Synthesis of heterocyclic analogues of Benzo-TCNQ

The combination of electron deficient and electron rich species to form charge transfer complexes has led to the observation of conductivity and superconductivity in organic and organometallic systems. Heterocyclic electron acceptors analogous to TCNQ are of particular interest, since heteroatoms can lead to greater planarity, which can increase dimensionality and ultimately improve conductivity. The reaction of phthalonitrile and aqueous methylamine formed 2-methyl-3- methylimino-2,3-dihydroisoindol-l-one. Analogous reactions with aqueous cthylamine and benzylamine did not yield corresponding products. 1,3-Dialkyliminoisoindolines resulted from the reaction of ethylamine and benzylamine with phthalonitrile. Treatment o f 2-methyl-3-methylimino-2,3-dihydroisoindol-l-one in ethanol with malononitrile produced a methylammonium salt while a similar reaction in acetic acid yielded a monocondensation product 2-(2-methyl-3-oxo-2,3-dihydro-isoindol-l-ylidene)-malononitrile. An analogous mono-condensation product was obtained from 1,3-diethyliminoisoindoline and malononitrile in acetic acid. The Mitsunobu reaction of 2-(3-dicyanomethylene-2,3-dihydro-isoindol-lylidene)- malononitrile with activated primary alcohols generated the desired N-alkylated tetra-cyano isoindolines. Similarly the Mitsunobu reaction of 2-(3-oxo-2,3-dihydroisoindol-l-ylidene)-malononitrile with various alcohols produced the desired N-alkylated products. The presence o f a carbonyl group meant that 2-(3-oxo-2,3-dihydro-isoindol-lylidene)-malononitrile would react with more alcohols than its tetra-cyano analogue. Treatment of 2-(3-oxo-2-pentyl-2,3-dihydro-isoindol-l-ylidene)-malononitrile and 2-(3-oxo-2-decyl-2,3-dihydro-isoindol-l-ylidene)-malononitrile with titanium tetrachloride and bis(trimethylsilyl)carbodiimide gave compounds that possessed both a dicyanomethylene group and a cyanoimino group. Cyclic voltammetric analysis of these three families of compounds showed that they were all electrochemically reducible. Solid charge transfer complexes were formed between TTF and the N-alkylated tetra-cyano isoindolines and between TTF and Nalkylated isoindolines that contained a dicyanomethylene and a cyanomino group. X-ray crystallography showed that the CT complex between 2-(2-allyl-3-dicyanomethylene-2,3- dihydro-isoindol-l-ylidene)-malononitrile and TTF had a mixed stack arrangement

2,2'-{2-[(E)-3-Phenylprop-2-enyl]-2,3-dihydro-1H-isoindol-1,3-diylidene}dimalononitrile, a π-deficient system for π...π (1:1) stacking investigations

The title compound, C₂₃H₁₃N₅, derived from cinnamyl alcohol and 2,2'-(isoindolin-1,3-diylidene)bispropanedinitrile, is a heterocyclic TCNQ analogue of interest as an electron-deficient component in charge-transfer complexes. A small perturbation of the four C-C≡N angles from linearity is observed, which are in the range 173.41 (18)-176.3 (2)°; the C≡N bond lengths are in the range 1.144 (2)-1.146 (2) Å. The terminal phenyl group is oriented at an angle of 77.17 (6)° to the C₄N ring and the C=C bond is short, 1.319 (2) Å. There are no classical hydrogen bonds, although intramolecular C-H...N and intermolecular C-H...π(arene) interactions influence the crystal-structure packing

In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation

Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations

Modulation of expression in BEAS-2B airway epithelial cells of a-l-fucosidase A1 and A2 by Th1 and Th2 cytokines, and overexpression of a-l-fucosidase 2

Chronic Th2-driven airway inflammation with excessive mucus production occurs in asthma. The regulation of FUCA1 and FUCA2 gene expression and enzyme activity in response to asthma-associated Th2 cytokines and, for contrast, Th1 cytokine IFN-γ, were investigated in a human airway cell line. BEAS-2B cells were supplemented with Th2-derived cytokines (IL-13, IL-4, IL-5) or/and IFN-γ. RNA and cell supernatants from stimulated and unstimulated cells were collected over a period of 3 h. Alpha-l-fucosidase A1 and A2 gene expression were assessed using real time RT-PCR, while enzymatic activities were measured using a fluorescent assay. To characterise α-l-fucosidase A2, CHO-K1 and BEAS-2B cell lines were transiently transfected, the FUCA2 gene was overexpressed, and the protein was immunoprecipitated. The transcription of FUCA1 was upregulated (p twofold induction), whereas secreted enzyme activity in BEAS-2B cells was significantly increased 1 h after IFN-γ addition. IL-4, IL-5 and IL-13 had no effect on FUCA1 and FUCA2 expression and activity. The IFN-γ-induced increase in expression and activity was repressed by the presence of the Th2 cytokine IL-5. Enzymatically active α-l-fucosidase 2 was immunoprecipitated from BEAS-2B cells, with highest activity at pH 4.9. IL-13, IL-4 and IL-5 have no effect on the expression of FUCA1 and FUCA2, but its expression is upregulated by IFN-γ, a Th1 cytokine. Active α-l-fucosidase 2 was overexpressed in BEAS-2B cells