Papers - Ogura, Akihiro

Synthetic Studies of Polycyclic Polyprenylated Acylphloroglucinols: Asymmetric Construction of a Cyclohexanone Moiety

Nanataki, S; Aoki, D; Onozawa, H; Akiya, T; Okuyama, G; Abo, K; Yoshida, K; Ogura, A; Takao, KI

Synlett 36 ( 10 ) 1375 - 1378 2025.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0936-5214

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As a common intermediate for polycyclic polyprenylated acylphloroglucinols (PPAPs), we successfully synthesized a cyclohexanone moiety that contains two adjacent stereocenters, one of which is a quaternary carbon. Our synthetic strategy relied on an asymmetric Claisen rearrangement using Oppolzer's camphorsultam and a regioselective Dieckmann condensation.

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Synthesis of Tetrahydro‐β‐carbolines via Cascade Sigmatropic Rearrangements

Oka, D; Ohtsuka, T; Takao, KI; Ogura, A

Advanced Synthesis & Catalysis 367 ( 3 )  2024.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1615-4150

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We have developed a synthesis for tetrahydro-β-carbolines involving cascade sigmatropic rearrangements. The substrates were conveniently prepared from parent anilines via a [2,3]-sigmatropic rearrangement and cyanomethylation. Silver-mediated decyanation afforded the corresponding iminium cation, which underwent a cascade consisting of an aza-Cope rearrangement, an aza-oxa-Cope rearrangement, an aromatization, and a Pictet-Spengler reaction, and tetrahydro-β-carbolines were obtained as the single product. The reaction involved seven bond scissions and four bond formations and was triggered by a single reagent.

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Antiproliferative activities through accelerating autophagic flux by basidalin and its analogs in human cancer cells.

Matagawa T, Sasazawa Y, Agui K, Fujimaki M, Kawano S, Ogura A, Takao KI, Igarashi M, Simizu S

Bioorganic & medicinal chemistry letters (Bioorganic and Medicinal Chemistry Letters)  104   129713 - 129713 2024.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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Basidalin, isolated from the basidiomycete Leucoagaricus naucina, has previously demonstrated antibacterial and antitumor properties against murine cancer cells in vivo, but its effects on human cancer cells remain unknown. In this study, we found that basidalin possesses antiproliferative activity against human cancer cell lines. To elucidate the antiproliferative mechanism of basidalin, we focused on autophagy. Treatment with basidalin led to an increase in LC3-II expression level, and accelerated autophagic flux through an mTOR-independent pathway. Moreover, according to the structure-activity relationship analysis-including newly synthesized basidalin analogs-the formyl group, not the amino group, contributes to the antiproliferative activities of basidalin against human cancer cells. Additionally, the antiproliferative activity of basidalin analogs was strongly correlated with autophagy-inducing activity, indicating that basidalin exhibits antiproliferative activity through autophagy induction. These data suggest that basidalin, characterized by its ability to upregulate autophagic flux, emerges as a novel anticancer drug.

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Synthesis of Indoles via Sigmatropic Rearrangements and Olefin Isomerization

Tomoki Uchida, Ryosuke Saito, Ken‐ichi Takao, Akihiro Ogura

Advanced Synthesis & Catalysis (Advanced Synthesis and Catalysis)  366 ( 3 ) 465 - 472 2024.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1615-4150

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Indoles are important heterocycles in pharmaceuticals and agrochemicals, and their atom-economical synthesis is needed. Herein, we describe the synthesis of indoles using sigmatropic rearrangements. The N-allylaniline was oxidized by environmentally benign hydrogen peroxide, and spontaneous [2,3]-Meisenheimer rearrangement gave N-allyloxyaniline. Subsequent treatment with a ruthenium catalyst afforded N-vinyloxyaniline, which underwent [3,3]-sigmatropic rearrangement to give indoles, expelling water as the only byproduct. The whole sequence is free of quantitative salt byproducts, thereby avoiding aqueous work up and cutting off the inorganic waste.

