Synthesis of Polyfluorinated Thia- and Oxathiacalixarenes Based on Perfluoro-m-xylene.

Perfluorinated tetrathiacalix[4]arene was obtained by heating perfluoro-m-xylene with thiourea or 2,5-difluoro-4,6-bis(trifluoromethyl)benzene-1,3-dithiol at 90 °C. Interaction of perfluoro-m-xylene with resorcinol or orcinol under mild conditions and subsequent heating of the mixture with 2,5-difluoro-4,6-bis(trifluoromethyl)benzene-1,3-dithiol leads to polyfluorinated dioxadithiacalix[4]arenes. Triphenyl and pentaphenyl ethers formed by the interaction of perfluoro-m-xylene with resorcinol under heating with thiourea gives polyfluorinated oxathiacalixarenes containing six and five aromatic nuclei, respectively.

Evaluating the in vivo glial response to miniaturized parylene cortical probes coated with an ultra-fast degrading polymer to aid insertion.

OBJECTIVE: Despite the feasibility of short-term neural recordings using implantable microelectrodes, attaining reliable, chronic recordings remains a challenge. Most neural recording devices suffer from a long-term tissue response, including gliosis, at the device-tissue interface. It was hypothesized that smaller, more flexible intracortical probes would limit gliosis by providing a better mechanical match with surrounding tissue. APPROACH: This paper describes the in vivo evaluation of flexible parylene microprobes designed to improve the interface with the adjacent neural tissue to limit gliosis and thereby allow for improved recording longevity. The probes were coated with an ultrafast degrading tyrosine-derived polycarbonate (E5005(2K)) polymer that provides temporary mechanical support for device implantation, yet degrades within 2 h post-implantation. A parametric study of probes of varying dimensions and polymer coating thicknesses were implanted in rat brains. The glial tissue response and neuronal loss were assessed from 72 h to 24 weeks post-implantation via immunohistochemistry. MAIN RESULTS: Experimental results suggest that both probe and polymer coating sizes affect the extent of gliosis. When an appropriate sized coating dimension (100 µm × 100 µm) and small probe (30 µm × 5 µm) was implanted, a minimal post-implantation glial response was observed. No discernible gliosis was detected when compared to tissue where a sham control consisting of a solid degradable polymer shuttle of the same dimensions was inserted. A larger polymer coating (200 µm × 200 µm) device induced a more severe glial response at later time points, suggesting that the initial insertion trauma can affect gliosis even when the polymer shuttle degrades rapidly. A larger degree of gliosis was also observed when comparing a larger sized probe (80 µm × 5 µm) to a smaller probe (30 µm × 5 µm) using the same polymer coating size (100 µm × 100 µm). There was no significant neuronal loss around the implantation sites for most device candidates except the group with largest polymer coating and probe sizes. SIGNIFICANCE: These results suggest that: (1) the degree of mechanical trauma at device implantation and mechanical mismatches at the probe-tissue interface affect long term gliosis; (2) smaller, more flexible probes may minimize the glial response to provide improved tissue biocompatibility when used for chronic neural signal recording; and (3) some degree of glial scarring did not significantly affect neuronal distribution around the probe.

Pd-Catalyzed Aerobic Oxidative Biaryl Coupling: Non-Redox Cocatalysis by Cu(OTf)2 and Discovery of Fe(OTf)3 as a Highly Effective Cocatalyst.

Copper salts find widespread use in Pd-catalyzed oxidation reactions, and they are typically used as oxidants or redox-active cocatalysts. Here, we probe the origin of a dramatic acceleration effect of Cu(OTf)2 in the C-H/C-H aerobic oxidative coupling of o-xylene. NMR spectroscopic analysis of the PdII catalyst in the presence of Cu(OTf)2, together with other experimental and DFT computational studies of the catalytic reaction, show that Cu(OTf)2 activates the PdII catalyst for C-H activation via a non-redox pathway and has negligible impact on catalyst reoxidation. These observations led to the testing of other metal triflate salts as cocatalysts, the results of which show that Fe(OTf)3 is even more effective than Cu(OTf)2.

A Simple and Mild Approach for the Synthesis of p-Xylene from Bio-Based 2,5-Dimethyfuran by Using Metal Triflates.

