Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring

Migrastatin and isomigrastatin analogues have been synthesised in order to contribute to structure–activity studies on tumour cell migration inhibitors. These include macrocycles varying in ring size, functionality and alkene stereochemistry, as well as glucuronides. The synthesis work included application of the Saegusa–Ito reaction for regio‐ and stereoselective unsaturated macroketone formation, diastereoselective Brown allylation to generate 9‐methylmigrastatin analogues and chelation‐induced anomerisation to vary glucuronide configuration. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound‐healing (scratch) and Boyden chamber assays. One unsaturated macroketone showed low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects.     

Comparative evaluation of antioxidant capacities of thiol-based antioxidants measured by different in vitro methods

Thiol-type compounds are an important class of strong antioxidants and main determinants of total antioxidant capacity (TAC) of cellular homogenates. The TAC of thiol mixtures and the corresponding TEAC (trolox equivalent antioxidant capacity) values of individual thiols were determined by the CUPRAC (CUPric Reducing Antioxidant Capacity) method, and the results were compared with those found by reference assays for method validation. Synthetic mixtures of thiols were prepared, and the expected and found TAC values (in mM trolox (TR) equivalents) of these mixtures showed a good agreement. The technique of standard additions was performed for thiol mixtures and human serum, and the absorbance results confirmed that apparent chemical deviations from Beer's law were absent in the system. The CUPRAC results were compared with those of reference methods, namely 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)/persulphate and Ferric Reducing Antioxidant Power (FRAP). As being a most important thiol (-SH) peptide at in vivo conditions, glutathione (GSH) showed a TEAC value of 0.57 in the CUPRAC method, as opposed to the corresponding value (1.51) in the ABTS/persulphate method. The ABTS/persulphate result was not in accordance with the reversible 1-e oxidation of GSH to the corresponding disulfide that is expected to occur under physiological conditions. FRAP did not give consistent results, and even at relatively high concentrations of GSH, the TEAC_FRAP value was only 0.07. The thiol-type antioxidant-bearing pharmaceuticals of Brunac eye drop, Trom and Mentopin effervescent tablets containing N-acetyl-l-cysteine (NAC) were assayed with HPLC for comparison, and the obtained results for NAC were in accordance with those found with CUPRAC.     

1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one: selected chemistry at the C-6, C-7 and C-8 positions

1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one (6) reacts with tetracyanoethylene (TCNE) or tetracyanoethylene oxide (TCNEO) to give the deep green 2-[1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-ylidene]propanedinitrile (11) in 17 and 15% yields, respectively. Nucleophiles such as amines, alkoxides, thiols and Grignard reagents all reacted with the 1,3-diphenylbenzotriazinone 6 regioselectively at C-6, while halogenating agents reacted exclusively at C-8. Furthermore, 8-iodo-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (32) undergoes palladium-catalysed Suzuki-Miyaura and Stille coupling reactions to give 8-aryl- or heteroaryl-substituted benzotriazinones. By combining both the C-6 and C-8 chemistries 1,3,6,8-tetraphenylbenzo[e][1,2,4]triazin-7(1H)-one (42) and 1,3-diphenyl-6,8-di(thien-2-yl)-benzo[e][1,2,4]triazin-7(1H)-one (43) can be prepared. All new compounds are fully characterized.     

A novel fiber optic spectrophotometric determination of nitrite using Safranin O and cloud point extraction

A novel fiber optic spectrophotometric method for nitrite determination in different samples is suggested, based on the reaction of nitrite with Safranin O in acidic medium to form a diazo-safranin, which is subsequently coupled with pyrogallol in alkaline medium to form a highly stable, red azo dye, followed by cloud point extraction (CPE) using a mixed micelle of a nonionic surfactant, Triton X-114, with an anionic surfactant, sodium dodecyl sulphate (SDS). The reaction and extraction conditions (e.g., acidity for diazotization and alkalinity for pyrogallol coupling, and other reagent concentrations, time, and tolerance to other ions) were optimized. Linearity was obeyed in a concentration range up to 230 μg L⁻¹, and the detection limit of the method is 0.5 μg L⁻¹ of nitrite ion. The molar absorptivity for nitrite of the Safranin-diazonium salt (?_610 nm = 4 × 10³ L mol⁻¹ cm⁻¹) existing in literature was greatly enhanced by pyrogallol coupling and CPE enrichment (?_592 nm = 1.39 × 10⁵ L mol⁻¹ cm⁻¹). The method was applied to the determination of nitrite in tap water, lake water and milk samples with an optimal preconcentration factor of 20.     

