HPLC with fluorescence detection assay of perampanel,a novel AMPA receptor antagonist,in human plasma for clinical pharmacokinetic studies

Perampanel (Fycompa®), a novel α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, is registered for the adjunctive treatment of patients (aged ≥12 years) with refractory partial‐onset seizures. To support therapeutic drug monitoring, a simple high‐performance liquid chromatography (HPLC) assay with fluorescence detection was developed to determine perampanel concentrations in human plasma and validated to support clinical trials. Human plasma samples (1.0 mL) were processed by liquid extraction using diethyl ether, followed by chromatographic separation on a YMC Pack Pro C₁₈ column (150 × 4.6 mm i.d., 5 µm) with isocratic elution of acetonitrile–water–acetic acid–sodium acetate (840:560:3:1.8, v/v/v/w) at a flow rate of 1.0 mL/min. Column eluent was monitored at excitation and emission wavelengths of 290 and 430 nm, respectively. The assay was linear (range 1.0–500 ng/mL) and this could be extended to 25 µg/mL by 50‐fold dilution integrity. No endogenous peaks were detected in the elution of analytes in drug‐free blank human plasma from six individuals and no interference was observed with co‐medications tested. Intra‐ and inter‐batch reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. Validation data demonstrated that our assay is simple, selective, reproducible and suitable for therapeutic drug monitoring of perampanel. Copyright © 2015 John Wiley & Sons, Ltd.     

Influence of Intermolecular Interactions on Valence Tautomeric Behaviors in Two Polymorphic Dinuclear Cobalt Complexes

Two polymorphic structures have been well determined in a valence tautomeric (VT) dinuclear cobalt complex. These polymorphs showed distinct thermal‐ and photomagnetic behavior, and are thus ideal for studying the “pure” intermolecular factors to VT transitions. In polymorph 1A , the VT cations are arranged head‐to‐waist with their neighbors and exhibit weak π???π interactions, resulting in a gradual and incomplete thermal VT transition. In contrast, the cations in polymorph 1B are arranged head‐to‐tail and exhibit relatively strong π???π interactions, leading to an abrupt and complete thermal VT transition with adjustable hysteresis loop at around room temperature. The VT process for both polymorphs can be induced by light, but the light‐excited state of 1B? 2H₂O has a higher thermal relaxation temperature than that of 1A? 3H₂O.     

How Self-Assembled Nanodomains Can Impact the Organization of a Phospholipid Monolayer-Flower-Like Arrays

We found that monolayers of dipalmitoylphosphatidylcholine (DPPC) and semi-fluorinated tetrablock di(F10H16) self-assemble to form a new type of large, complex flower-like patterns on the surface of water and on solid substrates. The hierarchical organization of these unusual self-assemblies was investigated using compression and surface potential isotherms, in situ fluorescence and Brewster angle microscopies, and atomic force microscopy after transfer.     

Shimalactone Biosynthesis Involves Spontaneous Double Bicyclo-Ring Formation with 8π-6π Electrocyclization

Shimalactones A and B are neuritogenic polyketides possessing characteristic oxabicyclo[2.2.1]heptane and bicyclo[4.2.0]octadiene ring systems that are produced by the marine fungus Emericella variecolor GF10. We identified a candidate biosynthetic gene cluster and conducted heterologous expression analysis. Expression of ShmA polyketide synthase in Aspergillus oryzae resulted in the production of preshimalactone. Aspergillus oryzae and Saccharomyces cerevisiae transformants expressing ShmA and ShmB produced shimalactones A and B, thus suggesting that the double bicyclo-ring formation reactions proceed non-enzymatically from preshimalactone epoxide. DFT calculations strongly support the idea that oxabicyclo-ring formation and 8π-6π electrocyclization proceed spontaneously after opening of the preshimalactone epoxide ring through protonation. We confirmed the formation of preshimalactone epoxide in vitro, followed by its non-enzymatic conversion to shimalactones in the dark.     

X-ray Crystallographic Observation of Chiral Transformations within a Metal–Peptide Pore

Porous metal complexes enable single-crystal X-ray crystallographic observation of included guests or reaction intermediates through simple soaking with the guests/substrates. Previous studies on this technique have often encountered difficulties in the observation of chiral structures because the host frameworks had no chirality. We synthesized a new metal–peptide porous complex through a folding-and-assembly strategy and utilized the chiral pore for trapping chiral guests. Chiral alcohols and ketones were successfully included within the pore. Crystallographic analyses clearly revealed not only their chemical structures but also chiral transformation events within the pore such as fixed conformations or an unstable hemiacetal formation.     

Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels

A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their Na_V-inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX ( 3 a ) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC₅₀ and IC₅₀ values of 8.5 and 30.7 nm , respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of Na_V1.5, with an IC₅₀ value of 94.1 nm . Derivatives 3 a – d and 3 f showed low recovery rates from Na_V1.2 subtype (ca 45–79 %) compared to natural dcSTX ( 2 ), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with Na_V in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp¹⁷¹⁷.     

Macroscopic Polarization Change of Mononuclear Valence Tautomeric Cobalt Complexes Through the Use of Enantiopure Ligand

The crystallization of a complex having electron transfer properties in a polar space group can induce the polarization switching of a crystal in a specific direction, which is attractive for the development of sensors, memory devices, and capacitors. Unfortunately, the probability of crystallization in a polar space group is usually low. Noticing that enantiopure compounds crystallize in Sohncke space groups, this paper reports a strategy for the molecular design of non-ferroelectric polarization switching crystals based on the use of intramolecular electron transfer and chirality. In addition, this paper describes the synthesis of a mononuclear valence tautomeric (VT) cobalt complex bearing an enantiopure ligand. The introduction of enantiomer enables the crystallization of the complex in the polar space group (P2₁). The polarization of the crystals along the b-axis direction is not canceled out and the VT transition is accompanied by a change in the macroscopic polarization of the polar crystal. Polarization switching via electron transfer is realized at around room temperature.