analysis of the molecular orbitals reveals the origin of the peaks in the dibenzodioxin optical spectra. Select examples exhibit in vitro neuro-cytotoxicity against glioma cell line C6, a finding which enhances existing knowledge about the pharmacologically relevant structural motifs in dibenzodioxins., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We present, in this study, mechanistic and kinetic accounts of the formation of dibenzofuran (DF), dibenzo-p-dioxin (DD) and their hydroxylated derivatives (OHs-DF/OHs-DD) from the catechol (CT) molecule, as a model compound for phenolic constituents in biomass. Self-condensation of two CT molecules produces predominantly a DD molecule via open- and closed-shell corridors. Coupling modes involving the o-semiquinone radical and the CT molecule (o-SQ/CT) generate two direct structural blocks for the formation of OHs-DF/OHs-DD structures, ether-type intermediates and di-keto moieties. The calculated reaction rate constants indicate that the fate of ether-type intermediates is to make hydroxylated diphenyl ethers rather than to undergo cyclisation reactions leading to the formation of preDF structures. Unimolecular loss of a H or OH moiety from a pivotal carbon in these hydroxylated diphenyl ethers then produces hydroxylated and non-hydroxylated DD molecules. Formation of OHs-DF initiated by o(C)-o(C) cross-linkages involving o-SQ/o-SQ and o-SQ/CT reactions incurs very similar reaction and activation enthalpies encountered in the formation of chlorinated DFs from chlorophenols.

On the basis of laboratory experiments with model mixtures (active carbon+CuBr2 at different loads), this work studies the formation of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) by de novo synthesis. For the different samples, the temperature of the maximum carbon oxidation rate was determined by thermogravimetric analysis, and a kinetic model was proposed for the degradation of the materials in an oxidizing atmosphere (synthetic air). The effect of the addition of different amounts of CuBr2 was studied, finding that its presence accelerates the degradation of the carbonaceous structure in the presence of oxygen. The thermal degradation of the samples in air is satisfactorily described by a first-order single-reaction model. In addition, combustion runs of one of the mixtures (consisting of activated carbon+50 wt % CuBr2, pyrolyzed at 700 °C) were performed in a quartz horizontal laboratory furnace. The analysis of the emissions and the solid residue proved the formation of brominated dioxins and furans at 300, 400, and 500 °C, with a maximum yield at 300 °C (91.7 ng/g of total PBDD/Fs) and a higher bromination degree with increasing temperature.

A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a-5d and 8a-8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (Ki=17 nM) and 5-HT2A (Ki=0.71 nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A series of 2,3-dihydrobenzo[b][1,4]dioxin- and indolealkylamine derivatives were synthesized and the target compounds were evaluated for their binding affinities at the 5-HT1A receptor and serotonin transporter. Antidepressant-like activities of the compounds were screened using the tail suspension and forced swim tests in mice. Preliminary results indicated that the target compounds exhibited high binding affinities at the 5-HT1A receptor and serotonin transporter, and produced marked antidepressant-like effects. The best example from this study, compound 5, exhibited high binding affinities for the 5-HT1A receptor (Ki  = 96 nM) and serotonin transporter (Ki  = 9.8 nM). The intrinsic activity of compound 5 showed agonistic property to the 5-HT1A receptor and inhibition of the 5-HT transporter. Furthermore, compound 5 exhibited greater antidepressant efficacy than fluoxetine and showed acceptable pharmacokinetic properties., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This study presents a detailed mechanistic and kinetic investigation that explains the experimentally observed high yields of formation of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) from the polybrominated diphenyl ethers (PBDEs), commonly deployed in brominated flame retardants (BFRs). Theoretical calculations involved the accurate meta hybrid functional of M05-2X. The previously suggested pathways of debromination and generation of bromophenols/bromophenoxys/bromobenzenes were found to be unimportant corridors for the formation of PBDD/Fs. A loss of an ortho Br or H atom from PBDEs, followed by a ring-closure reaction, is the most accessible pathway for the production of PBDFs via modest reaction barriers. The initially formed peroxy-type adduct (RO₂) is found to evolve in a complex, nevertheless very exoergic, mechanism to produce PBDDs. Results indicate that, degree and pattern of bromination, in the vicinity of the ether oxygen bridge, has a minor influence on governing mechanisms and that even fully brominated isomers of BFRs are capable of forming PBDD/Fs. We thoroughly discuss bimolecular reactions of PBDEs with Br and H, as well as the Br-displacement reaction by triplet oxygen. The rate of the Br-displacement reaction significantly exceeds that of the unimolecular inititiation reactions due to loss of ortho Br or H. Results presented herein address conclusively the intriguing question of how PBDEs form PBDD/Fs, a matter that has been in the center of much debate among environmental chemists.

