Lysine-Reactive N-Acyl-N-aryl Sulfonamide Warheads: Improved Reaction Properties and Application in the Covalent Inhibition of an Ibrutinib-Resistant BTK Mutant.

The covalent inhibition of a target protein has gained widespread attention in the field of drug discovery. Most of the current covalent drugs utilize the high reactivity of cysteines toward modest electrophiles. However, there is a growing need for warheads that can target lysine residues to expand the range of covalently druggable proteins and to deal with emerging proteins with mutations resistant to cysteine-targeted covalent drugs. We have recently developed an N-acyl-N-alkyl sulfonamide (NASA) as a lysine-targeted electrophile. Despite its successful application, this NASA warhead suffered from instability in physiological environments, such as serum-containing medium, because of its high intrinsic reactivity. In this study, we sought to modify the structure of the NASA warhead and found that N-acyl-N-aryl sulfonamides (ArNASAs) are promising electrophiles for use in a lysine-targeted covalent inhibition strategy. We prepared a focused library of ArNASA derivatives with diverse structures and reactivity and identified several warhead candidates with suppressed hydrolysis-mediated inactivation and reduced nonspecific reactions with off-target proteins, without sacrificing the reactivity toward the target. These reaction properties enabled the improved covalent inhibition of intracellular heat shock protein 90 (HSP90) in the presence of serum and the development of the first irreversible inhibitor for ibrutinib-resistant Bruton's tyrosine kinase (BTK) bearing the C481S mutation. This study clearly demonstrated the use of a set of ArNASA warheads to create highly potent covalent drugs and highlighted the importance of enriching the current arsenal of lysine-reactive warheads.

Kinetic Analysis of the Photochemical Paths in Asymmetric Diarylethene Dimer.

An asymmetric diarylethene dimer composed of 2- and 3-thienylethene units linked by m-phenylene developed various colors upon UV irradiation via an independent photochromic reaction on each unit. The change in contents and the other photoresponses of the photogenerated four isomers were analyzed using quantum yield for all the possible photochemical paths, i. e., photoisomerization, fluorescence, energy transfer, and the other non-radiative paths. Almost all the rate constants of photochemical paths were calculated using measurable quantum yields and lifetimes. It was found that a significant contribution on photoresponse was the competition between photoisomerization and intramolecular energy transfer. The clear difference was observed in the photoresponses of the dimer and the 1 : 1 mixture solution of the model compounds. The m-phenylene spacer appropriately regulated the rate of energy transfer in the asymmetric dimer, and the spacer enabled isolation of the excited state of the dimer, making the above quantitative analysis possible.

All-Visible (>500 nm)-Light-Induced Diarylethene Photochromism Based on Multiplicity Conversion via Intramolecular Energy Transfer.

Photoswitching molecules that reversibly switch upon visible-light irradiation are some of the most attractive targets for biological and imaging applications. In this study, we found a diarylethene (DAE) derivative having a covalently attached perylenebisimide (PBI) unit (DAE-PBI dyad) underwent an unexpected cyclization reaction upon irradiation with green (500-550 nm) light, where the DAE unit has no absorbance. The photoreactivity was enhanced in solvents containing heavy atoms and in the presence of oxygen. As inferred from the solvent dependence and the calculated excited-state energies of DAE and PBI units, it was suggested that the probable mechanism for this unique visible-light-induced cyclization reaction is multiplicity conversion based on intramolecular energy transfer from the excited singlet state of the PBI unit to the triplet state of DAE units (i.e., DAE-1[PBI]* → 3[DAE]*-PBI). Such a unique photoreaction mechanism with the assistance of oxygen will pave the way for new molecular design for the development of visible-light switching molecules.

Re-entrant Photoinduced Morphological Transformation and Temperature-Dependent Kinetic Products of a Rectangular Amphiphilic Diarylethene Assembly.

An amphiphilic rectangular-shaped photochromic diarylethene bearing two hydrophobic alkyl chains and two hydrophilic tri(ethylene glycol) chains was synthesized, and its photoinduced morphological transformation in water was investigated. Two unexpected phenomena were revealed in the course of the experiments: a re-entrant photoinduced macroscopic morphological transformation and temperature-dependent kinetic products of supramolecular assembly. When the pure closed-ring isomer was dispersed in water, a re-entrant photoinduced morphological transformation, that is, a photoinduced transition from the hydrated phase to the dehydrated phase and then back to the hydrated phase, was observed by optical microscopy upon irradiation with green light at 20 °C; this was interpreted by the V-shaped phase diagram of the LCST transition. The aqueous assembly of the pure closed-ring isomer was controlled by changing the temperature; specifically, rapid cooling to 15 and 5 °C gave J and H aggregates, respectively, as the kinetic products. The thermodynamic product at both temperatures was a mixture of mostly H aggregate with a small amount of J aggregate. This behavior was rationalized by the temperature-dependent potential energy surface of the supramolecular assembly.

