Language：English   Publisher：ACS Chemical Biology  

Stomata are pores in the leaf epidermis of plants and their opening and closing regulate gas exchange and water transpiration. Stomatal movements play key roles in both plant growth and stress responses. In recent years, small molecules regulating stomatal movements have been used as a powerful tool in mechanistic studies, as well as key players for agricultural applications. Therefore, the development of new molecules regulating stomatal movement and the elucidation of their mechanisms have attracted much attention. We herein describe the discovery of 2,6-dihalopurines, AUs, as a new stomatal opening inhibitor, and their mechanistic study. Based on biological assays, AUs may involve in the pathway related with plasma membrane H+-ATPase phosphorylation. In addition, we identified leucine-rich repeat extensin proteins (LRXs), LRX3, LRX4 and LRX5 as well as RALF, as target protein candidates of AUs by affinity based pull down assay and molecular dynamics simulation. The mechanism of stomatal movement related with the LRXs-RALF is an unexplored pathway, and therefore further studies may lead to the discovery of new signaling pathways and regulatory factors in the stomatal movement.

DOI： 10.1021/acschembio.2c00771

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Aromatic polymers are the first-choice platform for current organic materials due to their distinct optical, electronic, and mechanical properties as well as their biocompatibility. However, bare aromatic polymer backbones tend to strongly aggregate, rendering them essentially insoluble in organic solvent. While the typical solution is to install many solubilizing substituents on the backbones, this often provokes undesired property changes. Herein, we report the synthesis of bare aromatic polymers enabled by a dendrimer support. An initiator arene containing a diterpenoid-based dendrimer undergoes Pd-catalyzed polymerization with monomers bearing no solubilizing substituents to furnish bare aromatic polymers such as polythiophenes and poly(para-phenylene)s. The high solubility of dendrimer-ligated polymers allows not only the unveiling of the properties of unsubstituted π-conjugated backbone, but also mild release of dendrimer-free aromatic polymers and even transfer of aromatic polymers to other materials, such as silica gel and protein, which may accelerate the creation of hybrid materials nowadays challenging to access.

DOI： 10.1038/s41467-022-33100-7

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Other Link： https://www.nature.com/articles/s41467-022-33100-7

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/jacs.0c12280

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Language：English   Publishing type：Research paper (scientific journal)  

Cryptochrome 1 (CRY1) and CRY2 are core regulators of the circadian clock, and the development of isoform-selective modulators is important for the elucidation of their redundant and distinct functions. Here, we report the identification and functional characterization of a small-molecule modulator of the mammalian circadian clock that selectively controls CRY1. Cell-based circadian chemical screening identified a thienopyrimidine derivative KL201 that lengthened the period of circadian rhythms in cells and tissues. Functional assays revealed stabilization of CRY1 but not CRY2 by KL201. A structure-activity relationship study of KL201 derivatives in combination with X-ray crystallography of the CRY1-KL201 complex uncovered critical sites and interactions required for CRY1 regulation. KL201 bound to CRY1 in overlap with FBXL3, a subunit of ubiquitin ligase complex, and the effect of KL201 was blunted by knockdown of FBXL3. KL201 will facilitate isoform-selective regulation of CRY1 to accelerate chronobiology research and therapeutics against clock-related diseases.

DOI： 10.1016/j.chembiol.2020.05.008

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.chempr.2020.08.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. The fast inhibitory actions of GABA are mainly mediated by GABA(A) receptors (GABA(A)Rs), which are widely recognized as clinically relevant drug targets. However, it remains difficult to create screening systems for drug candidates that act on GABA A Rs because of the existence of multiple ligand-binding sites and the delicate pentameric structures of GABA(A)Rs. We here developed the first turn-on fluorescent imaging probe for GABA(A)Rs, which can be used to quantitatively evaluate ligand-receptor interactions under live cell conditions. Using noncovalent labeling of GABA(A)Rs with this turn-on probe, a new imaging-based ligand assay system, which allows discovery of positive allosteric modulators (PAMs) for the GABA(A)R, was successfully constructed. Our system is applicable to high-throughput ligand screening, and we discovered new small molecules that function as PAMs for GABA(A)Rs. These results highlight the power of the use of a turn-on fluorescent probe to screen drugs for complicated membrane proteins that cannot be addressed by conventional methods.

DOI： 10.1021/acscentsci.9b00539

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We have achieved a synthesis of multiply arylated pyridines by using a [4 + 2] cycloaddition of 2,4-diaryl-5-chloroxazoles and cinnamic acids as a key reaction. The resulting hydroxytriarylpyridines can be derivatized into triarylpyridines, tetraarylpyridines and pentaarylpyridines by sequential cross couplings. This synthetic method allows for facile and rapid access to highly arylated pyridines with different aryl substituents. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2017.03.095