The photochemical conversion of selected hydroxylated polybrominated diphenyl ethers (OH-PBDEs) to dioxins and other products was investigated. OH-PBDEs, which are both transformation products of polybrominated diphenyl ethers and naturally occurring compounds, undergo direct photolysis to yield a number of products that may have a higher toxicity than their parent. The compounds investigated were 6-OH-PBDE 99, 6'-OH-PBDE 100, and 6'-OH-PBDE 118. Of special interest was 6'-OH-PBDE 118, a potential transformation product of PBDE 153 that is capable of photochemically generating 2,3,7,8-tetrabromodibenzo-p-dioxin, the most toxic brominated dioxin congener. Photolysis experiments were conducted at two different pH values to assess the photochemical behavior of both the phenol and phenolate form of the compounds. The percent conversion to dioxin and other photoproducts was determined and the natural product, 6-OH-PBDE 99, was found to have the highest conversion to dioxin (7%). The reaction quantum yields ranged from 0.027 to 0.16 across all photolysis conditions. In addition, it is shown that all three compounds are capable of photochemically generating other compounds of concern, including brominated phenols and a dibenzofuran.

In this Letter, we first investigated the barrier protective effects of eckol and its derivatives against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice. Data showed that eckol (1) and dieckol (2) inhibited lipopolysaccharide (LPS)-mediated barrier disruption and transendothelial migration of leukocytes to human endothelial cells. Eckol (1) also suppressed acetic acid induced-hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Interestingly, the barrier protective effects of dieckol (2) were better than those of eckol (1) and hydroxyl groups in dieckol (2) positively regulate protective effects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs),which may be generated from PBDEs, are more toxic than their matrix and have been detected in organisms. In this article, we have focused on the gas phase formation of polyhalogenated dibenzo-p-dioxins from several OH-PBDEs and their chlorinated derivatives. All of the geometries and frequencies are calculated at the MPWB1K/6-31+G(d,p) level of theory. The single point energy is obtained at the MPWB1K/6-311+G(3df,2p) level. Rate constants of each step have been calculated over a wide range of 200-2000 K using the canonical variational transition state (CVT) theory with small curvature tunneling (SCT) contribution. The rate equations are shown through Arrhenius formulas. The presence of chlorine atoms increases the reaction barrier for the formation of major products.

The synthesis of biologically active o-aminoalkyl resorcylates and related dihydroxyisoindolinones from functionalized α-amino acids without the use of phenolic protection is described. The key aminoalkyl-diketo-dioxinone intermediates were prepared utilizing a crossed Claisen condensation reaction in the presence of diethylzinc. The aromatic unit was constructed via late stage cyclization and aromatization, and subsequent modification provided the novel resorcylates which showed activity against a selection of receptors and kinases, including 5-HT and CDK.

To improve understanding of human background exposure to dioxins, the influence of cooking on dioxin concentrations in food has received much attention. Studies have focused on changes in the distribution of dioxins that originate from raw foods. However, the possibility of dioxin formation during cooking has been neglected. In this study, cooking experiments were designed to investigate the generation of dioxins during cooking at high temperature and with flavorings containing organic chlorine. Solid, liquid, and gas phase samples were collected during cooking. The results indicate that dioxins can be generated during some cooking processes, such as burning, or when cooking with reactive organic chlorides, and the dioxins are more likely to be present in the smoke (gas phase) than the edible portion (solid and liquid phases). Thus, more attention should be given to cooking of raw foods and organic chlorine-containing flavorings at high temperature. Maintaining good ventilation during cooking is also necessary to reduce human exposure risk to dioxins.

This study investigated the homogeneous gas-phase formation of polybrominated dibenzo-p-dioxin/dibenzofurans (PBDD/Fs) from 2-BP, 2,4-DBP, and 2,4,6-TBP as precursors. First, density functional theory (DFT) calculations were carried out for the formation mechanism. The geometries and frequencies of the stationary points were calculated at the MPWB1K/6-31+G(d,p) level, and the energetic parameters were further refined by the MPWB1K/6-311+G(3df,2p) method. Then, the formation mechanism of PBDD/Fs was compared and contrasted with the PCDD/F formation mechanism from 2-CP, 2,4-DCP, and 2,4,6-TCP as precursors. Finally, the rate constants of the crucial elementary reactions were evaluated by the canonical variational transition-state (CVT) theory with the small curvature tunneling (SCT) correction over a wide temperature range of 600-1200 K. Present results indicate that only BPs with bromine at the ortho position are capable of forming PBDDs. The study, together with works already published from our group, clearly shows an increased propensity for the dioxin formations from BPs over the analogous CPs. Multibromine substitutions suppress the PBDD/F formations.