Chemometrics‐enhanced laser‐induced thermal emission detection of PETN and other explosives on various substrates

Infrared emissions (IREs) of samples of pentaerythritol tetranitrate (PETN) deposited as contamination residues on various substrates were measured to generate models for the detection and discrimination of the important nitrate ester from the emissions of the substrates. Mid‐infrared emissions were generated by heating the samples remotely using laser‐induced thermal emission (LITE). Chemometrics multivariate analysis techniques such as principal component analysis (PCA), soft independent modeling by class analogy (SIMCA), partial least squares‐discriminant analysis (PLS‐DA), support vector machines (SVMs), and neural network (NN) were employed to generate the models for the classification and discrimination of PETN IREs from substrate thermal emissions. PCA exhibited less variability for the LITE spectra of PETN/substrates. SIMCA was able to predict only 44.7% of all samples, while SVM proved to be the most effective statistical analysis routine, with a discrimination performance of 95%. PLS‐DA and NN achieved prediction accuracies of 94% and 88%, respectively. High sensitivity and specificity values were achieved for five of the seven substrates investigated. Copyright © 2015 John Wiley & Sons, Ltd.     

Photochemical Synthesis of Gold and Silver Nanoparticles—A Review

Nanomaterials have supported important technological advances due to their unique properties and their applicability in various fields, such as biomedicine, catalysis, environment, energy, and electronics. This has triggered a tremendous increase in their demand. In turn, materials scientists have sought facile methods to produce nanomaterials of desired features, i.e., morphology, composition, colloidal stability, and surface chemistry, as these determine the targeted application. The advent of photoprocesses has enabled the easy, fast, scalable, and cost- and energy-effective production of metallic nanoparticles of controlled properties without the use of harmful reagents or sophisticated equipment. Herein, we overview the synthesis of gold and silver nanoparticles via photochemical routes. We extensively discuss the effect of varying the experimental parameters, such as the pH, exposure time, and source of irradiation, the use or not of reductants and surfactants, reagents’ nature and concentration, on the outcomes of these noble nanoparticles, namely, their size, shape, and colloidal stability. The hypothetical mechanisms that govern these green processes are discussed whenever available. Finally, we mention their applications and insights for future developments.     

PEP-1-GLRX1 Reduces Dopaminergic Neuronal Cell Loss by Modulating MAPK and Apoptosis Signaling in Parkinson’s Disease

Parkinson’s disease (PD) is characterized mainly by the loss of dopaminergic neurons in the substantia nigra (SN) mediated via oxidative stress. Although glutaredoxin-1 (GLRX1) is known as one of the antioxidants involved in cell survival, the effects of GLRX1 on PD are still unclear. In this study, we investigated whether cell-permeable PEP-1-GLRX1 inhibits dopaminergic neuronal cell death induced by 1-methyl-4-phenylpyridinium (MPP⁺) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We showed that PEP-1-GLRX1 protects cell death and DNA damage in MPP⁺-exposed SH-SY5Y cells via the inhibition of MAPK, Akt, and NF-κB activation and the regulation of apoptosis-related protein expression. Furthermore, we found that PEP-1-GLRX1 was delivered to the SN via the blood–brain barrier (BBB) and reduced the loss of dopaminergic neurons in the MPTP-induced PD model. These results indicate that PEP-1-GLRX1 markedly inhibited the loss of dopaminergic neurons in MPP⁺- and MPTP-induced cytotoxicity, suggesting that this fusion protein may represent a novel therapeutic agent against PD.     

Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey

Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes’ properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.     

Supersingular quotients of Fermat curves

We give formulas for the genera of all the possible quotient of a Fermat curve by a group of automorphisms in characteristic zero and for many classes of quotient curves also in positive characteristic. We use those results for giving evidence to the conjecture that, in any fixed positive characteristic, there should exist supersingular curves for any genus.