Hirohisa Nagatani

Cell penetrating peptides (CPPs) have a potential ability to transport physiologically active substances into cells. Most of the experiments have addressed the effects of amino acid sequence of CPPs on their transmembrane mechanism in the artificial liposome system. In contrast, the interactions between CPPs and lipids consisting of cell membranes are mainly studied through computational simulations. In order to elucidate those interactions experimentally, the reaction behavior of carboxyfluorescein (FAM)-labeled ε-poly-l-lysine (FAM-εPL) and octa-arginine (FAM-R8), which have the differently charged headgroup and hydrophobic acyl tails, was studied at the lipid monolayer-modified water|1,2-dichloroethane interfaces. FAM-R8 showed a high affinity for the lipid layer surface, whereas FAM-εPL predominately exhibited the phase transfer process. Nevertheless, the interfacial mechanism of FAM-εPL varied with the charge and structure of the lipid headgroup. The adsorption process of FAM-εPL became dominant for the lipid with multiple interaction points. It has been revealed that not only the structure of CPPs but also the properties of lipids play a key role in the transmembrane pathway.

The ionic partition property and transfer mechanism of the anthraquinone antitumor agent mitoxantrone (MTX) were studied in detail at the water|1,2-dichloroethane (DCE) interface by means of surface-sensitive spectroelectrochemical techniques. The interfacial mechanism of the cationic MTX species was composed of potential-driven ion transfer and adsorption processes. The ion association between MTX and zwitterionic polyamidoamine (PAMAM) dendrimers with peripheral carboxy groups was also investigated in terms of the effects of pH and dendritic generation. The monovalent HMTX⁺ interacted effectively with the negatively charged dendrimers at neutral pH, while the divalent H₂MTX²⁺ exhibited a weak association under acidic conditions. The higher stability of the dendrimer-MTX associates in the interfacial region was found for higher dendritic generations: G3.5 ≥ G2.5 > G1.5. The interfacial behavior of MTX and its dendrimer associates was further analyzed at the phospholipid-modified interface as a model biomembrane surface. The adsorption process of HMTX⁺ occurred mainly on the hydrophilic side of the phospholipid layer. The spectroelectrochemical results indicated that the dendrimers penetrate into the phospholipid layer and alter the transfer mechanism of HMTX⁺ across the interface.

The transfer reaction of anthracycline antibiotics, daunorubicin (DNR) and doxorubicin (DOX), was investigated at the water|1,2‐dichloroethane (DCE) interface. Spectroelectrochemical analysis demonstrated significant changes in the transfer mechanism of anthracycline cations with a slight structural difference across the bare water|DCE interface and the biomimetic interface with a phospholipid layer. The facilitated ion transfer feature was found for both HDNR⁺ and HDOX⁺ at the biomimetic interface, where the adsorption process of HDOX⁺ was observed over a wide potential range at the aqueous side of the interface, that is, the polar headgroup region of the phospholipid layer. The molecular association between the carboxylate‐terminated generation 3.5 polyamidoamine (G3.5 PAMAM) dendrimer and anthracycline derivatives occurred preferentially under neutral pH conditions. The negatively charged G3.5 PAMAM dendrimer induced positive shifts of the transfer potential of anthracycline cations at the water|DCE interface, indicating its ability as potential‐ and pH‐responsive drug carriers.

Soft molecular assemblies that respond reversibly to external stimuli are attractive materials as on/off switches, in optoelectronic, memory and sensor technologies. In this Edge Article, we present the reversible structural rearrangement of a soft porphyrin membrane under an electrical potential stimulus in the absence of solid-state architectures. The free-floating porphyrin membrane lies at the interface between immiscible aqueous and organic electrolyte solutions and is formed through interfacial self-assembly of zinc(II) meso-tetrakis(4-carboxyphenyl)porphyrins (ZnPor). A potential difference between the two immiscible electrolyte solutions induces the intercalation of bis(triphenylphosphoranylidene)ammonium cations from the organic electrolyte that exchange with protons in the porphyrin membrane. In situ UV/vis absorbance spectroscopy shows that this ionic intercalation and exchange induces a structural interconversion of the individual porphyrin molecules in the membrane from an H- to a J-type molecular configuration. These structural rearrangements are reversible over 30 potential cycles. In situ polarisation-modulation fluorescence spectroscopy further provides clear evidence of structural interconversion of the porphyrin membrane, as intercalation of the organic electrolyte cations significantly affects the latter's emissive properties. By adjusting the pH of the aqueous phase, additional control of the electrochemically reversible structural interconversion can be achieved, with total suppression at pH 3.

