Elizabeth Tyrrell

Resveratrol 3-O-d-glucuronide and resveratrol 4'-O-d-glucuronide inhibit colon cancer cell growth: Evidence for a role of A3 adenosine receptors, cyclin D1 depletion, and G1 cell cycle arrest

SCOPE Resveratrol is a plant-derived polyphenol with chemotherapeutic properties in animal cancer models and many biochemical effects in vitro. Its bioavailability is low and raises the possibility that the metabolites of resveratrol have biological effects. Here we investigate the actions of resveratrol 3-O-D-glucuronide, resveratrol 4-O-D-glucuronide, and resveratrol 3-O-Dsulfate on the growth of colon cancer cells in vitro. METHODS AND RESULTS The growth of Caco-2, HCT-116, and CCL-228 cells was measured using the neutral red and MTT assays. Resveratrol and each metabolite inhibited cell growth with IC50 values of 9.8–31 μM. Resveratrol caused S phase arrest in all three cell lines. Resveratrol 3-O-D-glucuronide and resveratrol 4-O-D-glucuronide caused G1 arrest in CCL-228 and Caco-2 cells. Resveratrol 3-O-D-sulfate had no effect on cell cycle. Growth inhibition was reversed by an inhibitor of AMP-activated protein kinase (compound C) or an adenosine A3 receptor antagonist (MRS1191). The A3 receptor agonist 2Cl-IB-MECA inhibited growth and A3 receptors were detected in all cell lines. The resveratrol glucuronides also reduced cyclin D1 levels but at higher concentrations than in growth experiments and generally did not increase phosphorylated AMP-activated protein kinase. CONCLUSION Resveratrol glucuronides inhibit cell growth by G1 arrest and cyclin D1 depletion, and our results strongly suggest a role for A3 adenosine receptors in this inhibition.

The application of 1H nuclear magnetic resonance spectroscopy for the determination of the absolute configuration of chiral carboxylic acids

Abstract A modification of a model, described by Mosher, allows a correlation to be made between the absolute configuration of a range of simple chiral carboxylic acids with the corresponding nmr chemical shifts of their esters derived from (S)-methyl mandelate.

A diastereoselective synthesis of benzopyrans using a novel intramolecular Nicholas reaction in the key cyclisation step

Abstract A novel intramolecular cyclisation reaction between an organocobalt stabilised cation and a trisubstituted alkene was accomplished to afford a new family of benzopyran derivatives.

The synthesis and biological evaluation of a range of novel functionalised benzopyrans as potential potassium channel activators

A range of novel benzopyrans have been synthesised and biologically evaluated for K(ATP) channel activity employing cromakalim 1 as a benchmark K(ATP) channel opener. Although the compounds that were evaluated demonstrated a reduced ability to relax phenylephrine stimulated rat thoracic tissue, we provide evidence that benzopyrans 7a-h may be operating via an alternative mechanism than ATP-sensitive K(+) channel activity.

Novel tandem diastereoselective cyclisation reactions of dicobalt hexacarbonyl complexed propargyl cations

Abstract The diastereoselective one-pot synthesis of tricyclic compounds is described that involves a tandem sequence of intermolecular and intramolecular Nicholas reactions followed by a further intramolecular cyclisation process.

Simple, novel synthesis for 1-carbamoyl-1H-benzotriazole and some of its analogs

Abstract 1-Carbamoyl-1H-benzotriazole (benzotriazole-1-carboxamide, 2a), an effective carbamoyl chloride substitute, and a range of its analogs can be synthesized in good yields in two very simple steps from 1,2-diaminobenzene. The facile preparation of the intermediate o-aminophenylurea is key to this process. A preliminary study of the reactivity of 2a has shown that once in solution in tetrahydrofuran (THF), the 1-carbamoyl isomer equilibrates to give a mixture of both 1- and 2-isomers. If the solvent is ethanol or water, equilibration occurs rapidly compared to the ultimate formation of solvolysis products.

An Investigation into the Anticancer Effects and Mechanism of Action of Hop β-Acid Lupulone and Its Natural and Synthetic Derivatives in Prostate Cancer Cells

Lupulone, a β-acid derived from hop extracts has been shown to exhibit antibacterial and anticancer activity. In this study we investigated the anticancer potency of lupulone and its novel derivatives and their mechanism of action on prostate cancer cells. Cell viability was determined using the MTT assay, and the ELISA approach was used to investigate induction of apoptosis. Immunoblot analysis was carried out to determine activation and regulation of proteins associated with cell death. Screening of natural and new lupulone derivatives for their anticancer activity demonstrated that one (lupulone derivative 1h) displayed stronger anticancer activity than lupulone itself on PC3 and DU145 prostate cancer cells. We further found that lupulone derivatives induced caspase-dependent apoptosis that is associated with activation of caspases 8, 9, and 3. Furthermore, caspase 8 inhibitor Z-IETD-fmk reduced cell death induced by lupulone derivatives, suggesting that apoptosis is mediated by caspase 8. Finally, we found that lupulone and its synthetic derivatives also increased formation of LC3II suggesting that autophagy is also implicated in prostate cancer cell death. The new lupulone derivatives induce caspase-dependent apoptosis and autophagy in prostate cancer cells and appear to be good candidates for further preclinical studies of prostate cancer treatment.

The anion of 3-methyl-2-pyridin-4-yl- 1,3-oxazine

Abstract n-Butyllithium at −78°C readily abstracts the methine proton from the title compound. The anion reacts efficiently with a range of electrophiles to provide 4-pyridyl ketones upon acid hydrolysis.

A diastereoselective cobalt-mediated synthesis of benzopyrans using a novel variation of an intramolecular Nicholas reaction in the key cyclisation step: optimisation and biological evaluation1

A range of novel intramolecular cyclisation reactions between an organocobalt stabilised cation and a trisubstituted alkene have been accomplished that provide a concise route for the diastereoselective synthesis of a range of functionalised benzopyrans. In addition to the usual Lewis acids employed in the Nicholas reaction our studies have identified several other reagents for effecting the cyclisation reaction. In some examples sub-stoichiometric quantities of Lewis acid were successfully employed. These studies were concluded with a biological evaluation of specific derivatives, conducted by comparing their activity with the antihypertensive agent cromakalim 2, a drug whose mode of action is known to occur via the modulation of potassium channel activity.