The synthesis and medicinal applications of pyrogallol4arenes

To date almost all pyrogallol[4]arenes reported in the literature have been prepared from alkyl aldehydes. We were interested in preparing more pyrogallol[4]arenes from commercially available benzaldehydes. On synthesising these compounds we discovered that they are structurally unique, compared to previously reported pyrogallol[4]arenes, as they exist in a rctt chair conformation as determined by X-ray crystallography and 1HNMR. We also discovered from our synthetic studies that the yields for the pyrogallol[4]arenes depend strongly on the electron donating/withdrawing ability of substituents placed in the benzaldehyde, the more electron withdrawing the higher the yield. We also discovered a unique metal salt effect on the condensation of pyrogallol with 4-fluorobenzaldehyde that doubled the yields o f the resulting macrocycle. Interestingly, this effect is absent with the condensation of pyrogallol with alkyl aldehydes. The role of steric effects, using bulky substituted benzaldehydes was also investigated to determine whether the stereochemical outcome for these condensation reactions could be controlled. The further derivatisation of the pyrogallol[4]arenes was also investigated. The preparation of partially and completely alkylated derivatives of these macrocycles was of interest to us. We found that the introduction of acetate groups could be readily accomplished, however other alkyl groups could not be efficiently introduced into the pyrogallol[4]arenes. The partially and completely alkylated acetate derivatives of pyrogallol[4]arene were screened for biological activity against HIV-1. It was discovered that the partially alkylated derivatives possessed higher selectivity indexes than the completely alkylated derivatives indicating that biological activity may not be dependent on charge

Pyrogallol inhibits NFAT signal

As the expression level of allergic disease sensitive genes are correlated with the severity of allergic symptoms, suppression of these gene expressions could be promising therapeutics. We demonstrated that protein kinase Cδ / heat shock protein 90-mediated H1R gene expression signaling and nuclear factor of activated T-cells (NFAT)-mediated IL-9 gene expression signaling are responsible for the pathogenesis of pollinosis. Treatment with Awa-tea combined with wild grape hot water extract suppressed these signaling and alleviated nasal symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats. However, the underlying mechanism of its anti-allergic activity is not elucidated yet. Here, we sought to identify an anti-allergic compound from Awa-tea and pyrogallol was identified as an active compound. Pyrogallol strongly suppressed ionomycin-induced up-regulation of IL-9 gene expression in RBL-2H3 cells. Treatment with pyrogallol in combination with epinastine alleviated nasal symptoms and suppressed up-regulation of IL-9 gene expression in TDI-sensitized rats. Pyrogallol itself did not inhibit calcineurin phosphatase activity. However, pyrogallol suppressed ionomycin-induced dephosphorylation and nuclear translocation of NFAT. These data suggest pyrogallol is an anti-allergic compound in Awa-tea and it suppressed NFAT-mediated IL-9 gene expression through the inhibition of dephosphorylation of NFAT. This might be the underlying mechanism of the therapeutic effects of combined therapy of pyrogallol with antihistamine

Bioavailability of black tea theaflavins: absorption, metabolism, and colonic catabolism

Data obtained with in vitro fecal incubations and a feeding study indicate black tea theaflavin and its galloyl derivatives are not absorbed in detectable amounts in either the upper or lower gastrointestinal tract. The theaflavin skeleton is comparatively resistant to degradation by colonic bacteria with a 67% recovery being obtained after a 24 h incubation, which yielded 21 phenolic and aromatic catabolites. The theaflavin galloyl moiety was removed by the microbiota, and the released gallic acid further transformed to 3-O- and 4-O-methyl gallic acids, pyrogallol-1-sulfate and pyrogallol-2-sulfate, which were excreted in urine in amounts equivalent to 94% of intake. The main urinary product potentially derived from breakdown of the theaflavin skeleton was 3-(4′-hydroxyphenyl)propionic acid. A number of the colonic catabolites originating from gallic acid and theaflavins has been reported to be bioactive in ex vivo and in vitro models with a variety of potential modes of action

Modelling aspects of solid cancer growth

The modelling of cancer provides an enormous mathematical challenge because of its inherent multiscale nature. For example, in vascular tumours, nutrient is transported by the vascular system, which operates on a tissue level. However, it affects processes occurring on a molecular level. Molecular and intra-cellular events in turn effect the vascular network and therefore the nutrient dynamics. Our modelling approach is to model, using partial differential equations, processes on the tissue level and couple these to the intercellular events (modelled by ordinary differential equations) via cells modelled as automaton units. Thusfar, within this framework we have modelled structural adaptation at the vessel level and the effects of growth factor production in response to hypoxia. We have also investigated the effects of acid production, mutation and phenotypic evolution driven by tissue environment. These results will be presented

In vitro bioconversion of polyphenols from black tea and red wine/grape juice by human intestinal microbiota displays strong interindividual variability

Dietary polyphenols in tea and wine have been associated with beneficial health effects. After ingestion, most polyphenols are metabolized by the colonic microbiota. The current study aimed at exploring the interindividual variation of gut microbial polyphenol bioconversion from 10 healthy human subjects. In vitro fecal batch fermentations simulating conditions in the distal colon were performed using polyphenols from black tea and a mixture of red wine and grape juice. Microbial bioconversion was monitored by NMR- and GC-MS-based profiling of diverse metabolites and phenolics. The complex polyphenol mixtures were degraded to a limited number of key metabolites. Each subject displayed a specific metabolite profile differing in composition and time courses as well as levels of these metabolites. Moreover, clear differences depending on the polyphenol sources were observed. In conclusion, varying metabolite pathways among individuals result in different metabolome profiles and therefore related health effects are hypothesized to differ between subjects