The synthesis of novel fused-ring bicyclic (4-6) and tricyclic (7-10) nicotine derivatives from natural (S)-nicotine are described. Enantiopure bicyclic dioxino, dihydrofuro, and dihydropyranol nicotine derivatives as well as tricylic benzofuro and benzopyran derivatives were synthesized from simple alkoxy or halonicotine intermediates. Attempts to synthesize furonicotines (11, 12) resulted in formation of the furonicotine dimers 42 and 49.

Thirty eight heterocyclic chalcones were synthesized by condensing formylquinolines with diverse methyl arylketones. The target compounds were characterized by spectroscopic techniques (NMR, IR, MS) and elemental analysis. The X-ray crystallographic study of (2E)-3-(2-chloro-6-methylquinolin-3-yl)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-en-1-one (1p) was also performed for the structure confirmation. The title compounds were screened for anti-microbial and antileishmanial activities. The compounds 1c-e, 1g, 1j-m, 1p, 1r-s, 2g, 2j-p, and 2r-s were found potentially active antileishmanial agents, while 1f-i, 1l, 1o-p, 2f-i, 2l, and 2o-p showed remarkable antibacterial activity. Only compounds 1g and 2g-h exhibited significant antifungal activity.

2,3-Dihydro-1,4-benzodioxins can be prepared in a tandem one-pot procedure by reaction of o-iodophenols with epoxides catalyzed by Cu2O/1,10-phenanthroline/Cs2CO3 system. The reaction is suggested to occur via a novel ring-opening/coupling mechanism, giving moderate to good yields. Moreover, both aryl and aliphatic epoxides are tolerated under these conditions.

Dioxin emission factors for different combustion categories range over five orders of magnitude. Both chlorine (Cl(2)) and transition metals, including copper (Cu) have been suggested to promote the formation of dioxin in incinerators, and sulphur (S) has been suggested to inhibit dioxin formation. We show that dioxin (PCDD and PCDF) emission factors from 17 different combustion categories are approximately linearly correlated with the average copper or chlorine content of the combusted material, and inverse linearly correlated with the average sulphur content of the material. Copper and chlorine are correlated and, thus cannot be distinguished. The analysis suggests that the wide range of dioxin emission factors could be explained by the content of sulphur and transition metals or chlorine in combusted materials.