A diarylethene annulated isomer as a highly-conductive molecular wire evaluated by the exchange interaction between two nitroxides.

Bis(imino nitroxide) bridged by a diarylethene annulated isomer was synthesized and the exchange interaction between the two radicals was determined by the simulation of the ESR spectrum. The exchange interaction was found to be as large as that of the closed-ring isomer, suggesting that the annulated isomer can be used as a highly-conductive molecular wire in molecular electronics.

Photoinduced repetitive separation of a supramolecular assembly composed of an amphiphilic diarylethene mixture.

A supramolecular assembly composed of a two-component mixture of amphiphilic diarylethenes, which have octyloxycarbonyl and N-octylcarbamoyl groups, showed a unique macroscopic transformation upon irradiation with UV light and subsequent standing in the dark. Unlike the pure compounds, the assembly was repetitively separated into a blue sphere and a red-purple sparse structure. Both the blue sphere and the sparse structure turned into colorless spheres upon irradiation with visible light and the divided colorless spheres showed the same response to UV and visible light. Phase diagrams based on the change in absorption spectra upon temperature change suggested that the transformation originates from a LCST transition. In the 0.5 : 0.5 mixture, in contrast to the pure compounds, the transition temperature sharply changed at around 50% of the fraction of the closed-ring isomer. TEM imaging showed that the 0.5 : 0.5 mixture with high photoisomerization yield formed a 10 nm-sized network. Judging from the phase diagram and TEM images, the separation is understood as the local phase transition of the regions with a high fraction of the closed-ring isomer.

Structural Colored Balloon Composed of Temperature-Responsive Polymers Showing LCST Behavior.

Structural colored balloons (SCBs) consisting of polymer thin film developed structural color by thin-layer interference on the shell. Thermoresponsive SCBs were prepared with poly(diethylene glycol monomethyl ether methacrylate)- co-poly( N-phenylacrylamide), which shows lower critical solution temperature (LCST) behavior. When cooling gelatin aqueous solution in which osmotic pressure was not operated, only hydration of the copolymer progressed due to LCST transition. The optical path length of the SCB increased due to swelling by water and subsequently decreased due to dissolution. The structural color changed according to the change in optical path length. In cold pure water, in addition to the hydration, osmotic pressure was operated to induce an influx of the outer solvent and the resulting diameter change also affected the shell thickness. The structural color change was analyzed to reveal that the dissolution of the polymer had significant effect on the developed structural color.

Bundle formation of supramolecular fibers of amphiphilic diarylethene by depletion force.

Supramolecular nanofibers composed of the closed-ring isomer of a diarylethene formed bundles in a methylcellulose aqueous solution by depletion force while the spheres composed of the open-ring isomer were not coagulated. Upon irradiation with UV light to the suspension of the open-ring isomer, fibers were found to be generated and the formed submillimeter-sized bundles showed a photoinduced shrinking of more than 100 µm under visible light irradiation.

Phototransformative Supramolecular Assembly of Amphiphilic Diarylethenes Realized by a Combination of Photochromism and Lower Critical Solution Temperature Behavior.

Amphiphilic diarylethenes bearing octyloxycarbonyl and N-octylcarbamoyl groups have been designed and synthesized. These ester- and amide-linked compounds form micrometer-sized supramolecular assemblies in water, and these assemblies exhibit photoinduced macroscopic morphological transformations upon alternate irradiation with UV and visible light. The ester-linked diarylethene showed a transformation between colorless spheres and a red-purple hazy fringe, whereas the microspheres of the amide-linked diarylethene showed changes in color, size, and shape, but the spheres did not show division. TEM images revealed that the spheres of the open-ring isomers have coacervate structures, with bicontinuous aqueous and organic phases. The closed-ring isomers of the ester- and amide-linked compounds were found to form nanofibers and thin layers, respectively. These compounds showed absorption spectral shifts at temperatures corresponding to the lower critical solution temperature (LCST) transition. This morphological transformation can be rationalized as the photoinduced phase transition between the high- and low-temperature phases of the LCST transition. These results open up a new avenue for the design of phototransformative supramolecular assemblies based on a combination of photochromism and LCST behavior.

Photocontrol of Clustering, Retaining, and Releasing of Microbeads Concomitant with Phototransformation of Supramolecular Architecture of Amphiphilic Diarylethene.

