Structure-activity-relationships of the Stability of Six Pentathiepins Towards Glutathione: Possible Correlations with Biological Activities.

The biological properties of pentathiepins have been intensively studied in recent years. Although the proposed mechanism of action requires activation by intracellular thiols, the dependence of activity on the stability of pentathiepins towards glutathione (GSH) has not been directly investigated. Here, we determined the structure-related stability of six different pentathiepins with four different scaffolds in the presence of GSH by using reversed-phase high-performance liquid chromatography (RP-HPLC) and UV-vis spectroscopy over a wide range of GSH concentrations.

Cross-Coupling of NHC/CAAC-Based Carbodicarbene: Synthesis of Electron-Deficient Diradicaloids.

Herein, we report nickel(0)-catalyzed cross-coupling reactions of NHC/CAAC-based carbodicarbene (NHC = -heterocyclic carbene and CAAC = cyclic(alkyl)(amino)carbene) with different aryl chlorides, bromides, and iodides. The resulting aryl-substituted cationic carbodicarbene derivatives are prone to one-electron oxidation yielding radical-dications, which, depending on the aryl motif employed, follow different modes of radical-radical dimerization and constitute an entry point to carbon/nitrogen- and nitrogen/nitrogen-centered diradicaloids. Subsequently, this coupling strategy was strategically applied to the synthesis of -phenylene- and ,-biphenylene-bridged carbon/carbon-centered electron-deficient diradicaloids.

Pushing at the Boundaries of Pterin Chemistry.

Pterins are molecules of substantial interest as they occur in nature in a number of forms with quite distinct and often indispensable roles. Chemically, the synthesis of the principle pterin scaffold is comparably simple, while the insolubility of the pterin building block renders synthetic derivatization extremely difficult. When aiming at modeling naturally occurring pterins of extended chemical structure, this is a considerable problem.

The Role of -OEt Substituents in Molybdenum-Assisted Pentathiepine Formation-Access to Diversely Functionalized Azines.

1,2,3,4,5-pentathiepines (PTEs) are naturally occurring polysulfides of increasing scientific interest based on their identified pharmacological activities. Artificial PTEs with -heterocyclic backbones are efficiently synthesized via mediation by a molybdenum-oxo-bistetrasulfido complex. A common feature of all precursor alkynes successfully used to date in this reaction is the presence of a -CH(OEt) group since the previously postulated mechanism requires the presence of one OEt as the leaving group, and the second must become a transient ethoxonium moiety.

Synthesis of Seven Indolizine-Derived Pentathiepines: Strong Electronic Structure Response to Nitro Substitution in Position C-9.

Seven new 1,2,3,4,5-pentathiepino[6,7-]indolizines were synthesized in which the pentathiepine moieties bear an indolizine backbone that is derivatized from C-H to F-, Cl-, Br-, I-, NO-, and CH-substitutions, respectively, in a meta position relative to the aza group on the pyridine moiety. Their preparation took place via two common steps: (i) a Sonogashira coupling between (4-substituted) 2-bromo- or 2-chloropyridines and propynyl 3,3-diethylacetal, and (ii) a ring closing reaction mediated by a molybdenum oxo-bistetrasulfido complex and elemental sulfur. The latter simultaneously facilitates the 1,2,3,4,5-pentathiepino chain/ring- and indolizine ring-formations.

Fine-Tuning Redox Properties of Heteroleptic Molybdenum Complexes through Ligand-Ligand-Cooperativity.

Heteroleptic molybdenum complexes bearing 1,5-diaza-3,7-diphosphacyclooctane (P N ) and non-innocent dithiolene ligands were synthesized and electrochemically characterized. The reduction potentials of the complexes were found to be fine-tuned by a synergistic effect identified by DFT calculations as ligand-ligand cooperativity via non-covalent interactions. This finding is supported by electrochemical studies combined with UV/Vis spectroscopy and temperature-dependent NMR spectroscopy.