Goal, Scope and Background: Changes in German and European legislation shifted processing of polymer-rich shredding residues (SR) from landfill to thermal treatment. However, when waste of electric and electronic equipment (WEEE) is the source of SR, thermal treatment is complicated by halogens as well as the presence of polybrominated dioxins and furans (PBDD/F) and brominated flame retardants (BFR). Hence, WEEE requires high temperature incineration with sufficient residence times. Post-combustion synthesis of polyhalogenated dioxins and furans (PXDD/F) is dominant in the temperature range between 250-450 degrees C. Thus, a very rapid gas cooling from 450 degrees to 250 degrees C is important for proper raw gas treatment. The pebble heater technology developed by ATZ Entwicklungszentrum (Sulzbach-Rosenberg, Germany) might serve as an alternative to the state-of-the-art quench cooling. It is based on the application of a pebble bed of natural bulk material, which the exhaust gases flows through radially. It provides an excellent heat transfer and a temperature gradient in the range of 1,500-2,000 K/m. The paper presents data of a pilot application of the pebble heater technology for the treatment of raw gas derived from the incineration of polymeric materials from WEEE., Methods: A liquid fuel was chosen in order to minimise technical modifications of the plant. It was analysed for halogens by x-ray fluorescence, for brominated flame retardants by HPLC-UV/MS and for PXDD/F by GC-HRMS. Combustion gases were rapidly cooled down to temperatures below 200 degrees C and emissions of PBDD/F and PCDD/ F were estimated without further off-gas treatment. PBDD/F emissions were computed as PCDD/F toxicity equivalents applying two different calculation approaches., Results and Discussion: PCDD/F emissions accounted for 0.04 ng I-TEQ/Nm3 and are in compliance with European emission limits. Calculated PBDD/F toxicity equivalents exceeded the emission limit of 0.1 ng I-TEQ/Nm3 by factors of 75 and 208 depending on the calculation approach. A mass balance of PBDD/F and PCDD/F congeners revealed an efficient elimination of more than 95% in most cases. Lower reduction rates (76% for 2,3,7,8-TeBDF and 82% for 1,2,3,7,8-PeBDF) were attributed to incomplete combustion. An intended recovery of halogens by one-stage scrubbing downstream of the pebble heater was ineffective, recovering 28% of the applied chlorine and 9% of the bromine, only., Conclusions: Our pilot incineration test indicates that the pebble heater technology can effectively suppress a post-combustion synthesis of PCDD/F and PBDD/F, resulting in low PCDD/F emission levels without further off-gas treatment. The presented data state that WEEE is sensible to incomplete combustion, which will lead to increased PBDD/F emissions without increasing PCDD/F emission limits. This finding is especially relevant for small and low-technical incineration appliances, which have been reported to treat WEEE in developing countries and are considered to serve as a significant source of PXDD/F these days., Recommendations and Perspectives: Monitoring of PCDD/F emissions only might considerably underestimate the total emission of dioxins and dioxin-like compounds. It is therefore an ineffective means for assessing resulting health risks, at least for those waste treatment plants which are considered to handle the increasing amounts of PBDD/ F-containing polymers from WEEE in future. Consequently, it is recommended to initiate a screening programme for PXDD/F emissions in large scale incineration facilities which are capable of treating WEEE shredder residues.

Density functional theory (DFT) calculations have been carried out to explore the potential energy surface (PES) associated with the gas-phase reaction between 2,4,5-trichlorophenol and CuO. A gas-phase model was constructed to account, from a theoretical perspective, for the most important reaction steps reported experimentally for the interaction between chlorinated phenol and a CuO surface. This involves the facile production of the chlorophenoxy radical through hydroxyl H abstraction, formation of HOCu-2,4,5-trichlorophenolate complex, and reduction of Cu-(II) into Cu(I) through chlorophenoxy desorption from the chlorophenolate complex. The overall process: 2,4,5-trichlorophenol + CuO --> 2,4,5-trichlorophenoxy radical + CuOH is significantly exothermic and facile (unlike the strongly endothermic process of 2,4,5-trichlorophenol --> 2,4,5-trichlorophenoxy radical + H) suggesting that in the gas phase, at least, CuO would be an efficient catalyst for production of polychlorinated phenoxy radicals which are known precursors of dioxins. Hence, the present study should be an important preliminary to a detailed investigation of the efficacy of CuO surfaces toward catalysis of dioxin formation. Lastly, we estimate the reaction energies for the reaction 2,4,5-trichlorophenol + MO --> 2,4,5-trichlorophenoxy radical + MOH for the first-row transition metal monoxides. This reaction only becomes exothermic for elements which have at least a half-filled d shell. Although the results of the present thermodynamic analysis match the observed catalytic effect toward dioxin formation, kinetic considerations are expected to play a major role as well.

Novel 5-benzyl and 5-benzylidene-thiazolidine-2,4-diones carrying 2,3-dihydrobenzo[1,4]dioxin pharmacophore were synthesized and their glycogen phosphorylase inhibitor activity was also studied.

A set of disubstituted tetracyclic lactones has been synthesized and tested for potential antitumor activity. Several of them possess a noticeable cytotoxicity against L1210 and HT-29 colon cells in vitro. Relationships between chain nature and biological properties were sought. Lactones with a pentyl or hexyl substituent at C-11 are the most active ones. The introduction of a functional group at the side chain of C-11 modified the potency; carboxylic acid and primary amine decreased the cytotoxicity, whereas a cyano group increased the activity. An extensive structure-activity relationship study of these derivatives, including carbon homologues and bioisosteres has been performed. The synthesis and cytotoxicity of these compounds are discussed. Two lactones are recognized as potential lead compounds.

