Radical C-Glycosylation Using Photoexcitable Unprotected Glycosyl Borate.

We have developed radical C-glycosylation using photoexcitable unprotected glycosyl borate. The direct excitation of glycosyl borate under visible light irradiation enabled the generation of anomeric radical without any photoredox catalysts. The in situ generated anomeric radical was applicable to the radical addition such as Giese-type addition and Minisci-type reaction to introduce alkyl and heteroaryl groups at the anomeric position.

Endoplasmic reticulum transporter OAT2 regulates drug metabolism and interaction.

Xenobiotic metabolic reactions in the hepatocyte endoplasmic reticulum (ER) including UDP-glucuronosyltransferase and carboxylesterase play central roles in the detoxification of medical agents with small- and medium-sized molecules. Although the catalytic sites of these enzymes exist inside of ER, the molecular mechanism for membrane permeation in the ER remains enigmatic. Here, we investigated that organic anion transporter 2 (OAT2) regulates the detoxification reactions of xenobiotic agents including anti-cancer capecitabine and antiviral zidovudine, via the permeation process across the ER membrane in the liver.

Radical Caging Strategy for Cholinergic Optopharmacology.

Photo-caged methodologies have been indispensable for elucidating the functional mechanisms of pharmacologically active molecules at the cellular level. A photo-triggered removable unit enables control of the photo-induced expression of pharmacologically active molecular function, resulting in a rapid increase in the concentration of the bioactive compound near the target cell. However, caging the target bioactive compound generally requires specific heteroatom-based functional groups, limiting the types of molecular structures that can be caged.

Reverse mutants of the catalytic 19 kDa mutant protein (nanoKAZ/nanoLuc) from Oplophorus luciferase with coelenterazine as preferred substrate.

Native Oplophorus luciferase (OpLase) and its catalytic 19 kDa protein (wild KAZ) show highest luminescence activity with coelenterazine (CTZ) among CTZ analogs. Mutated wild KAZ with 16 amino acid substitutions (nanoKAZ/nanoLuc) utilizes bis-coelenterazine (bis-CTZ) as the preferred substrate and exhibits over 10-fold higher maximum intensity than CTZ. To understand the substrate selectivity of nanoKAZ between CTZ and bis-CTZ, we prepared the reverse mutants of nanoKAZ by amino acid replacements with the original amino acid residue of wild KAZ.

Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A.

DYRK1A phosphorylates proteins involved in neurological disorders in an intermolecular manner. Meanwhile, during the protein folding process of DYRK1A, a transitional folding intermediate catalyzes the intramolecular autophosphorylation required for the "one-off" inceptive activation and stabilization. In our previous study, a small molecule termed FINDY (1) was identified, which inhibits the folding intermediate-catalyzed intramolecular autophosphorylation of DYRK1A but not the folded state-catalyzed intermolecular phosphorylation.

Generation of Functionalized Alkyl Radicals via the Direct Photoexcitation of 2,2'-(Pyridine-2,6-diyl)diphenol-Based Borates.

A new type of alkylborate was developed for the purpose of generating radicals via direct photoexcitation. These borates were prepared using 2,2'-(pyridine-2,6-diyl)diphenol as a tridentate ligand together with organoboronic acids or potassium trifluoroborates. The ready availability of organoboron compounds is a significant advantage of this direct photoexcitation protocol.

Chiral deaza-coelenterazine analogs for probing a substrate-binding site in the Ca2+-binding photoprotein aequorin.

The Ca2+-binding photoprotein aequorin is a complex of apoAequorin (apoprotein) and (S)-2-peroxycoelenterazine. Aequorin can be regenerated by the incubation of apoAequorin with coelenterazine and molecular oxygen (O2). In this study, to investigate the molecular recognition of apoAequorin for coelenterazine using chemical probes, the chiral deaza-analogs of (S)- and (R)-deaza-CTZ (daCTZ) for coelenterazine and of (S)-2- and (R)-2-hydroxymethyl-deaza-CTZ (HM-daCTZ) for 2-peroxycoelenterazine were efficiently prepared by the improvement method.

Fluorescent-Oxaboroles: Synthesis and Optical Property by Sugar Recognition.

The optical property of fluorescent unit-conjugated aliphatic oxaboroles has been investigated. The oxaboroles provide good fluorescence quantum yields and selective recognition toward D-ribose and D-ribose containing molecules. The molecular recognition induced significant fluorescence quenching.

Synthesis of Dibenzofurans by Cu-Catalyzed Deborylative Ring Contraction of Dibenzoxaborins.

An efficient transformation of dibenzoxaborins to dibenzofurans by deborylative ring contraction was achieved under mild conditions using a copper catalyst. The method showed a broad substrate scope enabling the preparation of various dibenzofurans, including those bearing a functional group. The ready availability of various dibenzoxaborins enhances the utility of this method, as demonstrated by the regiodivergent synthesis of dibenzofurans.

Generation of Alkyl Radical through Direct Excitation of Boracene-Based Alkylborate.

The generation of tertiary, secondary, and primary alkyl radicals has been achieved by the direct visible-light excitation of a boracene-based alkylborate. This system is based on the photophysical properties of the organoboron molecule. The protocol is applicable to decyanoalkylation, Giese addition, and nickel-catalyzed carbon-carbon bond formations such as alkyl-aryl cross-coupling or vicinal alkylarylation of alkenes, enabling the introduction of various C(sp) fragments to organic molecules.

A study on an unusual S2 mechanism in the methylation of benzyne through nickel-complexation.

