Amanda L. Rousseau

6-Substituted imidazo[1,2-a]pyridines: synthesis and biological activity against colon cancer cell lines HT-29 and Caco-2.

A range of 6-substituted imidazo[1,2-a]pyridines were synthesized using a multicomponent coupling reaction. Most of these compounds were found to exhibit excellent activity against the colon cancer cell lines HT-29 and Caco-2, whilst not showing significant toxicity against white blood cells. Our studies have shown that the proteolytic phase of apoptosis was initiated 2 h after treatment with these imidazo-[1,2-a]pyridines. The data suggests that the imidazo[1,2-a]pyridine-induced cell death in HT-29 and Caco-2 cells is mediated via pathway(s) that include the release of cytochrome c from the mitochondria to the cytosol and the activation of caspase 3 and caspase 8.

A NOVEL SYNTHESIS OF SUBSTITUTED NAPHTHALENES

Irradiation of 2-allylated acylbenzenes in DMF in the presence of potassium tert-butoxide constitutes a novel synthesis of substituted naphthalenes, including arylnaphthalenes. Typical examples include the conversions (1) → (2), (8) → (11) and (15 → (16).

A novel method for the synthesis of phenanthrenes and benzo[a]carbazoles

Abstract The synthesis of several phenanthrenes and carbazoles utilising a novel reaction mediated by potassium t -butoxide and light through a quartz filter is described.

Metformin induces an intracellular reductive state that protects oesophageal squamous cell carcinoma cells against cisplatin but not copper-bis(thiosemicarbazones)

BackgroundOesophageal squamous cell carcinoma (OSCC) is a highly aggressive carcinoma with a poor survival rate. One of the most commonly used chemotherapeutic drugs, cisplatin, displays varied and often poor efficacy in vivo. Therefore, alternative, cost-effective and more efficacious treatments are required. Metformin has been previously shown to reduce proliferative rates in various carcinoma cell lines. We report for the first time, the effect of metformin on OSCC cell proliferation and show that it antagonises cisplatin-induced but not copper-bis(thiosemicarbazone)-induced cytotoxicity in OSCC cells.MethodsCell proliferation and stage of the cell cycle were quantified by trypan blue counts and flow cytometry, respectively. All cytotoxicity measurements were made using the tetrazolium based MTT assay. Metabolic alterations to cells were determined as follows: glycolysis via a lactate dehydrogenase assay, reducing equivalents by MTT reduction and reduced intracellular thiols by monobromobimane-thiol fluorescence, and glutathione depletion using buthionine sulfoximine. Inductively coupled plasma mass spectrometry was used to quantify cisplatin-DNA adduct formation.ResultsMetformin was found to reduce cell proliferation significantly in all OSCC cell lines, with an accumulation of cells in G0/G1 phase of the cell cycle. However, metformin significantly protected OSCC cells against cisplatin toxicity. Our results indicate that a major mechanism of metformin-induced cisplatin resistance results from a significant increase in glycolysis, intracellular NAD(P)H levels with a concomitant increase in reduced intracellular thiols, leading to decreased cisplatin-DNA adduct formation. The glutathione synthesis inhibitor buthionine sulfoximine significantly ablated the protective effect of metformin. We subsequently show that the copper-bis(thiosemicarbazones), Cu-ATSM and Cu-GTSM, which are trapped in cells under reducing conditions, cause significant OSCC cytotoxicity, both alone and in combination with metformin.ConclusionsThis is the first study showing that metformin can be used to decrease cell proliferation in OSCC cells. However, metformin protects against cisplatin cytotoxicity by inducing a reducing intracellular environment leading to lower cisplatin-DNA adduct formation. As such, we advise that caution be used when administering cisplatin to diabetic patients treated with metformin. Furthermore, we propose a novel combination therapy approach for OSCC that utilises metformin with metformin-compatible cytotoxic agents, such as the copper-bis(thiosemicarbazones), Cu-ATSM and Cu-GTSM.

Reactions of ferric porphyrins and thiols. The reaction of the haem octapeptide, N-acetylmicroperoxidase-8, with cysteine

The reaction of the N-acetylated haem octapeptide from cytochrome c, N-acetylmicroperoxidase-8 (NAcMP8), with cysteine at neural pH products the low-spin 6-coordinate Fe(III) species in which the thiol group of cysteine displaces H2O from the coordination sphere of Fe(III). It is suggested that reduction of Fe(III) to Fe(II) by bound thiol produces thiyl radicals which, in a reaction accelerated by O2, degrade haem c. Under anaerobic conditions at 5 °C, the equilibrium constant for coordination of a single cysteine by NAcMP8 is log K = 4.47 ± 0.05. From the temperature-dependence of the rate, the activation parameters of the second-order rate constant for this reaction were determined as ΔH≠ = 34.61 ± 0.02 kJ mol−1 and ΔS≠ = −16.40 ± 0.08 J K 1mol−1. Comparison of these values with those available for the reaction of the related haem peptide MP8 with CN− shows the reaction rate to be relatively insensitive to the nature of the incoming ligand, which is consistent with a dissociative mode of activation.