Potassium ion (K+) channels are attractive targets for drug discovery because of the essential roles played in biological systems. However, high-throughput screening (HTS) cannot be used to screen K+ channel blockers. To overcome this disadvantage of HTS, we have developed a virtual screening approach for discovering novel blockers of K+ channels. On the basis of a three-dimensional model of the eukaryotic K+ channels, molecular docking-based virtual screening was employed to search the chemical database MDL Available Chemicals Directory (ACD). Compounds were ranked according to their relative binding energy, favorable shape complementarity, and potential to form hydrogen bonds with the outer mouth of the K+ channel model. Twenty candidate compounds selected from the virtual screening were examined using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. Among them, six compounds (5, 6, 8, 18-20) potently blocked both the delayed rectifier (IK) and fast transient K+ currents (IA). When applied externally, these six compounds preferentially blocked IK with potencies 2- to 500-fold higher than that of tetraethylammonium chloride. Intracellular application of the six compounds had no effect on both K+ currents. In addition, the interaction models and binding free energy calculations demonstrated that hydrophobic interaction and solvent effects play important roles in the inhibitory activities of these compounds. The results demonstrated that structure-based computer screening strategy could be used to identify novel, structurally diverse compounds targeting the pore binding pocket of the outer mouth of voltage-gated K+ channels. This study provides an alternative way of finding new blockers of voltage-gated K+ channels, while the techniques for high-throughput screening of K+ channel drugs remain in development.

Dioxins in the combustion gas of municipal solid waste incinerators (MSWIs) are resynthesized when the combustion gas passes from the outlet exaust gas boiler to the outlet gas duct. The objective of the study was to estimate if the suppression of the formation of dioxins depends on the inlet gas temperature and diameter and/or temperature of droplet spray water using an actual incinerator operation data. The dioxin formation and/or the quenching temperature is revealed using the Altwicker theory equation with the information of inlet gas temperature and droplet spray water. The evaporation rate of a spray water droplet also can be estimated using the Mizutani theory. The highest dioxin formation was found at 350 degrees C; thereafter, it decreased quickly. When an area of 500 microm for droplet-formed dioxins is defined as 100%, the values of formed dioxins for 400, 300, 200 and 100 microm droplet areas are estimated as 71, 41, 25 and 18%, respectively. It is revealed that the smaller size of droplet spray water and lower inlet gas temperature enable the decrease in dioxin formation. The decreased dioxin formation and/or the lower quenching temperature is revealed using the Altwicker theory equation with the information of inlet gas temperature and droplet spray water size.

A 12-days photolysis experiment of triclosan, a widely used bactericide, was performed in freshwater and seawater under a low intensity artificial white light source. Photodegradation of triclosan was observed in both the freshwater and seawater samples. Assuming a first-order reaction, half-lives of triclosan in the freshwater and seawater were approximately 8 and 4 days, respectively. 2,8-Dichlorodibenzo-p-dioxin (DCDD) was detected in both the freshwater and seawater samples after 3 days of irradiation. The photodegradation of triclosan and the production of DCDD suggest that triclosan could be less stable and DCDD might be more stable in seawater than freshwater. As a result, DCDD produced from triclosan survives for a longer time in seawater.

[reaction: see text] The anodic oxidation of pyrogallol derivatives produces chemically unstable o-quinone heterodienes, which are trapped in situ by enamine dienophiles through regiospecific inverse-electron-demand Diels-Alder reactions. The possibility of introducing variations in both cycloaddition partners gives rise to highly substituted 1,4-benzodioxin cycloadducts with up to five elements of diversity. The reactions proceed under mild conditions with a good efficiency. The methodology should be amenable to the assembly of libraries of biologically relevant heterocycles.

The homogeneous, gas-phase pyrolytic thermal degradation of a 50:50 mixture of 2-bromophenol and 2-chlorophenol was studied in a 1 cm i.d., fused silica flow reactor at a total concentration of 88 ppm, reaction time of 2.0 s, and temperatures from 300 to 1000 degrees C. Observed products included (in decreasing yield) naphthalene, dibenzo-p-dioxin (DD), phenol, dibenzofuran (DF), bromobenzene, chloronaphthalene, 4-bromo-6-chlorodibenzofuran (4-B,6-CDF), bromonaphthalene, benzene, 4,6-dichlorodibenzofuran (4,6-DCDF), chlorobenzene, 4-monobromodibenzofuran (4-MBDF), 4-monochlorodibenzofuran (4-MCDF), 1-mono-bromodibenzo-p-dioxin (1-MBDD), 2-chloro,4-bromophenol, 2,4-dibromophenol, and 2-bromo-4-chlorophenol. Unlike the case for the pyrolysis of pure 2-chlorophenol, 4,6-DCDF was observed, but the analogous 4,6-DBDF remained undetected similar to the individual results with 2-MBP. This indicates that the presence of bromine increases the concentration of chlorine atoms available for the formation of 4,6-DCDF. Due to bromine atoms acting as better leaving groups than chlorine atoms, the yield of DD was increased over that observed for the pyrolysis of 2-chlorophenol. The addition of bromine to a chlorinated hydrocarbon system results in an increase in the total yield of PCDD/Fs as well as PBDD/Fs and mixed PBCDD/Fs due to the ease of bromine elimination reactions as well as an increase of the chlorine atom concentration.