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Open system massive synthesis of narrow-band blue and green fluorescent graphene quantum dots and their application in water sensing

Ochi, Y; Otani, A; Katakami, R; Ogura, A; Takao, K; Iso, Y; Isobe, T

Journal of Materials Chemistry C (Journal of Materials Chemistry C)  12 ( 18 ) 6548 - 6558 2024

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2050-7526

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Graphene quantum dots (GQDs) are environmentally friendly fluorescent carbon-based nanomaterials. However, there is no report on the massive synthesis of GQDs with narrow-band fluorescence and a high photoluminescence quantum yield (PLQY) using a simple liquid-phase method under atmospheric conditions. In this study, GQDs were successfully synthesized in ∼100% product yield by heating phloroglucinol (PG) with Na3PO4·12H2O in 1,2-pentanediol at 180 °C for 6 h in an open system with air flow, followed by dialysis purification. The high product yield was attributed to the addition of Na3PO4·12H2O as a base catalyst, which promoted the dehydration-condensation reaction between PG molecules. The dispersion of PG derived GQDs (PG-GQDs) in ethanol resulted in blue fluorescence with a full width at half maximum of 32 nm and a PLQY of 54%. Further purification of PG-GQDs by silica gel column chromatography improved the PLQY to 75%. Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, and X-ray photoelectron spectroscopy confirmed that dehydration-condensation reactions occurred not only between PGs but also between GQDs and 1,2-pentanediol. The binding of 1,2-pentanediol to the edges of GQDs suppressed the stacking of GQDs and prevented concentration quenching, resulting in a high PLQY. PG-GQDs exhibited negative fluorescence solvatochromism, i.e., the fluorescence wavelength blue-shifted with increasing solvent polarity. Dispersion of PG-GQDs in N-methyl-2-pyrrolidone (MP) resulted in green fluorescence with a PLQY of 96%. Dispersion of PG-GQDs in water resulted in blue fluorescence and a low PLQY of 6% at pH 7, while the PLQY was more than 50% at pH ≥ 11. Using these properties, the sensing of water (pH 13) in MP was investigated. The results showed that as the water content was increased from 0% to 100%, the fluorescence color gradually changed from green to blue and the fluorescence wavelength continuously shifted from 514 nm to 466 nm, indicating their applicability in water sensing.

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Open system synthesis of narrow-bandwidth red-fluorescent carbon quantum dots with a function of multi-metal ion sensing

Rika Katakami, Kohei Sato, Akihiro Ogura, Ken-ichi Takao, Yoshiki Iso, Tetsuhiko Isobe

Journal of Materials Chemistry C (Journal of Materials Chemistry C)  11 ( 12 ) 4143 - 4152 2023

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2050-7526

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Carbon quantum dots (CQDs) are environmentally friendly phosphors. However, there have been few reports on red-emitting CQDs with narrow-bandwidths, all of which were synthesized via solvothermal methods using autoclaves. Here, red-emitting CQDs were synthesized from 4,6-diaminoresorcinol dihydrochloride (DAR), which is an aromatic compound with electron-donating hydroxy and amino groups. The synthesis involved heating at 180 °C for 6 h in a high-boiling-point 1,2-pentanediol solvent in an open system without using autoclaves and catalysts. The DAR-derived-CQDs in ethanol exhibited red photoluminescence with a 0.14 eV full width at half-maximum that was comparable to that of narrow-bandwidth blue-fluorescent phloroglucinol (PG)-derived-CQDs. The red emission was attributed to a weakened quantum-size effect and electron-donating NH2 groups. The hydroxy groups of PG-derived-CQDs interacted with Al3+ and Fe3+ ions, resulting in fluorescence quenching. DAR-derived-CQDs have hydroxy and amino groups, which facilitate the fluorescence quenching for Al3+, Fe3+, Cu2+, and Pb2+ ions.

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Red-light-mediated Barton decarboxylation reaction and one-pot wavelength-selective transformations

Hiroki Yamamoto, Kohei Yamaoka, Ann Shinohara, Kouhei Shibata, Ken-ichi Takao, Akihiro Ogura

Chemical Science (Chemical Science)  14 ( 40 ) 11243 - 11250 2023

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2041-6520

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In organic chemistry, selecting mild conditions for transformations and saving energy are increasingly important for achieving sustainable development goals. Herein, we describe a red-light-mediated Barton decarboxylation using readily available red-light-emitting diodes as the energy source and zinc tetraphenylporphyrin as the catalyst, avoiding explosive or hazardous reagents or external heating. Mechanistic studies suggest that the reaction probably proceeds via Dexter energy transfer between the activated catalyst and the Barton ester. Furthermore, a one-pot wavelength-selective reaction within the visible light range is developed in combination with a blue-light-mediated photoredox reaction, demonstrating the compatibility of two photochemical transformations based on mechanistic differences. This one-pot process expands the limits of the decarboxylative Giese reaction beyond polarity matching.