Synthesis, Reactions and Uses of Isocyanides in Organic Synthesis. An Update

Isocyanides were formally discovered by Gautier1 and Hofmann2 in 1867 but the history of isocyanide chemistry in fact predates this discovery. Lieke carried out the first isocyanide synthesis in 18...

Disulfiram/copper-disulfiram Damages Multiple Protein Degradation and Turnover Pathways and Cytotoxicity is Enhanced by Metformin in Oesophageal Squamous Cell Carcinoma Cell Lines

Disulfiram (DSF), used since the 1950s in the treatment of alcoholism, is reductively activated to diethyldithiocarbamate and both compounds are thiol‐reactive and readily complex copper. More recently DSF and copper‐DSF (Cu‐DSF) have been found to exhibit potent anticancer activity. We have previously shown that the anti‐diabetic drug metformin is anti‐proliferative and induces an intracellular reducing environment in oesophageal squamous cell carcinoma (OSCC) cell lines. Based on these observations, we investigated the effects of Cu‐DSF and DSF, with and without metformin, in this present study. We found that Cu‐DSF and DSF caused considerable cytotoxicity across a panel of OSCC cells, and metformin significantly enhanced the effects of DSF. Elevated copper transport contributes to DSF and metformin‐DSF‐induced cytotoxicity since the cell‐impermeable copper chelator, bathocuproinedisulfonic acid, partially reversed the cytotoxic effects of these drugs, and interestingly, metformin‐treated OSCC cells contained higher intracellular copper levels. Furthermore, DSF may target cancer cells preferentially due to their high dependence on protein degradation/turnover pathways, and we found that metformin further enhances the role of DSF as a proteasome inhibitor. We hypothesized that the lysosome could be an additional, novel, target of DSF. Indeed, this acid‐labile compound decreased lysosomal acidification, and DSF‐metformin co‐treatment interfered with the progression of autophagy in these cells. In summary, this is the first such report identifying the lysosome as a target of DSF and based on the considerable cytotoxic effects of DSF either alone or in the presence of metformin, in vitro, and we propose these as novel potential chemotherapeutic approaches for OSCC. J. Cell. Biochem. 116: 2334–2343, 2015.

The synthesis of the pyranonaphthoquinones dehydroherbarin and anhydrofusarubin using Wacker oxidation methodology as a key step and other unexpected oxidation reactions with ceric ammonium nitrate and salcomine

The synthesis of two closely related pyranonaphthoquinones, dehydroherbarin and anhydrofusarubin, is described. The construction of the naphthalene nuclei was achieved using the Stobbe condensation reaction using 2,4-dimethoxybenzaldehyde and 2,4,5-trimethoxybenzaldehyde as their respective starting materials. Two key steps en route include a PIFA-mediated addition of a methoxy substituent onto the naphthalene skeleton and a Wacker oxidation reaction to construct the benzo[g]isochromene nucleus. Two interesting oxidation reactions of the intermediate isochromene enol ether of 7,9-dimethoxy-3-methyl-1H-benzo[g]isochromene-5-ol were observed. Treatment of the substrate with salcomine resulted in the formation of (3-formyl-4-hydroxy-6,8-dimethoxynaphthalene-2-yl)methyl acetate, while treatment of the same substrate with CAN resulted in the formation of racemic (3R,4R)-3-hydroxy-7,9-dimethoxy-3-methyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-benzo[g]isochromen-4-yl nitrate.

Carbamate substituted 2-amino-4,6-diphenylpyrimidines as adenosine receptor antagonists

A novel series of carbamate substituted 2-amino-4,6-diphenylpyrimidines was evaluated as potential dual adenosine A1 and A2A receptor antagonists. The majority of the synthesised compounds exhibited promising dual affinities, with A1Ki values ranging from 0.175 to 10.7 nM and A2AKi values ranging from 1.58 to 451 nM. The in vivo activity illustrated for 3-(2-amino-6-phenylpyrimidin-4-yl)phenyl morpholine-4-carboxylate (4c) is indicative of the potential of these compounds as therapeutic agents in the treatment of Parkinsons disease, although physicochemical properties may require optimisation.

A novel method for the synthesis of substituted naphthalenes and phenanthrenes

Heating of o-allyl-substituted acylbenzenes with potassium tert-butoxide in DMF with simultaneous irradiation from a high-pressure mercury lamp afforded substituted naphthalenes, including arylnaphthalenes. 2-(o-Tolyl)-substituted aromatic aldehydes were converted into phenanthrenes under the same conditions. A formal synthesis of tanshinone I has also been achieved.