Photoinduced clustering of polystyrene microbeads and photocontrol of their diffusion was achieved in water with the assistance of photoinduced transformation of supramolecular architecture of amphiphilic diarylethene between sphere and fiber states. When a suspension of polystyrene beads containing the sphere state of diarylethene was UV-irradiated from beneath, clustering of the polystyrene beads by thermal convection was observed. The velocity of clustering was dependent on the amount of photogenerated nanofibers that determines the viscosity of the water. Diffusion of the clustered polymer beads was suppressed by the surrounding fibers, but was restored to regular Brownian motion upon irradiation with visible light. It was suggested that the diffusion of the microbeads was controlled by the transformation of aggregates between the more viscous fiber state and the less viscous sphere state. These results provide new insight into the photocontrol of particle motion in fluidic media.

Laser Patterning of Optically Reconfigurable Transistor Channels in a Photochromic Diarylethene Layer.

Optical switching organic field-effect transistors (OFETs) provide a new direction for optoelectronics based on photochromic molecules. However, the patterning of OFETs is difficult because conventional fabrication processes, including lithography and ion etching, inevitably cause severe damage to organic molecules. Here, we demonstrate laser patterning of one-dimensional (1D) channels on an OFET with a photochromic diarylethene (DAE) layer. The main findings are (i) a number of 1D channels can be repeatedly written and erased in the DAE layer by scanning focused ultraviolet and visible light laser beams alternately between the source and drain electrodes, (ii) the conductivity (or resistivity) of the 1D channel can be controlled by the illumination conditions, such as the laser power density and the scan speed, and (iii) it is possible to draw an analogue adder circuit by optically writing 1D channels so that a portion of the channels overlaps and to perform optical summing operations by local laser illumination of the respective channels. These findings will open new possibilities for realizing various optically reconfigurable, low-dimensional organic transistor circuits, which are not possible with conventional thin film OFETs.

Photoswitching of Conductance of Diarylethene-Gold Nanoparticle Network Based on the Alteration of π-Conjugation.

Diarylethenes, which have same core structures but have different positions of thiol groups that are bound to gold nanoparticles, were prepared. In one diarylethene, which has two thiol groups at the positions equivalent to 5,5'-positions of di(3-thienyl)ethene, the π-connectivity between two thiol groups increases upon photocyclization, but in the other diarylethene, which has two thiol groups at 2- and 5-positions of one of the 3-thenyl group, the π-connectivity decreases upon photocyclization. The gold nanoparticle networks of these diarylethenes were prepared and the change in conductance was measured upon alternate irradiation with UV and visible light. For two diarylethenes, the direction of the photoswitching was opposite, reflecting the difference in the π-connectivity. The result suggests that the topology of π-conjugation between electrodes is the decisive factor in the conductance of gold nanoparticle network.

Structural Colored Balloons Responsive to pH Change.

Structural colored balloons (SCBs) composed of poly(4-vinylpyridine-co-styrene) (P4VP-PS) exhibited a pH-controlled structural color change in the presence and absence of p-toluenesulfonic acid. The diameter of the SCBs increased and decreased under acidic and neutral conditions, respectively. The different colors exhibited at different pH values supposedly resulted from a change in the shell thickness not only due to the change in the diameter of the SCBs but also due to the uptake of p-toluenesulfonic acid to the pyridyl side chain of P4VP-PS.

DNA Microenvironment Monitored by Controlling Redox Blinking.

The rate of a bimolecular reaction between a fluorophore and a freely diffusing molecule in the solvent depends on the accessibility of the fluorophore for collision with the molecule. We previously reported that the observation of blinking, caused by the formation of R6G in the excited triplet state ((3) R6G*) and its quenching reaction with O2 , allowed us to monitor the DNA conformational changes between a duplex and a hairpin. However, the small molecular size of O2 hampered sensitive monitoring of the microenvironment changes around R6G. In this study, we control redox blinking by adding a reductant ascorbic acid 2-phosphate (VcP), which converts (3) R6G* into the radical anion form R6G(.-) , and by adding a bulky oxidant FeDTPA. The bimolecular electron-transfer rate between R6G(.-) and bulky FeDTPA was more strongly affected by microenvironment changes around R6G, compared with that between (3) R6G* and the smaller O2 . This allowed us to monitor subtle DNA conformational changes caused by a single different nucleotide.

Photoinduced macroscopic morphological transformation of an amphiphilic diarylethene assembly: reversible dynamic motion.