The production of aromatic platform chemicals from biomass-derived feedstocks is of considerable importance in biomass conversion. However, the development of effective routes with simple steps and under mild conditions is still challenging. In this work, we report an original route for the direct synthesis of p-xylene from 2,5-dimethylfuran and acrylic acid catalyzed by scandium(III) triflate (Sc(OTf)3 ) in 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Emim]NTf2 ) under mild conditions. An overall 63 % selectivity towards p-xylene and 78 % selectivity towards aromatics were obtained at 90 % conversion of 2,5-dimethylfuran by enhancing the dehydration and introducing an extra one-pot decarboxylation step. Furthermore, various dienes and dienophiles were employed as reactants to extend the substrate scope. The aromatic compounds were obtained in moderate yields, which proved the potential of the method to be a generic approach for the conversion of bio-based furanics into renewable aromatics.

Multifunctional Surface Modification: Facile and Flexible Reactivity toward a Precisely Controlled Biointerface.

A multicomponent functional polymer is synthesized to support specific reactivity for successful conjugation with the vast array of functionality present in biological systems and the flexibility to conjugate biomolecules without requiring additional modification to install a terminal functional group. The multifunctional surface is realized using a novel coating composed of distinct N-hydroxysuccinimide (NHS) ester and benzoyl functionalities, which can provide accessibility to both the NHS ester-amine coupling reaction and the photochemically induced benzophenone crosslinking reaction, respectively. In addition, the multifunctional polymer is fabricated and transformed to form nanoscale colloids through the solvent displacement of a water/DMF system due to solubility characteristics of the resulting polymer with high polarity. A facile and efficient fabrication approach using the multifunctional nanocolloid is thus demonstrated to create a drug carrier by installing paclitaxel and folic acid for targeted cancer therapy.

Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety.

Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified.

Monooxime Bispyridinium Reactivators Bearing Xylene Linker Synthesis and In Vitro Evaluation on Model of Organophosphate-Inhibited Acetylcholinesterase.

Nine novel mono-oxime reactivators bearing xylene linker were synthesized in an effort to improve previously prepared xylene bisoximes and monocarbamoyl-monooximes. The novel compounds were tested in vitro on the model of tabun-, paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Their reactivation ability was compared to pralidoxime, asoxime, obidoxime and two previously prepared xylene linked bisoximes (K107, K108). All compounds showed minimal reactivation of tabun-inhibited AChE at selected concentration scale. This finding was explained by molecular modelling study. Bisoximes obidoxime and K108 resulted as the best reactivators for paraoxon-, methylparaoxon- and DFP-inhibited AChE. The loss of nonoxime moiety lead to the loss of reactivation ability within the novel compounds. Though the novel reactivators did not exceed previously known compounds, they confirmed former SAR findings for xylene-linked AChE reactivators.

Anticancer efficacy of unique pyridine-based tetraindoles.

Results of previous studies demonstrated that the tetraindole, SK228, which has a high lipid but low water solubility, displayed moderate anticancer efficacy in a xenograft model of breast cancer. This finding led to the proposal that new, pyridine based tetraindole (PBT) analogs of SK228, containing tetraindole moieties distributed about central protonated pyridine cores, would have enhanced bioavailabilities and anticancer efficacies. Among the PBTs prepared and subjected to biological studies, 3f (FCW81) was observed to display the highest antiproliferative activity against the two triple negative breast cancer (TNBCs) cell lines, MDA-MB-231 and BT549. In addition, its mode of action was shown to involve G2/M arrest of the cell cycle along with the promotion of increased levels of cyclin B1 and p-chk2 and a decreased level of p-cdc2. DNA damage and induction of apoptosis caused by FCW81 was found to be associated with a decrease in DNA repair. Significantly, FCW81 displays therapeutic efficacy in a xenograft model of human breast cancer by not only serving to inhibit markedly the growth of cancer cells but also to block effectively cancer cell metastasis. Collectively, the results of these studies have led to the identification of novel pyridine-tetraindole based anticancer agents with potential use in TNBC therapy.

Synthesis, spectral, structural characterization and biological investigation of m-Xylylenediaminium-bis (p-toluenesulfonate) monohydrate.

