Papers - Nishiyama, Shigeru

Oxidative Cleavage of the Acyl-Carbon Bond in Phenylacetone with Electrogenerated Superoxide Anions

Zhang Y., Sugai T., Yamamoto T., Yamamoto N., Kutsumura N., Einaga Y., Nishiyama S., Saitoh T., Nagase H.

ChemElectroChem (ChemElectroChem)  6 ( 16 ) 4194 - 4198 2019

　View Summary

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim An oxidative cleavage reaction of the acyl−carbon bond in phenylacetone derivatives under cathodic reduction is reported. This particular transformation is driven by the cathodic reduction of dissolved molecular oxygen to superoxide anions. Various cathode materials were examined, and we discovered that boron-doped diamond (BDD) enables highly efficient molecular conversion, owing to BDD's outstanding electrochemical property for utilizing the small amounts of molecular oxygen effectively. The scope of the reaction is broad and can be applied to a variety of substrates, ranging from ketones to esters and amides. As an electric current is directly employed to generate the superoxide anion, the reaction is metal- and catalyst-free. Electro-organic synthesis using the carbon-based BDD electrode thus provides access to sustainable molecular transformations.

• Access to Document (DOI)

Near-Infrared Bioluminescence Imaging with a through-Bond Energy Transfer Cassette

Abe M., Nishihara R., Ikeda Y., Nakajima T., Sato M., Iwasawa N., Nishiyama S., Paulmurugan R., Citterio D., Kim S., Suzuki K.

ChemBioChem (ChemBioChem)  20 ( 15 ) 1919 - 1923 2019

ISSN  14394227

　View Summary

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim A coelenterazine (CTZ) analogue emitting near-infrared (NIR) bioluminescence was synthesized for through-bond energy transfer (TBET)-based imaging modalities. The analogue, named Cy5-CTZ, was prepared by conjugating cyanine-5 (Cy5) dye to CTZ through an acetylene linker. This novel derivative is intrinsically fluorescent and emits NIR-shifted luminescence upon reacting with an appropriate luciferase, the Renilla luciferase. This Cy5-CTZ substrate is optically stable in physiological samples and rapidly permeabilize through the plasma membrane into the cytosolic compartment of live cells.

• Access to Document (DOI)

Highly bright and stable NIR-BRET with blue-shifted coelenterazine derivatives for deep-tissue imaging of molecular events in vivo

Nishihara R., Paulmurugan R., Nakajima T., Yamamoto E., Natarajan A., Afjei R., Hiruta Y., Iwasawa N., Nishiyama S., Citterio D., Sato M., Kim S., Suzuki K.

Theranostics (Theranostics)  9 ( 9 ) 2646 - 2661 2019

　View Summary

© Ivyspring International Publisher. Background: Bioluminescence imaging (BLI) is one of the most widely used optical platforms in molecular imaging, but it suffers from severe tissue attenuation and autoluminescence in vivo. Methods: Here, we developed a novel BLI platform on the basis of bioluminescence resonance energy transfer (BRET) for achieving a ∼300 nm blue-to-near infrared shift of the emission (NIR-BRET) by synthesizing an array of 18 novel coelenterazine (CTZ) derivatives, named “Bottle Blue (BBlue)” and a unique iRFP-linked RLuc8.6-535SG fusion protein as a probe. Results: The best NIR-BRET was achieved by tuning the emission peaks of the CTZ derivatives to a Soret band of the iRFP. In mammalian cells, BBlue2.3, one of the CTZ derivatives, emits light that is ∼50-fold brighter than DBlueC when combined with RLuc8.6-535SG, which shows stable BL kinetics. When we used a caged version of BBLue2.3, it showed a BL half decay time of over 60 minutes while maintaining the higher signal sensitivity. This NIR BL is sufficiently brighter to be used for imaging live mammalian cells at single cell level, and also for imaging metastases in deep tissues in live mice without generating considerable autoluminescence. A single-chain probe developed based on this BLI platform allowed us to sensitively image ligand antagonist-specific activation of estrogen receptor in the NIR region. Conclusion: This unique optical platform provides the brightest NIR BLI template that can be used for imaging a diverse group of cellular events in living subjects including protein‒protein interactions and cancer metastasis.

• Access to Document (DOI)

Electrochemical Pinacol Coupling of Acetophenone Using Boron-Doped Diamond Electrode

Nakahara K., Naba K., Saitoh T., Sugai T., Obata R., Nishiyama S., Einaga Y., Yamamoto T.

