Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1 inhibitors.

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 (IC50 = 12 µM), 4 (IC50 = 5.8 µM), and 10 (IC50 = 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, IC50 = 0.082 µM) as the most potent inhibitor of PARP1 from the series.

Stereoretentive Etherification of an α-Aryl-ß-amino Alcohol Using a Selective Aziridinium Ring Opening for the Synthesis of AZD7594.

A selective aziridinium ring-opening was used to etherify an α-aryl-ß-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-ß-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.

Design, synthesis and molecular docking of 1,4-benzodioxane thiazolidinedione piperazine derivatives as FabH inhibitors.

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 (IC50 = 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.

Synthesis and electronic properties of ester substituted 1,4-dicyanodibenzodioxins and evaluation of anti-proliferative activity of all isomeric 1,2-, 2,3- and 1,4-dicyanodibenzodioxins against HeLa cell line.

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.

Exploring the Sponge Consortium Plakortis symbiotica-Xestospongia deweerdtae as a Potential Source of Antimicrobial Compounds and Probing the Pharmacophore for Antituberculosis Activity of Smenothiazole A by Diverted Total Synthesis.

Fractionation of the bioactive CHCl3-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 H37Rv, 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.

Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors.

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.

Synthesis and photophysical characterization of quasi push-pull dicyanodibenzodioxins and their anti-tumor activity against glioma cell line C6.

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.

Formation of dibenzofuran, dibenzo-p-dioxin and their hydroxylated derivatives from catechol.

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.

Synthesis and biological evaluation of a series of benzoxazole/benzothiazole-containing 2,3-dihydrobenzo[b][1,4]dioxine derivatives as potential antidepressants.

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.

De novo synthesis of brominated dioxins and furans.

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.

Synthesis and evaluation of novel 2,3-dihydrobenzo[b][1,4]dioxin- and indolealkylamine derivatives as potential antidepressants.

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.

A mechanistic and kinetic study on the formation of PBDD/Fs from PBDEs.

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.

Vascular barrier protective effects of eckol and its derivatives.

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.

Photochemical formation of brominated dioxins and other products of concern from hydroxylated polybrominated diphenyl ethers (OH-PBDEs).

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.

Conversion of α-amino acids into bioactive o-aminoalkyl resorcylates and related dihydroxyisoindolinones.

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.

Mechanism and direct kinetics study on the homogeneous gas-phase formation of PBDD/Fs from 2-BP, 2,4-DBP, and 2,4,6-TBP as precursors.

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.

Mechanical and kinetic studies of the formation of polyhalogenated dibenzo-p-dioxins from hydroxylated polybrominated diphenyl ethers and chlorinated derivatives.

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.

Synthesis of fused-ring nicotine derivatives from (S)-nicotine.

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.

Antimicrobial and antileishmanial studies of novel (2E)-3-(2-chloro-6-methyl/methoxyquinolin-3-yl)-1-(aryl)prop-2-en-1-ones.

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.

Facile synthesis of bromo- and mixed bromo/chloro dibenzo-p-dioxins and [14C]-labeled 1,3,7,8-tetrabromodibenzo-p-dioxin.

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, [14C]-1,3,7,8-tetrabromodibenzo-p-dioxin (0.26 µCi/µmol; 11% overall yield) was synthesized from commercially available [14C]-phenol to allow an ADME study to be conducted.