Terephthalamide derivatives as mimetics of helical peptides: disruption of the Bcl-x(L)/Bak interaction

A series of Bcl-x(L)/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the alpha-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting the Bcl-x(L)/Bak BH3 domain complex (terephthalamides 9 and 26, K(i) = 0.78 +/- 0.07 and 1.85 +/- 0.32 microM, respectively). Extensive structure-affinity studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-x(L)/Bak complex formation and the size of variable side chains on these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted in disruption of the Bcl-x(L)/Bax interaction in whole cells with an IC(50) of 35.0 microM. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-x(L) is the target area for these synthetic inhibitors.     

Matching unknown empirical formulas to chemical structure using LC/MS TOF accurate mass and database searching: example of unknown pesticides on tomato skins

Traditionally, the screening of unknown pesticides in food has been accomplished by GC/MS methods using conventional library searching routines. However, many of the new polar and thermally labile pesticides and their degradates are more readily and easily analyzed by LC/MS methods and no searchable libraries currently exist (with the exception of some user libraries, which are limited). Therefore, there is a need for LC/MS approaches to detect unknown non-target pesticides in food. This report develops an identification scheme using a combination of LC/MS time-of-flight (accurate mass) and LC/MS ion trap MS (MS/MS) with searching of empirical formulas generated through accurate mass and a ChemIndex database or Merck Index database. The approach is different than conventional library searching of fragment ions. The concept here consists of four parts. First is the initial detection of a possible unknown pesticide in actual market-place vegetable extracts (tomato skins) using accurate mass and generating empirical formulas. Second is searching either the Merck Index database on CD (10,000 compounds) or the ChemIndex (77,000 compounds) for possible structures. Third is MS/MS of the unknown pesticide in the tomato-skin extract followed by fragment ion identification using chemical drawing software and comparison with accurate-mass ion fragments. Fourth is the verification with authentic standards, if available. Three examples of unknown, non-target pesticides are shown using a tomato-skin extract from an actual market place sample. Limitations of the approach are discussed including the use of A + 2 isotope signatures, extended databases, lack of authentic standards, and natural product unknowns in food extracts.     

Cyclopentathiadiazines, new heterocyclic materials from cyclic enaminonitriles

Indene and cyclopentene enaminonitriles were reacted with SCl2, iBu3N and NCS to give the first cyclopenta[1,2,6]thiadiazines that showed unusual characteristics, one as a NIR dye and another as a liquid crystal.     

Determination of parabens in wastewater samples via robot-assisted dynamic single-drop microextraction and liquid chromatography–tandem mass spectrometry

Dynamic single-drop microextraction (SDME) was automatized employing an Arduino-based lab-made Cartesian robot and implemented to determine parabens in wastewater samples in combination with liquid chromatography–tandem mass spectrometry. A dedicated Arduino sketch controls the auto-performance of all the stages of the SDME process, including syringe filling, drop exposition, solvent recycling, and extract collection. Univariate and multivariate experiments investigated the main variables affecting the SDME performance, including robot-dependent and additional operational parameters. Under selected conditions, limit of detections were established at 0.3 µg/L for all the analytes, and the method provided linear responses in the range between 0.6 and 10 µg/L, with adequate reproducibility, measured as intraday relative standard deviations (RSDs) between 5.54% and 17.94%, (n = 6), and inter-days RSDs between 8.97% and 16.49% (n = 9). The robot-assisted technique eased the control of dynamic SDME, making the process more feasible, robust, and reliable so that the developed setup demonstrated to be a competitive strategy for the automated extraction of organic pollutants from water samples.     

Enantioselective Synthesis of Acyclic Stereotriads Featuring Fluorinated Tetrasubstituted Stereocenters

Elaboration of enantioenriched complex acyclic stereotriads represents a challenge for modern synthesis even more when fluorinated tetrasubstituted stereocenters are targeted. We have been able to develop a simple strategy in a sequence of two unprecedented steps combining a diastereoselective aldol-Tishchenko reaction and an enantioselective organocatalyzed kinetic resolution. The aldol-Tishchenko reaction directly generates a large panel of acyclic 1,3-diols possessing a fluorinated tetrasubstituted stereocenter by condensation of fluorinated ketones with aldehydes under very mild basic conditions. The anti 1,3-diols featuring three contiguous stereogenic centers are generated with excellent diastereocontrol (typically >99 : 1 dr). Depending upon the precursors both diastereomers of stereotriads are accessible through this flexible reaction. Furthermore, from the obtained racemic scaffolds, development of an organocatalyzed kinetic resolution enabled to generate the desired enantioenriched stereotriads with excellent selectivity (typically er >95 : 5).     

The covalent functionalization of few-layered MoTe2 thin films with iodonium salts

Covalent functionalization of 2D materials provides a tailored approach towards tuning of their chemical, optical, and electronic properties making the search for new ways to graft small molecules important. Herein, the reaction with (3,5-bis(trifluoromethyl)phenyl)iodonium salt is revealed as an effective strategy for functionalization of MoTe₂ thin films. Upon decomposition of the salt, the generated radicals graft covalently as aryl-(CF₃)₂ groups at the surface of both metallic (1T’) and semiconducting (2H) polymorphs of MoTe₂. Remarkably, the reactivity of the salt is governed by the electronic structure of the given polymorph. While the functionalization of the metallic MoTe₂ occurs spontaneously, the semiconducting MoTe₂ requires activation by light. The reaction proceeds with the elimination of oxide from the original films yielding the functionalized products that remain protected in ambient conditions, presenting a viable solution to the ageing of MoTe₂ in air.     

UV/Vis absorption spectroelectrochemistry of folic acid

Journal of Solid State Electrochemistry - UV/Vis absorption spectroelectrochemistry is a very promising analytical technique due to the complementary information that is simultaneously obtained...     

Structure Elucidation of a Complex Faldaprevir‐(±)‐α‐Tocopherol Addition Product Reveals Reactivity of Common Excipient Vitamin E‐TPGS

Vitamin E‐TPGS (d ‐α‐tocopheryl polyethylene glycol succinate) is a common excipient used in drug formulations. This excipient is formed by esterification of Vitamin E succinate with polyethylene glycol. As part of an oral formulation for active pharmaceutical ingredient (API) Faldaprevir, Vitamin E‐TPGS was found to decompose under ambient conditions producing free (±)‐α‐Tocopherol which subsequently formed an adduct composed of α‐Tocopherol and the API. The addition product was isolated using liquid chromatography with collections onto solid‐phase extraction cartridges, and full structure elucidation was achieved using mass spectrometry and nuclear magnetic resonance spectroscopy. The results revealed a regioselective addition of α‐Tocopherol to the API that likely occurs through the formation of a stabilized ortho‐quinone methide intermediate. This finding demonstrates the propensity of the common excipient (Vitamin E‐TPGS) to generate chemically active intermediates that may react with formulation ingredients.