Self-assembled microstructures of an amphiphilic diarylethene featuring an alkyl chain and triethylene glycol groups showed a photoinduced reversible morphological change in water. Reversible photoisomerization of the core diarylethene gave rise to a reversible morphological transformation between colorless microspheres and colored fibers. When colorless microspheres were irradiated with UV light, colored fibers were formed, and when the colored fibers were irradiated with visible light, the spheres were restored to their original positions where the spheres originally existed. This system showed reversible morphological change through not only photoirradiation but also temperature change. These behaviors can be interpreted as a phase transition between the sphere and fiber states. The dynamic process of the phase transition was monitored by polarized optical microscopy (POM), transmission electron microscopy (TEM), and X-ray diffraction (XRD). It was revealed that the formation of fibers upon UV irradiation occurred radially at the surface of the sphere and the formation of the spheres upon visible-light irradiation occurred at the middle of the fiber. The unique photoinduced mechanical motion provides useful information for the design of sophisticated photoactuators.

Investigation on CD inversion at visible region caused by a tilt of the π-conjugated substituent: theoretical and experimental approaches by using an asymmetric framework of diarylethene annulated isomer.

A substituent effect of asymmetric diarylethene annulated isomer on their chiroptical properties was investigated by means of theoretical and experimental approaches. The absolute configuration of the annulated isomer was determined by X-ray structural analysis and DFT calculation. The TD-DFT calculation successfully reproduced not only the sign but also the shape and magnitude of experimental CD spectrum by considering the Boltzmann-weighted average of four atrop-isomers. A fragment decomposition (FD) analysis of rotatory strength clearly revealed a noteworthy effect; the tilting motion concomitant with the rotating motion of the substituent affects the sign and magnitude of CD signals. It was found that even when the absolute structure of the chiral core moiety does not change, the slight motion of the substituent can trigger the inversion of the CD signal.

Photoisomerization-induced manipulation of single-electron tunneling for novel Si-based optical memory.

We demonstrated optical manipulation of single-electron tunneling (SET) by photoisomerization of diarylethene molecules in a metal-insulator-semiconductor (MIS) structure. Stress is placed on the fact that device operation is realized in the practical device configuration of MIS structure and that it is not achieved in structures based on nanogap electrodes and scanning probe techniques. Namely, this is a basic memory device configuration that has the potential for large-scale integration. In our device, the threshold voltage of SET was clearly modulated as a reversible change in the molecular orbital induced by photoisomerization, indicating that diarylethene molecules worked as optically controllable quantum dots. These findings will allow the integration of photonic functionality into current Si-based memory devices, which is a unique feature of organic molecules that is unobtainable with inorganic materials. Our proposed device therefore has enormous potential for providing a breakthrough in Si technology.

Evaluation of the ß value of the phenylene ethynylene unit by probing the exchange interaction between two nitronyl nitroxides.

A series of nitronyl nitroxide radicals having different lengths of phenylene ethynylene molecular wire were synthesized to investigate the decay constant of p-phenylene ethynylene. By the measurement and simulation of the ESR spectra of the biradicals, it was found that the exchange interaction decreased with a decay constant (ß) of 0.39 Å(-1) as the length of the molecule increased. This result indicates that the spin-spin exchange interaction between neutral radicals has a decay constant similar to that of the molecular conductance. This value of the decay constant indicates that a hopping mechanism does not take place in the measurement of the exchange interaction between neutral radicals even when the molecular wire has enough length to show hopping conduction of electrons.

Photocontrol of solvent responsiveness of structural colored balloons.

The structural colored balloons (SCBs) composed of poly(vinyl cinnamate) (PVCi) showed solvent responsiveness of structural color by the change of shell thickness along with the size change by osmotic pressure, and the gradual color change could be stopped by UV irradiation. The rate of size change was decreased by the increase of the molecular weight upon photo-cross-linking reaction of PVCi.

Optically and electrically driven organic thin film transistors with diarylethene photochromic channel layers.

We achieved drain-current switching of diarylethene-channel field-effect transistors with light- and electric-field effects. The drain current was reversibly changed by alternating ultraviolet and visible light irradiation. Stress is placed on the fact that the on/off ratio realized by light irradiation was 1 × 10(2) (1 × 10(4)%) and this value is much larger than those in other photochromism-based transistors. These results indicate that the drain current was effectively controlled by light irradiation. Furthermore, the on and off states modulated by light were maintained without light irradiation even after 1 week, exhibiting that our transistor works as an optical memory. We clarified that the light-driven modulation can be attributed to the transformation in the π-conjugation system accompanied by photoisomerization. These findings have the potential to attain high-performance optoelectrical organic devices including optical sensors, optical memory, and photoswitching transistors.