Statistical Verification of Anomaly in Chiral Angle Distribution of Air-Suspended Carbon Nanotubes

Single-walled carbon nanotubes (SWCNT) have long attracted attention due to their distinct physical properties, depending on their chiral structures (chiralities). Clarifying their growth mechanism is important toward perfect chirality-controlled bulk synthesis. Although a correlation between the chirality distribution and the carbon atom configuration at an open tube edge has been predicted theoretically, lack of sufficient statistical data on metallic and semiconducting SWCNTs prohibited its verification. Here, we report statistical verification of the chirality distribution of 413 as-grown individual air-suspended SWCNTs with a length of over 20 μm using broadband Rayleigh spectroscopy. After excluding the impact of the difference in the number of possible SWCNT structures per chiral angle interval, the abundance profile with chiral angle exhibits an increasing trend with a distinct anomaly at a chiral angle of approximately 20°. These results are well explained considering the growth rate depending on armchair-shaped site configurations at the catalyst–nanotube interface

Reductive stability evaluation of 6-azopurine photoswitches for the regulation of CKI alpha activity and circadian rhythms

Photopharmacology develops bioactive compounds whose pharmacological potency can be regulated by light. The concept relies on the introduction of molecular photoswitches, such as azobenzenes, into the structure of bioactive compounds, such as known enzyme inhibitors. Until now, the development of photocontrolled protein kinase inhibitors proved to be challenging for photopharmacology. Here, we describe a new class of heterocyclic azobenzenes based on the longdaysin scaffold, which were designed to photo-modulate the activity of casein kinase I alpha (CKI alpha) in the context of photo-regulation of circadian rhythms. Evaluation of a set of photoswitchable longdaysin derivatives allowed for better insight into the relationship between substituents and thermal stability of the cis-isomer. Furthermore, our studies on the chemical stability of the azo group in this type of heterocyclic azobenzenes showed that they undergo a fast reduction to the corresponding hydrazines in the presence of different reducing agents. Finally, we attempted light-dependent modulation of CKI alpha activity together with the accompanying modulation of cellular circadian rhythms in which CKI alpha is directly involved. Detailed structure-activity relationship (SAR) analysis revealed a new potent reduced azopurine with a circadian period lengthening effect more pronounced than that of its parent molecule, longdaysin. Altogether, the results presented here highlight the challenges in the development of light-controlled kinase inhibitors for the photomodulation of circadian rhythms and reveal key stability issues for using the emerging class of heteroaryl azobenzenes in biological applications

Controlling the Circadian Clock with High Temporal Resolution through Photodosing

Circadian clocks, biological timekeepers that are present in almost every cell of our body, are complex systems whose disruption is connected to various diseases. Controlling cellular clock function with high temporal resolution in an inducible manner would yield an innovative approach for the circadian rhythm regulation. In the present study, we present structure-guided incorporation of photoremovable protecting groups into a circadian clock modifier, longdaysin, which inhibits casein kinase I (CKI). Using photodeprotection by UV or visible light (400 nm) as the external stimulus, we have achieved quantitative and light-inducible control over the CKI activity accompanied by an accurate regulation of circadian period in cultured human cells and mouse tissues, as well as in living zebrafish. This research paves the way for the application of photodosing in achieving precise temporal control over the biological timing and opens the door for chronophotopharmacology to deeper understand the circadian clock system

Reversible modulation of circadian time with chronophotopharmacology

The circadian clock controls daily rhythms of physiological processes. The presence of the clock mechanism throughout the body is hampering its local regulation by small molecules. A photoresponsive clock modulator would enable precise and reversible regulation of circadian rhythms using light as a bio-orthogonal external stimulus. Here we show, through judicious molecular design and state-of-the-art photopharmacological tools, the development of a visible light-responsive inhibitor of casein kinase I (CKI) that controls the period and phase of cellular and tissue circadian rhythms in a reversible manner. The dark isomer of photoswitchable inhibitor 9 exhibits almost identical affinity towards the CKIα and CKIδ isoforms, while upon irradiation it becomes more selective towards CKIδ, revealing the higher importance of CKIδ in the period regulation. Our studies enable long-term regulation of CKI activity in cells for multiple days and show the reversible modulation of circadian rhythms with a several hour period and phase change through chronophotopharmacology

Photopharmacological Manipulation of Mammalian CRY1 for Regulation of the Circadian Clock