Soft molecular assemblies that respond reversibly to external stimuli are attractive materials as on/off switches, in optoelectronic, memory and sensor technologies. In this article, we present the reversible structural rearrangement of a soft porphyrin membrane under an electrical potential stimulus in the absence of solid-state architectures. The free-floating porphyrin membrane lies at the interface between immiscible aqueous and organic electrolyte solutions and is formed through interfacial self-assembly of zinc(II) meso-tetrakis(4-carboxyphenyl)porphyrins (ZnPor). A potential difference between the two immiscible electrolyte solutions induces the intercalation of bis(triphenylphosphoranylidene)ammonium cations from the organic electrolyte that exchange with protons in the porphyrin membrane. In situ UV/vis absorbance spectroscopy shows that this ionic intercalation and exchange induces a structural interconversion of the individual porphyrin molecules in the membrane from an H- to a J-type molecular configuration. These structural rearrangements are reversible over 30 potential cycles. In situ polarisation-modulation fluorescence spectroscopy further provides clear evidence of structural interconversion of the porphyrin membrane, as intercalation of the organic electrolyte cations significantly affects the latter’s emissive properties. By adjusting the pH of the aqueous phase, additional control of the electrochemically reversible structural interconversion can be achieved, with total suppression at pH 3.

Aggregation-induced emission (AIE) behavior of water-soluble tetraphenylethene (TPE) derivatives bearing carboxy and sulfo groups was studied at polarized liquid|liquid interfaces. The aggregation behavior of TPE derivatives in solution and at the water|1,2-dichloroethane (DCE) interface was highly dependent on their ionizable functional groups. Spectroelectrochemical analysis elucidated that the TPE derivatives were transferred across the interface accompanied by the adsorption process at the interface. The ion transfer and interfacial AIE features of TPEs responded reversibly to the externally applied potential, indicating no rigid crystalline structure formation in the interfacial region. The red-shift measured in intense interfacial emission spectra demonstrated that the carboxylate derivatives formed their J-aggregates specifically at the polarized water|DCE interface, while the aggregation processes with distinguishable emission properties took place in both interfacial region and organic solution in the sulfonate derivative system. The AIE features were also investigated at a glycerophospholipid-adsorbed interface as a model of biomembrane surface. The aggregation process of TPE derivatives was significantly modified through the interaction with phospholipid layers which stimulate the interfacial AIE process of tetra-anionic TPEs.

Various cathinone‐derived designer drugs (CATs) have recently appeared on the drug market. This study examined the mechanism for the generation of dehydrated ions for CATs during electrospray ionization collision‐induced dissociation (ESI‐CID). The generation mechanism of dehydrated ions is dependent on the amine classification in the cathinone skeleton, which is used in the identification of CATs. The two hydrogen atoms eliminated during the dehydration of cathinone (primary amine) and methcathinone (secondary amine) were determined, and the reaction mechanism was elucidated through the deuterium labeling experiments. The hydrogen atom bonded to the amine nitrogen was eliminated with the proton added during ESI, in both of the tested compounds. This provided evidence that CATs with tertiary amine structures (such as dimethylcathinone and α‐pyrrolidinophenones [α‐PPs]) do not undergo dehydration. However, it was shown that the two major tertiary amine metabolites (1‐OH and 2″‐oxo) of CATs generate dehydrated ions in ESI‐CID. The dehydration mechanisms of the metabolites of α‐pyrrolidinobutiophenone (α‐PBP) belongs to α‐PPs were also investigated. Stable‐isotope labeling showed the dehydration of the 1‐OH metabolite following a simple mechanism where the hydroxy group was eliminated together with the proton added during ESI. In contrast, the dehydration mechanism of the 2″‐oxo metabolite involved hydrogen atoms in three or more locations along with the carbonyl group oxygen, indicating that dehydration occurred via multiple mechanisms likely including the rearrangement reaction of hydrogen atoms. These findings presented herein indicate that the dehydrated ions in ESI‐CID can be used for the structural identification of CATs.