ChemElectroChem (ChemElectroChem)  6 ( 16 ) 4153 - 4157 2019

　View Summary

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim An electrochemical pinacol coupling reaction of acetophenone using a boron-doped diamond (BDD) electrode has been reported. This transformation is driven by the one-electron reduction of acetophenone on the BDD cathode, followed by an intermolecular radical coupling. Owing to the BDD's outstanding electrochemical properties, the pinacol-type compound has been obtained in good conversion yield. The roles of a supporting electrolyte and solvent were addressed; (1) lithium ions contribute to increase in the reactivity of the radical intermediate. (2) Addition of water promotes the electron transfer process at the BDD surface. The reaction is relatively tolerant to para-substituted acetophenone derivatives. Since electric current is directly employed as reducing reagents to generate a radical intermediate, the reaction is metal-free, sustainable, and inherently safe.

• Access to Document (DOI)

Azide- and Dye-Conjugated Coelenterazine Analogues for a Multiplex Molecular Imaging Platform

Nishihara R., Hoshino E., Kakudate Y., Kishigami S., Iwasawa N., Sasaki S., Nakajima T., Sato M., Nishiyama S., Citterio D., Suzuki K., Kim S.

Bioconjugate Chemistry (Bioconjugate Chemistry)  29 ( 6 ) 1922 - 1931 2018.06

ISSN  10431802

　View Summary

© 2018 American Chemical Society. Native coelenterazine (nCTZ) is a common substrate to most marine luciferases and photoproteins. In this study, nine novel dye- and azide-conjugated CTZ analogues were synthesized by conjugating a series of fluorescent dyes or an azide group to the C-2 or C-6 position of the nCTZ backbone to obtain bulkiness-driven substrate specificity and potential chemiluminescence/bioluminescence resonance energy transfer (C/BRET). The investigation on the optical properties revealed that azide-conjugated CTZs emit greatly biased bioluminescence to ALucs and ca. 130 nm blue-shifted bioluminescence with RLuc8.6 in living animal cells or lysates. The corresponding kinetic study explains that azide-conjugated CTZ exerts higher catalytic efficiency than nCTZ. Nile red-conjugated CTZ completely showed red-shifted CRET spectra and characteristic BRET spectra with artificial luciferase 16 (ALuc16). No or less spectral overlap occurs among [Furimazine-NanoLuc], [6-N 3 -CTZ-ALuc26], [6-pi-OH-CTZ-RLuc8.6], and [6-N 3 -CTZ-RLuc8.6] pairs, because of the substrate-driven luciferase specificity and color shifts, providing a crosstalk-free multiplex bioassay platform. The unique bioluminescence system appends a new toolbox to bioassays and multiplex molecular imaging platforms. This study is the first example that systematically synthesized fluorescent dye-conjugated CTZs and applied them for a bioluminescence assay system.

• Access to Document (DOI)

Thienyl-Substituted α-Ketoamide: A Less Hydrophobic Reactive Group for Photo-Affinity Labeling

Ota E., Usui K., Oonuma K., Koshino H., Nishiyama S., Hirai G., Sodeoka M.

ACS Chemical Biology (ACS Chemical Biology)  13 ( 4 ) 876 - 880 2018.04

ISSN  15548929

　View Summary

© 2018 American Chemical Society. Photoaffinity labeling (PAL) is an important tool in chemical biology research, but application of α-ketoamides for PAL has been hampered by their photoinstability. Here, we show that 2-thienyl-substituted α-ketoamide is a superior photoreactive group for PAL. Studies with a series of synthetic mannose-conjugated α-ketoamides revealed that 2-thienyl substitution of α-ketoamide decreased the electrophilicity of the keto group and reduced the rate of photodegradation. Mannose-conjugated thienyl α-ketoamide showed greater concanavalin A labeling efficiency than other alkyl or phenyl-substituted α-ketoamides. In comparison with representative conventional photoreactive groups, 2-thienyl ketoamide showed reduced labeling of nontarget proteins, probably owing to its lower hydrophobicity.

• Access to Document (DOI)

Toward bioluminescence in the near-infrared region: Tuning the emission wavelength of firefly luciferin analogues by allyl substitution

Kitada N., Saitoh T., Ikeda Y., Iwano S., Obata R., Niwa H., Hirano T., Miyawaki A., Suzuki K., Nishiyama S., Maki S.

Tetrahedron Letters (Tetrahedron Letters)  59 ( 12 ) 1087 - 1090 2018.03

ISSN  00404039

　View Summary

© 2018 The synthesis and bioluminescence of allyl-substituted luciferin derivatives as substrates for firefly luciferase are reported. The allylation of luciferins induced bathochromic shift (15–40 nm) of the bioluminescence emission. Upon combination with other chemical modifications for bioluminescence wavelength tuning, novel red emitting luciferin analogues were obtained with emission maxima at 685 and 690 nm.

• Access to Document (DOI)

Highly Sensitive Bioluminescent Probe for Thiol Detection in Living Cells

Hemmi M., Ikeda Y., Shindo Y., Nakajima T., Nishiyama S., Oka K., Sato M., Hiruta Y., Citterio D., Suzuki K.