CRY1 and CRY2 proteins are highly conserved components of the circadian clock that controls daily physiological rhythms. Disruption of CRY functions are related to many diseases, including circadian sleep phase disorder. Development of isoform-selective and spatiotemporally controllable tools will facilitate the understanding of shared and distinct functions of CRY1 and CRY2. Here, we developed CRY1-selective compounds that enable light-dependent manipulation of the circadian clock. From phenotypic chemical screening in human cells, we identified benzophenone derivatives that lengthened the circadian period. These compounds selectively interacted with the CRY1 photolyase homology region, resulting in activation of CRY1 but not CRY2. The benzophenone moiety rearranged a CRY1 region called the "lid loop"located outside of the compound-binding pocket and formed a unique interaction with Phe409 in the lid loop. Manipulation of this key interaction was achieved by rationally designed replacement of the benzophenone with a switchable azobenzene moiety whose cis-trans isomerization can be controlled by light. The metastable cis form exhibited sufficiently high half-life in aqueous solutions and structurally mimicked the benzophenone unit, enabling reversible period regulation over days by cellular irradiation with visible light. This study revealed an unprecedented role of the lid loop in CRY-compound interaction and paves the way for spatiotemporal regulation of CRY1 activity by photopharmacology for molecular understanding of CRY1-dependent functions in health and disease

遷移金属触媒を用いるビニルアレンの環化付加反応

京都大学0048新制・課程博士博士(工学)甲第7500号工博第1761号新制||工||1122(附属図書館)UT51-98-U167京都大学大学院工学研究科合成・生物化学専攻(主査)教授 伊藤 嘉彦, 教授 吉田 潤一, 教授 檜山 爲次郎学位規則第4条第1項該当Doctor of EngineeringKyoto UniversityDA

Switchable Decarboxylation by Energy- or Electron-Transfer Photocatalysis

Kolbe dimerization and Hofer-Moest reactions are well-investigated carboxylic acid transformations, wherein new carbon–carbon and carbon–heteroatom bonds are constructed via electrochemical decarboxylation. These transformations can be switched by choosing an electrode that allows control of the reactive intermediate such as carbon radical or carbocation. However, the requirement of a high current density diminishes the functional group compatibility with these electrochemical reactions. Here, we demonstrate the photocatalytic decarboxylative transformation of carboxylic acids in a switchable and functional group-compatible manner. We discovered that switching between Kolbe-type or Hofer-Moest-type reactions can be accomplished with suitable photocatalysts by controlling the reaction pathways: energy transfer (EnT) and single-electron transfer (SET). The EnT pathway promoted by an organo-photocatalyst yielded 1,2-diarylethane from arylacetic acids, whereas the ruthenium photoredox catalyst allows the construction of an ester scaffold with two arylmethyl moieties via the SET pathway. The resulting radical intermediates were coupled with olefins to realize multicomponent reactions. Consequently, four different products were selectively obtained from a simple carboxylic acid. This discovery offers new opportunities for selectively synthesizing multiple products via switchable reactions using identical substrates with minimum cost and effort

Infinitene: A Helically Twisted Figure-Eight [12]Circulene Topoisomer

New forms of molecular nanocarbons particularly looped polyarenes adopting various topologies contribute to the fundamental science and practical applications. Here we report on the synthesis of an infinity-shaped polycyclic aromatic hydrocarbon, infinitene 1 (cyclo[c.c.c.c.c.c.e.e.e.e.e.e]dodecakisbenzene) comprising consecutively fused 12-benzene rings forming an enclosed loop with a strain energy of 60.2 kcal·mol-1. Infinitene 1 represents a topoisomer of still-hypothetical [12]circulene, and its scaffold can be formally visualized as the outcome of the “stitching” of two homochiral [6]helicene subunits by their both ends. The synthetic strategy encompasses transformation of a rationally designed dithiacyclophane to cyclophadiene through the Stevens rearrangement and pyrolysis of the corresponding S,S′-bis(oxide) followed by the UV-light mediated twofold photocyclization. The structure of infinitene 1 is a unique hybrid of helicene and circulene with a molecular formula C48H24, which can be regarded as an isomer for kekulene, [6,6]carbon nanobelt ([6,6]CNB), [12]cyclacene, and tetrabenzo[8]circulene as well. Infinitene 1 is a bench-stable yellow solid with green fluorescence, and soluble to common organic solvents. The figure-eight molecular structure of 1 was unambiguously confirmed by X-ray crystallography. The scaffold of 1, reminiscent of a squeezed spring, stem from its enclosed, fully-fused architecture, is significantly compressed as manifested by a remarkably shortened distance (3.152–3.192 Å) between the centroids of two π-π stacked central benzene rings and the closest C···C distance of 2.920 Å. Combined lamellar and herringbone-like crystal packing suggested three-dimensional electronic inter-actions. Fundamental photophysical properties of infinitene 1 were thoroughly elucidated by means of UV-vis absorption and fluorescence spectroscopic studies as well as density functional theory (DFT) calculations. Its configurational stability enabled separation of the corresponding enantiomers (P,P) and (M,M) by a chiral HPLC. Circular dichroism (CD) and circularly polarized luminescence (CPL) measurements revealed that 1 has moderate |gCD| and |gCPL| values