Novel organic charge transfer complex, m-xylylenediaminium-bis (p-toluenesulfonate) monohydrate (XDPTS) have been synthesized and crystallized to the triclinic system with space group P-1 and the lattice parameters obtained are a=9.9265(7) Å, b=9.9676(6) Å, c=13.4948(10) Å, α=71.95(6)°, ß=77.02(6)°, γ=76.851(5)°. The synthesized complex structure was confirmed by IR, (1)H NMR and (13)C NMR spectral analysis. Pharmacology activities of charge transfer complex were evaluated through antimicrobial, DNA binding/cleavage, antioxidant and cytotoxicity studies. The results reveal that the compound shows good antimicrobial activity against various antibacterial and antifungal species. The DNA interaction indicated that the compound could interact with DNA through intercalation, which is further confirmed by viscosity measurements. The compound should have weak to moderate capacity of scavenging with DPPH, Hydroxyl and ABTS radicals. The cytotoxicity has been evaluated by MTT assay method against MCF-7 cancer cell line.

Crystal Structures and Cytotoxicity of Ortho-Xylene Linked Bis-benzimidazolium Salts.

Azolium (imidazolium and benzimidazolium) salts are known as stable precursors for the synthesis of Metal-N-Heterocyclic Carbene (M-NHC) complexes. Recently, some reports have been compiled indicating that benzimidazolium salts have anticarcinogenic properties. The current research is the further investigation of this phenomenon. Three ortho-xylene linked bis-benzimidazolium salts (1-3) with octyl, nonyl and decyl terminal chain lengths have been synthesized. Each of the compounds was characterized using FT-IR and NMR spectroscopic techniques. The molecular geometries of two of the salts (1-2) have been established using X-ray crystallographic technique. The compounds were tested for their cytotoxic properties against three cancerous cell lines namely, human colon cancer (HCT 116), human colorectal adenocarcinoma (HT- 29) and human breast adenocarcinoma (MCF-7). Mouse embryonic fibroblast (3T3-L1) was used as the model cell line of normal cells. The compounds showed selective anti-proliferative activities against the colorectal carcinoma cells. For HCT 116 and HT-29 cells, the IC50 values ranged 0.9-2.6 µM and 4.0-10.0 µM, respectively. The salts 1 and 3 displayed moderate cytotoxicity against the breast cancer (MCF-7) cells with IC50 58.2 and 13.3 µM, respectively. However, the salt 2 produced strong cytotoxicity against MCF-7 cells with IC50 4.4 µM. Interestingly, the compounds demonstrated poor cytotoxic effects towards the normal cells (3T3-L1) as the IC50 was found to be as high as 48.0 µM. Salts 2 and 3 demonstrated more pronounced anti-proliferative effect than the standard drugs used (5-Flourouracil and Tamoxifen).

Synthesis of 3,6-O-(o-xylylene)glucopyranosyl fluoride, an axial-rich glycosyl donor of ß-glycosylation.

Despite the reported complete ß-selectivity in glycosylation with 2,4-di-O-benzyl-3,6-O-(o-xylylene)glucopyranosyl fluoride, its preparation has been inefficient. This paper describes an improved route for the donor, including the formation of the 3,6-bridge on 1,2,4-orthoacetylglucose, the preparation of which was also refined, along with a discovered feature that the 3,6-bridged glucose prefers the furanose form. Although this feature made the synthesis of the desired glucopyranosyl donor difficult, application of thermal glycosylation solved the problem. With a modifiable intermediate, the improved availability of the donor would expand the applications.

Synthesis and characterization of phenolic Mannich bases and effects of these compounds on human carbonic anhydrase isozymes I and II.

Mannich bases 2a-f derived from 3,4-dimethylphenol (1), formaldehyde and different amines are prepared and subjected to spectral (IR, (1)H and (13)C NMR) and elemental analyses. The inhibition of two human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with 1 and synthesized Mannich bases 2a-f and acetazolamide (AAZ) as a control compound was investigated in vitro by using the hydratase and esterase assays. In relation to hydratase and esterase activities of the half maximal inhibitory concentration (IC(50)) and the inhibition equilibrium constants (K(i))values were determined. Only two compounds (2a and 2e)exhibit weak hCA II inhibitory effects on esterase activity. IC(50) and Ki values for 2a and 2e with respect to esterase activity of hCA II are0.88 × 10(3) and 6.3-7.6 µM and 0.44 × 10(3) and 19.0-96.4 µM,respectively. On the contrary, compounds 2b and 2d might be used as CA activators due to increasing esterase activity of hCA I and hCA II isozymes.

Molecular gauge blocks for building on the nanoscale.