The Mechanism of Metal-Containing Formate Dehydrogenases Revisited: The Formation of Bicarbonate as Product Intermediate Provides Evidence for an Oxygen Atom Transfer Mechanism.

Mo/W-containing formate dehydrogenases (FDH) catalyzed the reversible oxidation of formate to carbon dioxide at their molybdenum or tungsten active sites. While in the reaction of formate oxidation, the product is CO, which exits the active site via a hydrophobic channel; bicarbonate is formed as the first intermediate during the reaction at the active site. Other than what has been previously reported, bicarbonate is formed after an oxygen atom transfer reaction, transferring the oxygen from water to formate and a subsequent proton-coupled electron transfer or hydride transfer reaction involving the sulfido ligand as acceptor.

Comprehensive Evaluation of Biological Effects of Pentathiepins on Various Human Cancer Cell Lines and Insights into Their Mode of Action.

Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines.

Pentathiepins: A Novel Class of Glutathione Peroxidase 1 Inhibitors that Induce Oxidative Stress, Loss of Mitochondrial Membrane Potential and Apoptosis in Human Cancer Cells.

A novel class of glutathione peroxidase 1 (GPx1) inhibitors, namely tri- and tetracyclic pentathiepins, has been identified that is approximately 15 times more potent than the most active known GPx1 inhibitor, mercaptosuccinic acid. Enzyme kinetic studies with bovine erythrocyte GPx1 indicate that pentathiepins reversibly inhibit oxidation of the substrate glutathione (GSH). Moreover, no inhibition of superoxide dismutase, catalase, thioredoxin reductase or glutathione reductase was observed at concentrations that effectively inhibit GPx1.

Pd/PTABS: Low-Temperature Thioetherification of Chloro(hetero)arenes.

The thioetherification of heteroaryl chlorides is an essential synthetic methodology that provides access to bioactive drugs and agrochemicals. Due to their (actual or potential) industrial importance, the development of efficient and low-temperature protocols for accessing these compounds is a requirement for economic and ecologic reasons. A particular highly effective catalytic protocol using the Pd/PTABS system at only 50 °C was developed accordingly.

Pd/PTABS: An Efficient Water-Soluble Catalytic System for the Amination of 6-Chloropurine Ribonucleoside and Synthesis of Alogliptin.

The synthesis and catalytic applications of the highly water-soluble ligand 7-phospha-1,3,5-triaza-admantane butane sultonate (PTABS) has been described. The synthesized PTABS ligand along with palladium acetate exhibits excellent reactivity towards the amination reaction of 6-chloro-9-(β-D-ribofuranosyl)-9H-purine at ambient temperature. This protocol offers an advantage over the previously published procedures for the amination of 6-chloropurine nucleoside furnishing 6-N-substituted adenosine analogues.

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[]quinolizinium derivatives by Palladium-mediated cross-coupling reactions.

9-Arylbenzo[]quinolizinium derivatives were prepared with base-free Suzuki-Miyaura coupling reactions between benzo[]quinolizinium-9-trifluoroborate and selected benzenediazonium salts. In addition, the Sonogashira coupling reaction between 9-iodobenzo[]quinolizinium and the arylalkyne derivatives yielded four novel 9-(arylethynyl)benzo[]quinolizinium derivatives under relatively mild reaction conditions. The 9-(,-dimethylaminophenylethynyl)benzo[]quinolizinium is only very weakly emitting, but the emission intensity increases by a factor >200 upon protonation, so that this derivative may operate as pH-sensitive light-up probe.

Crystal structure of 4-(pyrazin-2-yl)morpholine.

The mol-ecular structure of the title compound, CHNO, is nearly planar despite the chair conformation of the morpholine moiety. In the crystal, the mol-ecules form sheets parallel to the axis, which are supported by non-classical hydrogen-bonding inter-actions between C-H functionalities and the O atom of morpholine and the 4-N atom of pyrazine, respectively. The title compound crystallizes in the monoclinic space group 2/ with four mol-ecules in the unit cell.