Simultaneous LC?CMS?CMS Determination of HM30181A, [2-(2-{4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl]amide, as a new P-Glycoprotein Inhibitor and Its Two Metabolites, M1 and M2, in Human Plasma: Application to a Pharmacokinetic Study

A simultaneous simple, rapid, and sensitive LC?CMS?CMS method was developed and validated for the determination of HM30181A, [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl]-4,5-dimethoxy-phenyl]amide, as a P-glycoprotein inhibitor and its two metabolites, M1 and M2, in human plasma using docetaxel as an internal standard (IS). The analytes were extracted from 200???L of biological sample by liquid?Cliquid extraction using 1?mL of methyl-t-butyl ether. Chromatographic separation was carried on a Luna C8 column at 30???C with mobile phase consisting of distilled water with 0.1% formic acid and acetonitrile (75:25, v/v) at a flow rate of 0.7?mL?min^?1 for human plasma samples. The method was linear over concentration ranges of 0.5?C50, 0.1?C10, and 0.1?C10?ng?mL^?1 for HM30181A, M1, and M2, respectively, in human plasma. The values of coefficient variation for the assay precision were <12.5, <9.10, and <9.96% for HM30181A, M1, and M2, respectively, in human plasma. The values of accuracy were 93.0?C108, 94.7?C104%, and 95.7?C105% for HM30181A, M1, and M2, respectively, in human plasma. This method is simple, sensitive, and applicable for the pharmacokinetic studies of HM30181A and its metabolites in humans.     

Surface-segregated, high-voltage spinel LiMn1.5Ni0.42Ga0.08O4 cathodes with superior high-temperature cyclability for lithium-ion batteries

The substitution of a small amount of Ga in the high-voltage spinel cathode LiMn_1.5Ni_0.42Ga_0.08O₄ leads to superior cyclability at room temperature and 55 °C along with higher rate capability with conventional electrolytes compared to that found with the LiMn_1.5Ni_0.5O₄ cathode. The superior performance is attributed to the segregation of the inert Ga³⁺ ions to the surface during the synthesis process, providing a robust, more stable interface with the electrolyte at the high operating voltage (~ 4.7 V), along with the stabilization of the spinel structure with a disordering of the cations in the octahedral sites.     

Linking Conformational Flexibility and Kinetics: Catalytic 1,4‐Type Friedel–Crafts Reactions of Phenols Utilizing 1,3‐Diamine‐Tethered Guanidine/Bisthiourea Organocatalysts

Herein, we present details of our conformationally flexible, 1,3‐diamine‐tethered guanidine/bisthiourea organocatalysts for chemo‐, regio‐, and enantioselective 1,4‐type Friedel–Crafts reactions of phenols. These organocatalysts show a unique stereo‐discrimination governed by the differential activation entropy (ΔΔS^≠), rather than by the differential activation enthalpy (ΔΔH^≠). Extensive kinetic analyses using Eyring plots for a series of guanidine/bisthiourea organocatalysts revealed the key structural motif in the catalysts associated with a large magnitude of differential activation entropy (ΔΔS^≠). A plausible guanidine–thiourea cooperative mechanism for the enantioselective Friedel–Crafts reaction is proposed.     

Helical silica nanotubes: Nanofabrication architecture,transfer of helix and chirality to silica nanotubes

A series of neutral gelators and cationic amphiphiles derived from 1,2 diphenylethylenediamine (I) and 1,2-cyclohexanediamine (II) was synthesised. Helical silica nanotubes were prepared utilising these organic gelators through sol-gel polycondensation of tetraethoxy silane, (TEOS-silica source). Right- and left-handed helical nanotubes respectively were obtained from a 1: 1 mass mixture of optically active, (1S,2S)-III-(1S,2S)-V neutral gelator and (1S,2S)-IV-(1S,2S)-VI cationic amphiphile and a 1: 1 mass mixture of optically active, (1R,2R)-III-(1R,2R)-V neutral gelator and (1R,2R)-IV-(1R,2R)-VI cationic amphiphile, indicating that the handedness of the helical nanotubes varied with the change in the neutral gelator precursors used. The nanotubes were characterised by SEM images.     

Visible-Light-Induced ortho-Selective Migration on Pyridyl Ring: Trifluoromethylative Pyridylation of Unactivated Alkenes

The photocatalyzed ortho-selective migration on a pyridyl ring has been achieved for the site-selective trifluoromethylative pyridylation of unactivated alkenes. The overall process is initiated by the selective addition of a CF₃ radical to the alkene to provide a nucleophilic alkyl radical intermediate, which enables an intramolecular endo addition exclusively to the ortho-position of the pyridinium salt. Both secondary and tertiary alkyl radicals are well-suited for addition to the C2-position of pyridinium salts to ultimately provide synthetically valuable C2-fluoroalkyl functionalized pyridines. Moreover, the method was successfully applied to the reaction with P-centered radicals. The utility of this transformation was further demonstrated by the late-stage functionalization of complex bioactive molecules.     

Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations

Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.     

Thermal processes in the systems with Li-battery cathode materials and LiPF6 -based organic solutions

Thermodynamic instability of positive electrodes (cathodes) in Li-ion batteries in humid air and battery solutions results in capacity fading and batteries degradation, especially at elevated temperatures. In this work, we studied thermal interactions between cathode materials Li₂MnO₃, xLi₂MnO₃ ^.(1???x)Li(MnNiCo)O₂,LiNi_0.33Mn_0.33Co_0.33O₂, LiNi_0.4Mn_0.4Co_0.2O₂, LiNi_0.8Co_0.15Al_0.05O₂ LiMn_1.5Ni_0.5O₄, LiMn(or Fe)PO₄, and battery solutions containing ethylene carbonate (EC) or propylene carbonate (PC), dimethyl carbonate (DMC) or ethylmethyl carbonate (EMC) and LiPF₆ salt in the temperature range of 40–400 °C. It was found that these materials are stable chemically and well performing in LiPF₆-based solutions up to 60 °C. The thermal decomposition of the electrolyte solutions starts >180 °C. The macro-structural transformations of cathode materials upon exothermic reactions were studied by transmission electron microscopy (TEM), X-ray difraction (XRD) and Raman spectroscopy. Differential scanning calorimetry (DSC) studies have shown that the exothermic reactions in the temperature range of 60–140 °C lead to partial decomposition of both the cathode material and electrolyte solution. The systems thus formed consisted of partially decomposed solutions and partially chemically delithiated cathode materials covered by reactions products. Thermal reactions terminate and this system reaches equilibrium at about 120 °C. It remains stable up to the beginning of the solution decomposition at about 180 °C. The increased content of surface Li₂CO₃ is found to significantly affect the thermal processes at high temperature range due to extensive exothermic decomposition at low temperatures.