A Cyclized Helix‐Loop‐Helix Peptide as a Molecular Scaffold for the Design of Inhibitors of Intracellular Protein–Protein Interactions by Epitope and Arginine Grafting

The design of inhibitors of intracellular protein–protein interactions (PPIs) remains a challenge in chemical biology and drug discovery. We propose a cyclized helix‐loop‐helix (cHLH) peptide as a scaffold for generating cell‐permeable PPI inhibitors through bifunctional grafting: epitope grafting to provide binding activity, and arginine grafting to endow cell‐permeability. To inhibit p53–HDM2 interactions, the p53 epitope was grafted onto the C‐terminal helix and six Arg residues were grafted onto another helix. The designed peptide cHLHp53‐R showed high inhibitory activity for this interaction, and computational analysis suggested a binding mode for HDM2. Confocal microscopy of cells treated with fluorescently labeled cHLHp53‐R revealed cell membrane penetration and cytosolic localization. The peptide inhibited the growth of HCT116 and LnCap cancer cells. This strategy of bifunctional grafting onto a well‐structured peptide scaffold could facilitate the generation of inhibitors for intracellular PPIs.     

Synthesis of 10‐Aryl‐ and 10‐(Arylmethyl)acridin‐9(10H)‐ones via the Reaction of (2‐Fluorophenyl)(2‐halophenyl)methanones with Benzenamines and Arylmethanamines

The reaction of 1‐fluoro‐2‐lithiobenzenes, generated from 1‐bromo‐2‐fluorobenzenes 1 and BuLi, with 2‐halobenzaldehydes and subsequent oxidation of the resulting alcohols 2 afforded (2‐fluorophenyl)(2‐halophenyl)methanones 3 , which, on treatment with benzenamines or arylmethanamines, followed by NaH, gave rise efficiently to 10‐aryl‐ or 10‐(arylmethyl)acridin‐9(10H)‐ones ( 5 or 7 ), respectively.     

Chemical Dynamic Kinetic Resolution and S/R Interconversion of Unprotected α‐Amino Acids

Reported herein is the first purely chemical method for the dynamic kinetic resolution (DKR) of unprotected racemic α‐amino acids (α‐AAs), a method which can rival the economic efficiency of the enzymatic reactions. The DKR reaction principle can be readily applied for S/R interconversions of α‐AAs, the methodological versatility of which is unmatched by biocatalytic approaches. The presented process features a virtually complete stereochemical outcome, fully recyclable source of chirality, and operationally simple and convenient reaction conditions, thus allowing its ready scalability. A quite unique and novel mode of the thermodynamic control over the stereochemical outcome, including an exciting interplay between axial, helical, and central elements of chirality is proposed.     

In Vivo Remote Control of Reactions in Caenorhabditis elegans by Using Supramolecular Nanohybrids of Carbon Nanotubes and Liposomes

A supramolecular nanohybrid based on carbon nanotubes and liposomes that is highly biocompatible and capable of permeation through cells is described. The nanohybrid can be loaded with a variety of functional molecules and is structurally controlled by near‐infrared laser irradiation for the release of molecules from the nanohybrids in a targeted manner via microscopy. We implemented the controlled release of molecules from the nanohybrids and demonstrated remote regulation of the photoinduced nanohybrid functions. As a proof of principle, nanohybrids loaded with amiloride were successfully used in the spatiotemporally targeted blocking of amiloride‐sensitive mechanosensory neurons in living Caenorhabditis elegans. Our prototype could inspire new designs for biomimetic parasitism and symbiosis, and biologically active nanorobots for the higher‐level manipulation of organisms.     

A color reaction of mono-nitrobenzene derivatives with phenylacetonitrile in an alkaline dimethylformamide medium

Summary A simple spot test for mono-nitrobenzenes is described. It is based on the production of an orange-yellow to blue color when mono-nitrobenzenes are treated with phenylacetonitrile in alkaline dimethylformamide solution. About 60 nitrobenzenes were tested by the present method, and the limits of identifications were tabulated. The reaction mechanisms were also studied.

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Zusammenfassung Eine einfache Tüpfelreaktion auf Mononitrobenzole wird beschrieben. Piese geben mit Phenylacetonitril in alkalischer Dimethylformamidlösung eine orangegelbe bis blaue Färbung. Etwa 60 Mononitrobenzole wurden nach der angegebenen Methode getestet und deren Erfassungsgrenzen verglichen. Der Reaktionsmechanismus wurde untersucht.

     

Sonodynamic Therapeutic Effects of Sonosensitizers with Different Intracellular Distribution Delivered by Hollow Nanocapsules Exhibiting Cytosol Specific Release

Sonodynamic therapy (SDT) is a novel promising noninvasive therapy involving utilization of low‐intensity ultrasound and sonosensitizer, which can generate reactive oxygen species (ROS) by sonication. In SDT, a high therapeutic effect is achieved by intracellular delivery and accumulation at the target sites of sonosensitizer followed by oxidative damage of produced ROS by sonication. Here, pH‐ and redox‐responsive hollow nanocapsules are prepared through the introduction of disulfide cross‐linkages to self‐assembled polymer vesicles formed from polyamidoamine dendron‐poly(l‐ lysine) for the efficient delivery of sonosensitizer. As sonosensitizer, doxorubicin (DOX), an anticancer drug accumulating into cell nucleus, is selected. Also, the conjugate of DOX and triphenylphosphonium (TPP‐DOX) is synthesized as sonosensitizer with mitochondrial targeting ability. DOX and TPP‐DOX are delivered to nucleus and mitochondria by nanocapsules. Furthermore, DOX‐ or TPP‐DOX‐loaded nanocapsules exhibit in vitro sonodynamic therapeutic effect to HeLa cells with sonication, which might be through oxidative damage to nucleus and mitochondria.