Derivatives of the natural product 11-hydroxy-3-[(S)-1-hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxocin-5-one 1 were studied as novel CETP inhibitors. Compound 2 was identified from HTS as a micromolar inhibitor. The compound suffered from very low stability in plasma. Optimisation by partial synthesis started from 1 and led to low-nanomolar inhibitors with good stability in rat plasma.

The homogeneous, gas-phase oxidative thermal degradation of 2-bromophenol was studied in a 1 cm i.d., fused silica flow reactor at a concentration of 88 ppm, reaction time of 2.0 s, over a temperature range from 300 to 1000 degrees C. Observed products in order of yield were dibenzo-p-dioxin (DD) > 4,6-dibromodibenzofuran (4,6-DBDF) > 4-monobromodibenzofuran (4-MCDF), dibenzofuran (DF), 1-monobromodibenzo-p-dioxin (1-MBDD), naphthalene, bromonaphthalene, 2,4-dibromophenol, 2,6-dibromophenol, phenol, bromobenzene, and benzene. This result is in contrast to the oxidation of 2-chlorophenol, where the major product is 4,6-dichlorodibenzofuran (4,6-DCDF). 4,6-DBDF was observed in high yields in contrastto our previous results for the pyrolysis of 2-bromophenol, where 4,6-DBDF was not detected. The increase in 4,6-DBDF yields is attributed to hydroxyl radical being the major chain carrier under oxidative conditions, which favors hydrogen-abstraction reactions that lead to formation of 4,6-DBDF. However, DD is still the highest yield product under oxidative conditions because of the relative ease of displacement of Br in the ring-closure reaction.

Safe animal by-product disposal is a priority target as a result of the Bovine Spongiform Encephalopathy crisis in the European beef industry. One such disposal option is the incineration of by-product material such as meat and bone meal residues (MBM) for the purpose of energy recovery. Although currently applied, the thermal decomposition of MBM wastes has not been scientifically studied until now. A series of experiments has been performed to study the thermal behavior of MBM both in inert (N2) and reactive atmosphere (air), both by thermogravimetry and in a horizontal laboratory furnace. As a general trend, MBM gives low PCDD/F values, compared with incineration of other wastes. Maximum yield of pollutants is observed at a nominal temperature between 700 and 800 degrees C.

The objectives of this work are to understand the details of the mechanism of dioxin formation in the part of a sintering bed termed the dry zone, and to obtain ideas on how to prevent their formation. Sinter mixtures of various composition types were heated in a packed bed reactor, and dioxins in the outlet gas and in the sinter mixture residue were measured. The dioxin formation potential of a simple sinter mixture composed of iron ore, coke and limestone was markedly lower than that of fly ash from a municipal solid waste incinerator (MSWI). In consideration of this result, a series of experiments were conducted using a sinter mixture impregnated with CuCl2. Experimental results showed that dioxin formation was temperature-dependent in the range of 300-550 degrees C, with the maximum observed at around 300 degrees C, which was quite similar to that of fly ash from the MSWI. The homologue distribution of PCDD/Fs in gas and solid reflected the possible difference in carbonaceous materials in coke and activated coke. Gaseous hydrogen chloride acted as a chlorinating reagent for dioxin formation.