Molecular gauge blocks, based on 1-7, 9-11 paraxylene rings, have been synthesized as part of a homologous series of oligoparaxylenes (OPXs) with a view to providing a molecular tool box for the construction of nano architectures-such as spheres, cages, capsules, metal-organic frameworks (MOFs), metal-organic polyhedrons (MOPs) and covalent-organic frameworks (COFs), to name but a few-of well-defined sizes and shapes. Twisting between the planes of contiguous paraxylene rings is generated by the steric hindrance associated with the methyl groups and leads to the existence of soluble molecular gauge blocks without the need, at least in the case of the lower homologues, to introduce long aliphatic side chains onto the phenylene rings in the molecules. Although soluble molecular gauge blocks with up to seven consecutive benzenoid rings have been prepared employing repeating paraxylene units, in the case of the higher homologues it becomes necessary to introduce hexyl groups instead of methyl groups onto selected phenylene rings to maintain solubility. A hexyl-doped compound with seven substituted phenylene rings was found to be an organogelator, exhibiting thermally reversible gelation and a critical gelation concentration of 10 mM in dimethyl sulfoxide. Furthermore, control over the morphology of a series of hexyl-doped OPXs to give microfibers, microaggregates, or nanofibers, was observed as a function of their lengths according to images obtained by scanning electron microscopy. The modular syntheses of the paraphenylene derivatives rely heavily on Suzuki-Miyaura cross-coupling reactions. The lack of π-π conjugation in these derivatives that is responsible for their enhanced solubilities was corroborated by UV/Vis and fluorescent spectroscopy. In one particular series of model OPXs, dynamic (1)H NMR spectroscopy was used to probe the stereochemical consequences of having from one up to five axes of chirality present in the same molecule. The Losanitsch sequence for the compounds with 1-3 chiral axes was established, and a contemporary mathematical way was found to describe the sequence. The development of the ways and means to make molecular gauge building blocks will have positive repercussions on the control of nanostructures in general. Their incorporation into extended structures with the MOF-74 topology provides an excellent demonstration of the potential usefulness of these molecular gauge blocks.

Vapor-based synthesis of maleimide-functionalized coating for biointerface engineering.

Chemical vapor deposition polymerization was used to deposit a novel maleimide-functionalized poly-p-xylylene coating on various substrates. The coated substrates are readily able to undergo thiol-maleimide click reaction under mild conditions. Applications using this coating technology are highlighted in low-protein-fouling modification as well as manipulated attachments and growth of bovine arterial endothelial cells.

Production of p-xylene from biomass by catalytic fast pyrolysis using ZSM-5 catalysts with reduced pore openings.

Pores for thought: Chemical liquid deposition of silica onto ZSM-5 catalysts led to smaller pore openings that resulted in >90% selectivity for p-xylene over the other xylenes in the catalytic fast pyrolysis of furan and 2-methylfuran (see scheme). The p-xylene selectivity increased from 51% with gallium spray-dried ZSM-5 to 72% with a pore-mouth-modified catalyst in the pyrolysis of pine wood.

Synthesis of p-xylene from ethylene.

As oil supplies dwindle, there is a growing need to develop new routes to chemical intermediates that utilize alternative feedstocks. We report here a synthesis of para-xylene, one of the highest volume chemicals derived from petroleum, using only ethylene as a feedstock. Ethylene is an attractive alternative feedstock, as it can be derived from renewable biomass resources or harnessed from large domestic shale gas deposits. The synthesis relies on the conversion of hexene (from trimerization of ethylene) to 2,4-hexadiene followed by a Diels-Alder reaction with ethylene to form 3,6-dimethylcyclohexene. This monoene is readily dehydrogenated to para-xylene uncontaminated by the ortho and meta isomers. We report here a selective synthesis of para-xylene, uncontaminated by the ortho or meta isomers, using ethylene as the sole feedstock.

Influence of donor-acceptor distance variation on photoinduced electron and proton transfer in rhenium(I)-phenol dyads.