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Catalyst-mediated protein modification is a powerful approach for the imaging and engineering of natural proteins. We have previously developed affinity-guided 4-dimethylaminopyridine (AGD) chemistry as an efficient protein modification method using a catalytic acyl transfer reaction. However, because of the high electrophilicity of the thioester acyl donor molecule, AGD chemistry suffers from nonspecific reactions to proteins other than the target protein in crude biological environments, such as cell lysates, live cells, and tissue samples. To overcome this shortcoming, we here report a new acyl donor/organocatalyst system that allows more specific and efficient protein modification. In this method, a highly nucleophilic pyridinium oxime (PyOx) catalyst is conjugated to a ligand specific to the target protein. The ligand-tethered PyOx selectively binds to the target protein and facilitates the acyl transfer reaction of a mild electrophilic N-acyl-N-alkylsulfonamide acyl donor on the protein surface. We demonstrated that the new catalytic system, called AGOX (affinity-guided oxime) chemistry, can modify target proteins, both in test tubes and cell lysates, more selectively and efficiently than AGD chemistry. Low-background fluorescence labeling of the endogenous cell-membrane proteins, carbonic anhydrase XII and the folate receptor, in live cells allowed for the precise quantification of diffusion coefficients in the protein's native environment. Furthermore, the excellent biocompatibility and bioorthogonality of AGOX chemistry were demonstrated by the selective labeling of an endogenous neurotransmitter receptor in mouse brain slices, which are highly complicated tissue samples.

DOI： 10.1021/JACS.7B07339

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Endogenous protein labeling is one of the most invaluable methods for studying the bona fide functions of proteins in live cells. However, multi-molecular crowding conditions, such as those that occur in live cells, hamper the highly selective chemical labeling of a protein of interest (POI). We herein describe how the efficient coupling of molecular recognition with a chemical reaction is crucial for selective protein labeling. Recognition-driven protein labeling is carried out by a synthetic labeling reagent containing a protein (recognition) ligand, a reporter tag, and a reactive moiety. The molecular recognition of a POI can be used to greatly enhance the reaction kinetics and protein selectivity, even under live cell conditions. In this review, we also briefly discuss how such selective chemical labeling of an endogenous protein can have a variety of applications at the interface of chemistry and biology.

DOI： 10.1039/C7CC07177A

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

We have described a C-H arylation/ring-transformation strategy for the synthesis of triarylpyridines, which form the core structure of thiopeptide antibiotics. This synthetic method readily gave 2,3,6-triarylpyridines in a regioselective manner by a two-phase approach: C-H arylation (a nickel-catalyzed decarbonylative Suzuki-Miyaura cross-coupling and decarbonylative C-H coupling for the synthesis of 2,4-diaryloxazoles) and ring transformation ([4+2] cycloaddition of 2,4-diaryloxazoles with (hetero)arylacrylic acids). To showcase these methods, we have accomplished the formal synthesis of thiopeptide antibiotics GE2270s and amythiamicins.

DOI： 10.1002/chem.201600351

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

DOI： 10.15227/ORGSYN.092.0373

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The first general beta-selective C-H arylation of pyrroles has been developed by using a rhodium catalyst. This C H arylation reaction, which is retrosynthetically straightforward but results in unusual regioselectivity, could result in de novo syntheses of pyrrole-derived natural products and pharmaceuticals. As such, we have successfully synthesized polycyclic marine pyrrole alkaloids, lamellarins C and I, by using this beta-selective arylation of pyrroles with aryl iodides (C-H/C-I coupling) and a new double C-H/C-H coupling as key steps.

DOI： 10.1021/ja508449y

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C-H coupling reaction, we rapidly synthesized 16 analogues (IYS-1 through IYS-15 and IYS-Me) of NCH-31 with different aryl groups at the C4-position of 2-aminothiazole core of NCH-31. Subsequent biological testing of these derivatives revealed that 3-fluorophenyl (IYS-10) and 4-fluorophenyl (IYS-15) derivatives act as potent pan-HDAC inhibitor. Additionally, 4-methylphenyl (IYS-1) and 3-fluoro-4-methylphenyl (IYS-14) derivatives acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C H coupling approach to rapidly identify novel and highly active/selective biofunctional molecules.

DOI： 10.1021/ml500024s

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A versatile strategy for C7-selective boronation of tryptophans, tryptamines, and 3-alkylindoles by way of a single-pot C2/C7-diboronationC2-protodeboronation sequence is described. The combination of a mild iridium-catalyzed C2/C7-diboronation followed by an in situ palladium-catalyzed C2-protodeboronation allows efficient entry to valuable C7-boroindoles that enable further C7-derivatization. The versatility of the chemistry is highlighted by the gram-scale synthesis of C7-boronated N-Boc-L-tryptophan methyl ester and the rapid synthesis of C7-halo, C7-hydroxy, and C7-aryl tryptophan derivatives.

DOI： 10.1021/JO502062Z

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Language：Japanese  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：SOC SYNTHETIC ORGANIC CHEM JPN  

Nickel-catalyzed cross-coupling reactions have recently been receiving significant attention from the synthetic community as a way to construct carbon-carbon or carbon-heteroatom bonds, because nickel catalysts are less expensive and less toxic than palladium catalysts.We herein describe our recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications to the synthesis of natural products and pharmaceuticals. In particular, we focus on nickel-catalyzed direct coupling reactions in which "unreactive" bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.

DOI： 10.5059/YUKIGOSEIKYOKAISHI.71.576

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A.

DOI： 10.1021/ja306062c

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