In this study, three reaction mechanisms of a benzyne-nickel (Ni) complex ([Ni(CH)(dcpe)]) with iodomethane during the methylation process were investigated, namely (a) S2 reaction of the benzyne-Ni complex with iodomethane, (b) concerted σ-bond metathesis during the bond breaking/forming processes, and (c) oxidative addition of iodomethane to the Ni-center and the subsequent reductive elimination process. DFT calculations revealed that the reaction barrier of the S2 reaction is slightly lower than those of the other mechanisms. The results of orbital analyses suggest that [Ni(CH)(dcpe)] forms a metallacycle structure between benzyne and the Ni (3d) center instead of the η-structure with the Ni (3d) center.

Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice.

Down syndrome (DS) caused by trisomy of chromosome 21 is the most common genetic cause of intellectual disability. Although the prenatal diagnosis of DS has become feasible, there are no therapies available for the rescue of DS-related neurocognitive impairment. A growth inducer newly identified in our screen of neural stem cells (NSCs) has potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and was found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS.

Preparation of Aryne-Nickel Complexes from ortho-Borylaryl Triflates.

A facile method for preparing diverse aryne-nickel complexes from readily synthesized ortho-borylaryl triflates is described. Exploratory synthetic applications, including the synthesis of 1,2-difunctionalized arenes, based on the nucleophilic character of the aryne-nickel complexes are also demonstrated.

Selective inhibition of the kinase DYRK1A by targeting its folding process.

Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY.

Identification of a DYRK1A Inhibitor that Induces Degradation of the Target Kinase using Co-chaperone CDC37 fused with Luciferase nanoKAZ.

The protein kinase family includes attractive targets for drug development. Methods for screening of kinase inhibitors remain largely limited to in vitro catalytic assays. It has been shown that ATP-competitive inhibitors antagonize interaction between the target kinase and kinase-specific co-chaperone CDC37 in living cells.

Concise Synthesis of v-Coelenterazines.

A novel synthetic method for v-coelenterazine (v-CTZ), which is a vinylene-bridged analog of native CTZ with a large red-shifted luminescence property, is described. The synthesis was achieved in a concise way through the use of three sequential cross-coupling reactions and ring-closing metathesis (RCM). A newly synthesized C2-modified trifluoromethyl analog cf3-v-CTZ showed slightly more red-shifted luminescence than v-CTZ when it was used as a substrate for Renilla luciferases.

Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a suppressor of adipogenesis.

Dysregulation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has been demonstrated in several pathological conditions, including Alzheimer's disease and cancer progression. It has been recently reported that a gain of function-mutation in the human DYRK1B gene exacerbates metabolic syndrome by enhancing obesity. In the previous study, we developed an inhibitor of DYRK family kinases (INDY) and demonstrated that INDY suppresses the pathological phenotypes induced by overexpression of DYRK1A or DYRK1B in cellular and animal models.

An Alternative Method for Generating Arynes from ortho-Silylaryl Triflates: Activation by Cesium Carbonate in the Presence of a Crown Ether.

An alternative method for generating arynes from ortho-silylaryl triflates using cesium carbonate and 18-crown-6 is reported. The method was efficiently applied to a variety of reactions between several arynes and arynophiles. We also demonstrated that the efficiency of aryne generation is significantly affected by the alkali metal countercation of the carbonate.

Boron-selective biaryl coupling approach to versatile dibenzoxaborins and application to concise synthesis of defucogilvocarcin M.

An efficient synthetic method for versatile dibenzoxaborins based on boron-selective Suzuki-Miyaura cross-coupling between o-borylphenols and aryl halides or triflates bearing a 1,8-diaminonaphthalene-protected o-boryl group is reported. A short synthesis of defucogilvocarcin M was achieved using the proposed method in combination with several other boron-mediated transformations.

Generation of arynes via ate complexes of arylboronic esters with an ortho-leaving group.

An efficient method of generating aryne has been achieved by treating ortho-(trifluoromethanesulfonyloxy)arylboronic acid pinacol ester with tert- or sec-butyllithium. Monitoring the reaction by (11)B NMR has indicated that a boron-ate complex formed in situ is the eventual precursor that converts into aryne near room temperature. The prior formation of the ate complex at a low temperature has enabled us to use various arynophiles, including those bearing base-sensitive groups.

Palladium-catalyzed regio- and stereoselective hydrosilylation of electron-deficient alkynes.

Highly regio- and stereoselective hydrosilylation applicable to a broad range of electron-deficient alkynes has been established using palladium catalysis. The synthetic utility of the method has been demonstrated by further transformations of α-silylalkenes, particularly Hiyama coupling and stereoinverting iododesilylation followed by Suzuki-Miyaura coupling, which enables stereodivergent syntheses of α-arylenoates.

Primer preactivation of peptidoglycan polymerases.

Peptidoglycan glycosyltransferases are highly conserved bacterial enzymes that catalyze glycan strand polymerization to build the cell wall. Because the cell wall is essential for bacterial cell survival, these glycosyltransferases are potential antibiotic targets, but a detailed understanding of their mechanisms is lacking. Here we show that a synthetic peptidoglycan fragment that mimics the elongating polymer chain activates peptidoglycan glycosyltransferases by bypassing the rate-limiting initiation step.

Nickel-catalyzed arylative ring-opening of 3-methylenecycloalkane-1,1-dicarboxylates.

An arylative ring-opening reaction of cyclic allylmalonates with arylzinc reagents under nickel catalysis has been developed. Upon the ring-opening sp(3)C-sp(3)C bond cleavage, the allylic moiety serves as an allylic electrophile to react with arylzinc reagents. Simultaneously, the malonate moiety is converted to the corresponding zinc enolate, which can react further with electrophiles.