A homologous series of four molecules in which a phenol unit is linked covalently to a rhenium(I) tricarbonyl diimine photooxidant via a variable number of p-xylene spacers (n = 0-3) was synthesized and investigated. The species with a single p-xylene spacer was structurally characterized to get some benchmark distances. Photoexcitation of the metal complex in the shortest dyad (n = 0) triggers release of the phenolic proton to the acetonitrile/water solvent mixture; a H/D kinetic isotope effect (KIE) of 2.0 ± 0.4 is associated with this process. Thus, the shortest dyad basically acts like a photoacid. The next two longer dyads (n = 1, 2) exhibit intramolecular photoinduced phenol-to-rhenium electron transfer in the rate-determining excited-state deactivation step, and there is no significant KIE in this case. For the dyad with n = 1, transient absorption spectroscopy provided evidence for release of the phenolic proton to the solvent upon oxidation of the phenol by intramolecular photoinduced electron transfer. Subsequent thermal charge recombination is associated with a H/D KIE of 3.6 ± 0.4 and therefore is likely to involve proton motion in the rate-determining reaction step. Thus, some of the longer dyads (n = 1, 2) exhibit photoinduced proton-coupled electron transfer (PCET), albeit in a stepwise (electron transfer followed by proton transfer) rather than concerted manner. Our study demonstrates that electronically strongly coupled donor-acceptor systems may exhibit significantly different photoinduced PCET chemistry than electronically weakly coupled donor-bridge-acceptor molecules.

Synthesis and evaluation of the cytotoxicities of tetraindoles: observation that the 5-hydroxy tetraindole (SK228) induces G2 arrest and apoptosis in human breast cancer cells.

Current chemical and biological interest in indole-3-carbinol (I3C) and its metabolites has resulted in the discovery of new biologically active indoles. As part of a program aimed at the development of indole analogues, tetraindoles 1-15 were prepared and their antiproliferative effects on human breast cancer cells were evaluated. The results show that the 5-hydroxy-tetraindole 8 (SK228) has optimum antiproliferative activity against breast adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity involves G(2)-phase arrest of the cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2. Further observations suggest that 5-hydroxy-tetraindole 8 induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. Given the fact that I3C and its metabolites have been shown to improve therapeutic efficacy and to have a broad range of antitumor activities in human cancer cells, the current findings have important pharmacological relevance as they open a promising route to the development of a potential chemotherapeutic application of tetraindoles as agents for the treatment of breast cancer.

Ultrasound-assisted phase-transfer catalysis: benzoylation of sodium 4-acetylphenoxide by dual-site phase-transfer catalyst in a tri-liquid system.

A novel dual-site phase-transfer catalyst (PTC) was prepared and used to conduct the benzoylation of sodium 4-acetylphenoxide by ultrasound-assisted third-liquid phase-transfer catalysis. The catalyst 1,4-bis(tributylammoniomethyl)benzene dibromide (BTBAMBB) was synthesized from the reaction of p-xylylene dibromide and tributylamine in toluene at 70°C. The dual-site PTC was employed to form the third-liquid phase by extra addition of 0.04-0.05 mol of NaCl into 10 cm(3) of water. In the condition of 0.0425 mol of NaCl at 30°C, the catalytic intermediate in the third-liquid phase reached a maximum value. Almost 80% of the catalyst was transferred from the aqueous phase into the third-liquid phase. The distributions of the catalytic intermediate and dual-site PTC between phases and the kinetics of benzoylation of sodium 4-acetylphenoxide catalyzed by BTBAMBB with ultrasound irradiation were performed. The pseudo-first-order kinetic equation was applied to describe the overall reaction. Under ultrasound irradiation (28 kHz/300 W) in a batch reactor, the yield of product 4-acetylphenyl benzoate in the organic phase was 98.1% in 2 min at 30°C and 250 rpm with the apparent rate constant k(app) to be 0.0075 s(-1), which was 6 times faster than that without using ultrasound (yield=14.4%, k(app)=0.0013 s(-1)). The present study provides a green method to synthesize esters by ultrasound-assisted third-liquid phase-transfer catalysis.

Preparation of new nitrogen-bridged heterocycles 67. syntheses of alpha,alpha'-Bis[(thieno[3,4-b]indolizin-3-yl)thio]-o-, m-, and p-xylene derivatives and their conformational structures.

The alkaline treatment and dehydrogenation of pyridinium salts, formed from the S-alkylations of 3-(1-pyridinio)thiophene-2-thiolates with alpha,alpha-dibromo-o-, m-, or p-xylene, provided the corresponding alpha,alpha'-bis[(thieno[3,4-b]indolizin-3-yl)thio]-o-, m-, and p-xylene derivatives in low to good yields. Both (1)H-NMR and UV-Vis spectra of these products supported distinctly the predominance of the gauche-gauche conformation in relation to the two sulfide linkages as the spacer in these molecules. On the other hand, the X-ray analyses indicated the expected gauche-gauche conformation for the m- and the p-xylene derivatives, but the anti-anti one for the o-xylene derivative.