Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity

Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) are known to bind to transthyretin (TTR) in vitro, possibly explaining their bioaccumulation, rodent toxicity, and presumed human toxicity. Herein, we show that several OH-PCBs bind selectively to TTR in blood plasma; however, only one of the PCBs tested binds TTR in plasma. Some of the OH-PCBs displace thyroid hormone (T4) from TTR, rationalizing the toxicity observed in rodents, where TTR is the major T4 transporter. Thyroid binding globulin and albumin are the major T4 carriers in humans, making it unlikely that enough T4 could be displaced from TTR to be toxic. OH-PCBs are excellent TTR amyloidogenesis inhibitors in vitro because they bind to the TTR tetramer, imparting kinetic stability under amyloidogenic denaturing conditions. Four OH-PCB/TTR cocrystal structures provide further insight into inhibitor binding interactions.     

Glass microfluidic devices with thin membrane voltage junctions for electrospray mass spectrometry

In this study a novel glass membrane was prepared for conducting high voltage (HV) to solution in the channel of a microfabricated device for generation of liquid electrospray. Taylor cone formation and mass spectra obtained from this microdevice confirmed the utility of the glass membrane, but voltage conduction through the membrane could not be successfully explained based solely on the conductivity of the glass itself. This novel method for developing a high-voltage interface for microdevices avoids direct metal/liquid contact eliminating bubble formation in the channel due to water hydrolysis on the surface of the metal. Further, this arrangement produces no dead volume as is often found with traditional liquid junctions. At the same time, preliminary investigations into the outlet design of glass microdevices for interfacing with electrospray mass spectrometry, was explored. Both the exit shape and the use of hydrophobic coatings at the channel exit of the microdevice electrospray interface were evaluated using standard proteins with results indicating the utility of this type of design after further optimization.     

A novel palladium-catalyzed synthesis of 1,2-dihydroquinoxalines and 3,4-dihydroquinoxalinones

Reactions of enamines, derived from 2-nitroanilines and alpha-substituted aldehydes, with carbon monoxide (6 atm) in the presence of a catalytic amount of bis(dibenzylideneacetone)palladium(0) (Pd(dba)(2)) and 1,3-bis(diphenylphosphino)propane (dppp) afford readily separated mixtures of 1,2-dihydroquinoxalines and 3,4-dihydroquinoxalinones. Addition of a catalytic amount of 1,10-phenanthroline to the reaction mixture substantially improved the yield of products. [reaction: see text]     

G-quartets 40 years later: from 5'-GMP to molecular biology and supramolecular chemistry

Molecular self-assembly is central to many processes in both biology and supramolecular chemistry. The G-quartet, a hydrogen-bonded macrocycle formed by cation-templated assembly of guanosine, was first identified in 1962 as the basis for the aggregation of 5'-guanosine monophosphate. We now know that many nucleosides, oligonucleotides, and synthetic derivatives form a rich array of functional G-quartets. The G-quartet surfaces in areas ranging from structural biology and medicinal chemistry to supramolecular chemistry and nanotechnology. This Review integrates and summarizes knowledge gained from these different areas, with emphasis on G-quartet structure, function, and molecular recognition.     

Supramolecular chemistry: Self-assembly of titanium based molecular squares

The interaction of Cp₂TiCl₂ with LiC₅H₅N and LiC₁₁H₈N provides Cp₂Ti(Cl)(C₅H₅N) and Cp₂Ti(Cl)(C₁₁H₈N), respectively. Reaction of these species with AgOSO₂CF₃ results in self-assembly of the respective cationic, tetranuclear molecular squares where the required 90° bond angles, demanded by a rectangle, is provided by the distorted tetrahedral bond angles of the coordinated Ti.     

Total synthesis of dendroamide a: oxazole and thiazole construction using an oxodiphosphonium salt

The total synthesis of dendroamide A (1), a multidrug-resistance reversing bistratamide-type peptide-derived macrocycle, has been accomplished in 19% yield. Fmoc-protected amino acids were condensed into appropriately protected dipeptides which were treated with bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate to afford oxazoles and thiazolines (oxidized to thiazoles) with high chemo- and stereoselectivity. The convergent condensation of three heterocyclic amino acids followed by macrocyclization afforded the natural product.     

Rapid Access to Azabicyclo[3.3.1]nonanes by a Tandem Diverted Tsuji–Trost Process

A three-step synthesis of the 2-azabicyclo[3.3.1]nonane ring system from simple pyrroles, employing a combined photochemical/palladium-catalysed approach is reported. Substrate scope is broad, allowing the incorporation of a wide range of functionality relevant to medicinal chemistry. Mechanistic studies demonstrate that the process occurs by acid-assisted C−N bond cleavage followed by β-hydride elimination to form a reactive diene, demonstrating that efficient control of what might be considered off-cycle reactions can result in productive tandem catalytic processes. This represents a short and versatile route to the biologically important morphan scaffold.     

Synthesis of 2‐Alkyl‐Substituted Benzimidazoles by Thermal Decomposition of 2‐Azidobenzenamines in thePresence of an Aldehyde

2‐Substituted benzimidazoles were prepared by reaction of 2‐azidoaminobenzenes with aldehydes under thermal conditions. The reaction probably proceeds via a sequential imine formation, azide decomposition forming a nitrene, and electrocyclization.