Experiments were conducted at the VERONA pilot plant, an incineration plant with stationary grate and separate post-combustion chamber, using wood and propane as basic combustible materials and with controlled dosage of various bromine-, chlorine- and copper-containing compounds. The behaviour of the following compounds was studied in the combustion chamber, after the post-combustion chamber and after the heat exchanger: polychlorinated phenols (PCPh), polybrominated phenols (PBrPh), polychlorinated benzenes (PCBz), polybrominated benzenes (PBrBz), polychlorinated dioxins and furans (PCDD/F) and polybrominated dioxins and furans (PBDD/F). The bromine co-incineration leaded to very high bromophenol concentrations after the post-combustion chamber. The formation of brominated and mixed-halogenated phenols and the further reaction to halogenated dioxins is apparently a relevant reaction mechanism for dioxin formation in processes involving bromine. This assumption is supported by the high formation rates of PBDD/F found in the heat exchanger, which were 4-20 times higher than those of PCDD/F. Moreover, the strong correlations found between the formation rates of PCPh, PCBz and PCDD/F in the heat exchanger indicate that in addition considerable new formation of dioxins takes place through de novo synthesis. Experiments involving the variation of primary operational parameters and fuel properties have shown that the quality of post-combustion plays a much greater role than the other parameters. Furthermore, it became apparent that the congeners of the chlorophenols and of the chlorobenzenes, measured in various incineration stages, do not correlate closely with the dioxin concentrations after the heat exchanger.

The total amounts of dioxins found in exhaust gases from combustion of polyethylene (PE), polystyrene (PS), and poly(ethylene terephthalate) (PET) with approximately 3% (w/ w) NaCl were 6.07, 17.7, and 28.9 ng/g, respectively. Plastics containing benzene rings produced more dioxins than plastic containing no benzene ring. The amounts of dioxin formed in the exhaust gases from the combustion of newspapers impregnated with CaCl2, KCl, and NaCl were 18.6, 28.6, and 49.0 ng/g, respectively. Dioxin formation was associated with the bond energy between metal atom and chlorine atom. When newspapers impregnated with four different amounts of NaCl were combusted, the highest NaCl content newspaper (chlorine content 4.08%, w/w; lignin content 19.8%, w/w) produced the greatest amount of dioxins (174 ng/g). Pulp with NaCl (chlorine content 4.25%, w/w; lignin content 0.69%, w/w) produced more dioxins (6.71 ng/g) than pulp alone (0.799 ng/g) did upon combustion. The lignin content in a combustion sample correlated with the amount of dioxin formation. The results exhibited that combustion conditions with low CO concentration (<2 ppm) produced much less dioxins than conditions with high CO concentration (159 ppm).

2,4,5,7,8-Pentamethyl-4H-1,3-benzodioxin-6-ol (PBD, 1) is a novel 3-oxa-tocopherol-type stabilizer, which is obtained as a mixture of two diastereomers by condensation of trimethylhydroquinone with acetaldehyde in an acid-catalyzed reaction. The oxidation behavior of 1 is governed by the amount of water available. In aqueous media, 1 is oxidized by one oxidation equivalent to 2,5-dihydroxy-3,4,6-trimethylacetophenone (3) via 2-(1-hydroxyethyl)-3,5,6-trimethylbenzo-1,4-quinone (2). The acid-catalyzed conversion of 2 into 3 proceeds in solution with first-order kinetics with regard to 2 but works also in solid phase. Oxidation in the presence of just 1 equiv of water produces acetophenone 3 as well, but according to a different mechanism involving o-quinone methide 5 and styrene derivative 6, from which finally acetaldehyde is released. A [1,5]-sigmatropic proton shift from the C-4a methyl group to the exocyclic methylene group in 5 causes formation of 6, as demonstrated by labeling experiments. In addition, the presence of both intermediates was proven by hetero-Diels-Alder trapping reactions. In the absence of water, oxidation of 1 produces chromenone 10 via the intermediates 5 and 6 and chromanone 9, and oxidation of 9 to 10 is preferred to oxidation of starting material 1. When the formation of an exocyclic methylene group at C-4 is impossible as a result of structural prerequisites, as in the diphenyl derivative 12, the initially generated o-quinone methide 5 cannot form 6 but undergoes dimerization to spiro-compounds. The transformation of p-quinone 2 into acetophenone 3 might contribute to the chemistry of tocopherols oxidized at C-4, i.e., 4-hydroxy-alpha-tocopherol and 4-oxo-alpha-tocopherol, which have been proposed as precursors of natural vitamin E metabolites.

A series of 6- or 7-substituted 2-carboxamido- or 2-(aminomethyl)-1,4-benzodioxin and -2,3-dihydro-1,4-benzodioxin derivatives were synthesized and evaluated to determine the necessary structural requirements for a high inhibition of human low-density lipoprotein copper-induced peroxidation. The most active compounds (21, 25, 28, 36, and 37) were found between 5 and >45 times more active than probucol itself. Due to both their potency and their structural features, compounds 25 and 36 were selected with others for complementary in vitro and in vivo investigations. Both of them exhibit calcium antagonist properties in the same range of potency as flunarizine itself. Compound 36 was also found to have significant hypolipaemic activity in mice at 100 and 300 mg/kg po, while compound 25 proved to be clearly active in a normobar hypoxia test.