Chemistry - An Asian Journal (Chemistry - An Asian Journal)  13 ( 6 ) 648 - 655 2018.03

ISSN  18614728

　View Summary

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim The sensitive detection of thiols including glutathione and cysteine is desirable owing to their roles as indispensable biomolecules in maintaining intracellular biological redox homeostasis. Herein, we report the design and synthesis of SEluc-1 (sulfinate ester luciferin), a chemoselective probe exhibiting a ratiometric and turn-on response towards thiols selectively in fluorescence and bioluminescence, respectively. The probe, which was designed based on the “caged” luciferin strategy, displays excellent selectivity, high signal/noise ratio (>240 in the case of bioluminescence), and a biologically relevant limit of detection (LOD, 80 nm for cysteine), which are all desirable traits for a sensitive bioluminescent sensor. SEluc-1 was further applied to fluorescence imaging of thiol activity in living human cervical cancer HeLa cell cultures, and was successfully able to detect fluctuations in thiol concentrations induced by oxidative stress in a bioluminescent assay utilizing African green monkey fibroblast COS-7 cells and human breast adenocarcinoma MCF-7 cells.

• Access to Document (DOI)

An allylated firefly luciferin analogue with luciferase specific response in living cells

Ikeda Y., Saitoh T., Niwa K., Nakajima T., Kitada N., Maki S., Sato M., Citterio D., Nishiyama S., Suzuki K.

Chemical Communications (Chemical Communications)  54 ( 14 ) 1774 - 1777 2018

ISSN  13597345

　View Summary

© The Royal Society of Chemistry 2018. An allylated firefly luciferin was successfully synthesized and its bioluminescence properties were evaluated. When applied to cellular imaging in combination with Eluc, which is one of the commercially available luciferases, this analogue displayed a luciferase-specific bioluminescence signal with prolonged emission (>100 min).

• Access to Document (DOI)

Application of electrochemically generated hypervalent iodine oxidant to natural products synthesis.

NISHIYAMA SHIGERU

Electrochemistry 81 ( 5 ) 319-324 2013.05

Research paper (scientific journal), Joint Work

ダイヤモンド電極を用いた環境低負荷型有機電解反応

NISHIYAMA SHIGERU

ニューダイヤモンド 107 ( 10 ) 20-23 2012

Research paper (scientific journal), Joint Work

Synthesis and biological evaluation of molecular probes based on the 9-methylstreptimidone derivative DTCM-glutarimide.

NISHIYAMA SHIGERU

Bioorg. Med. Chem. Lett. 22 ( 1 ) 164-167 2012

Research paper (scientific journal), Joint Work, Accepted

Anodic oxidation on a boron-doped diamond electrode mediated by methoxy radicals. Angew. Chem. Int. Ed. Engl.

NISHIYAMA SHIGERU

Angew. Chem. Int. Ed. Engl. 51 ( 22 ) 5443-5446 2012

Research paper (scientific journal), Joint Work, Accepted

Oxidative cyclization reactions of tryptamine utilizing hyper-valent iodobenzene in routes for pyrroloindole alkaloid synthesis.

NISHIYAMA SHIGERU

Synthesis  2012

Research paper (scientific journal), Joint Work

Total syntheses of amphidinolides B, G, and H.

NISHIYAMA SHIGERU

Angew. Chem. Int. Ed. Engl. 51 ( 39 ) 9877-9880 2012

Research paper (scientific journal), Joint Work, Accepted

Catalytic electrochemical C-H iodination and one-pot arylation by on/off switching of electric current.

NISHIYAMA SHIGERU

J. Org. Chem. 77 ( 17 ) 7718-7724 2012

Research paper (scientific journal), Joint Work, Accepted

Design and synthesis of biotinylated DHMEQ for direct identification of its target NF-κB components.

NISHIYAMA SHIGERU

Bioorg. Med. Chem. Lett. 21 ( 21 ) 6293-6296 2011

Research paper (scientific journal), Joint Work, Accepted

Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone.

NISHIYAMA SHIGERU

Inflammation Research 60 ( 9 ) 879 – 888 2011

Research paper (scientific journal), Joint Work, Accepted

Synthesis of key fragments of amphidinolide Q — A cytotoxic 12-membered macrolide. K. Kawa, A. Hara, Y. Ishikawa, and S. Nishiyama

NISHIYAMA SHIGERU

Molecules 16 ( 7 ) 5422-5436 2011

Research paper (scientific journal), Joint Work, Accepted

Synthesis of the C7-26 fragment of amphidinolides G and H.

NISHIYAMA SHIGERU

Org. Lett. 13 ( 15 ) 4036-4039 2011

Research paper (scientific journal), Joint Work