A method for two-step synthesis of dioxin derivatives containing the perfluoropyridine ring has been suggested. It consists of the preparation of corresponding predioxin in the first stage and its cyclization in the next stage. A number of new predioxins have been synthesized using the interaction of polyhalogenpyridines with pyrocatechin and its 4,5-dihaloid derivatives. Formation of dioxins on the basis of not very active arenes occurs smoothly without the necessity for the isolation of predioxin intermediates. For the first time, an interaction of polyhalogenpyridine-containing dioxins and predioxins with nucleophiles of various types (alkyl and arylamines, propylenediamine, hydroxyl anion, and ammonia) has been studied. It was shown that the pyridine fragment does not change the fundamental rules of orientation influence of substituents detemined for non-heterocyclic polyfluorinated arenes. The presence of the labile fluorine atoms reveals a possibility for various modifications of dioxins and predioxins.

We report the synthesis of five new tetracyclic benzodioxins, from reaction of 1,2-naphthalenediol, 7,8-dihydroxyquinoline or 7,8-dihydroxyisoquinoline with isopropyl 2-chloro-3-nitrobenzoate. Mixtures of isomeric esters were obtained which were separated by conventional flash silica chromatography or preparative HPLC and fully characterized by NMR. Ester hydrolysis and amide formation afforded the target carboxamides 7-9, 11 and 12. The biological activities of the benzodioxins broadly paralleled those of the corresponding phenazines. A tetracyclic pyrido derivative was the most cytotoxic, with an IC50 of 0.11 microM in P388 leukaemia cell culture, but did not represent a significant improvement over a number of 9-substituted tricyclic phenazines.

[reaction--see text] A variety of 2-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridines B have been synthesized from the readily available 2-nitro-3-oxiranylmethoxypyridine 1 via a Smiles rearrangement. We demonstrate how variations of reaction conditions affect the product distribution of A and B.

In connection with the development of new potential 5-HT1A ligands, multistep synthesis of N-substituted-3-aminomethyl-2,3-dihydro-1,4-dioxinol[2,3-b]pyridin e derivatives as ORG13514 analogs are described. Their biological activity as 5-HT1A type ligands is reported and compared with ORG13514 affinity and selectivity for 5-HT1A receptors.

The synthesis of 2H-benzopyrano[7,8-b][1,4]tetrahydrobenzodioxin-2-ones and 2H-benzopyrano [7,8-b][1,4]benzodioxin-2-ones is reported. This class of compounds, prepared with the aim of obtaining new monofunctional photosensitizing drug, appears to be ineffective upon UVA irradiation but shows a moderate but significant activity in the dark.

The enantiomers of trans-[2-(2,6-dimethoxyphenoxy)ethyl] [(3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-yl) methyl]amine (mephendioxan, 2) were synthesized from the chiral trans-3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-carboxylic acids [(+)-3 and (-)-3] which in turn were obtained through the resolution of the racemic acid with (R)- and (S)-alpha-methylbenzylamine. Comparison of CD spectra of the enantiomers of 2 with that of (2S,3S)-3-methyl-2-phenyl-1,4-benzodioxane allowed the assignment of the 2S,3S configuration to the (-)-enantiomer of 2 and of the 2R,3R configuration to the other enantiomer. The binding profile of the enantiomers of 2 was assessed at alpha 1, alpha 2, D2, and 5-HT1A receptors, in comparison to WB 4101 (1), 5-methylurapidil, and (+)-niguldipine. In addition, the two enantiomers were investigated at native and cloned alpha 1-adrenoreceptor subtypes. (-)-2 was 10-30 times as potent as the (+)-enantiomer at alpha 1-adrenoreceptor subtypes in both functional and binding assays. It was 36-fold selective for the alpha 1A- versus alpha 1B-adrenoreceptor and 60- and 20-fold selective in binding to the alpha 1a-adrenoreceptor relative to alpha 1b and alpha 1d subtypes, respectively. Furthermore, the enantiomer (-)-2 displayed selectivities of 12000-, 2500-, and 250-fold in binding to alpha 1a-adrenoreceptors relative to alpha 2-adrenoreceptors and 5-HT1A and D2 receptors. These results indicate that (-)-2 may be a valuable tool in the characterization of alpha 1-adrenoreceptor subtypes.