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In vivo imaging of fluorescent albumin modified with pyruvylated-human-type complex oligosaccharide reveals sialylation-like biodistribution and kinetics

Ryoichiro Fukuhara, Akihiro Ogura, Sho Yoshinaga, Takamasa Fukunaga, Takashi Kinoshita, Wataru Sumiyoshi, Yujiro Higuchi, Katsunori Tanaka, Kaoru Takegawa

Bioorganic & Medicinal Chemistry (Elsevier BV)  70   116943 - 116943 2022.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0968-0896

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Both pyruvylation and sialylation onto the terminus of oligosaccharides of N-glycoproteins seem to be structurally and functionally similar with a property of conferring negative charge. However, detailed molecular characteristics of pyruvylation and sialylation in vivo were elusive. Here, to investigate an effect of terminal pyruvylation to N-glycan on in vivo biodistribution and kinetics, we prepared human serum albumin (HSA) modified with pyruvylated N-glycan (PvG), conjugated with HiLyte Fluor 750 (FL750-PvGHSA). In vivo imaging by using FL750-PvGHSA revealed that terminally pyruvylated N-glycoalbumin was excreted like sialylated N-glycoalbumin, suggesting that pyruvylation mimics sialylation in in vivo biodistribution and kinetics of N-glycoproteins. Terminal pyruvylation onto N-glycans can be a potential tool for a novel glycoengineering strategy.

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Asymmetric Synthesis of Cyclopentene Compounds Containing All-Carbon Quaternary Stereocenters by (3 + 2) Cycloaddition and Its Application in the Formal Synthesis of (R)-(−)-Puraquinonic Acid

Miho Oga, Yusei Takamatsu, Akihiro Ogura, Ken-ichi Takao

The Journal of Organic Chemistry (American Chemical Society ({ACS}))  87 ( 13 ) 8788 - 8795 2022.07

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0022-3263

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A highly stereoselective (3 + 2) cycloaddition for the asymmetric synthesis of versatile cyclopentene compounds containing all-carbon quaternary stereocenters was developed. The phosphine-catalyzed reactions of alkynoates with α-alkylated electron-deficient alkenes bearing Oppolzer's camphorsultam showed high to excellent diastereoselectivities and perfect regioselectivities. The usefulness of this reaction was demonstrated in the concise formal synthesis of (R)-(-)-puraquinonic acid.

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Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor.

Junya Saegusa, Yoshiyuki Osada, Kazuki Miura, Yukiko Sasazawa, Akihiro Ogura, Ken-Ichi Takao, Siro Simizu

Bioorganic & medicinal chemistry letters (Bioorganic and Medicinal Chemistry Letters)  60   128589 - 128589 2022.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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Humulanolides are natural products isolated from Asteriscus, and the isolation and total synthesis of many types of humulanolides have been reported. In this study, we evaluated anti-proliferative activity of twelve humulanolides against various human cancer cell lines and found that humulanolide analog E, which was newly designed and synthesized, exhibited the highest anti-proliferative activity. Structure-activity relationship analysis revealed that α,β-unsaturated carbonyl moieties in humulanolides play an important role for anti-proliferative activity. To identify molecular targets of humulanolide analog E, we investigated various cell-based and in vitro assays. Treatment with humulanolide analog E against human fibrosarcoma HT1080 cells increased the expression level of HSP70 protein and decreased the levels of AKT and CDK4, which are HSP90 client proteins. Moreover, humulanolide analog E inhibited refolding of denatured luciferase protein via suppression of HSP90 activity in vitro. These results suggest that humulanolide analog E possesses the anti-proliferative activity against human cancer cells by inhibiting HSP90 functions.

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Diaryliodonium Salt-Based Synthesis of N-Alkoxyindolines and Further Insights into the Ishikawa Indole Synthesis

Kouhei Shibata, Ken-ichi Takao, Akihiro Ogura

The Journal of Organic Chemistry (American Chemical Society ({ACS}))  86 ( 15 ) 10067 - 10087 2021.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0022-3263

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A diaryliodonium salt-based strategy enabled the first systematic synthesis of rarely accessible N-alkoxyindolines. Mechanistic analyses suggested that the reaction likely involves reductive elimination of iodobenzene from iodaoxazepine via a four-membered transition state, followed by Meisenheimer rearrangement. Substrates with N-carbamate protection afforded indole in a manner similar to that of the Ishikawa indole synthesis. Preinstallation of a stannyl group as an iodonium salt precursor greatly expanded the substrate scope, and further mechanistic insights are discussed.

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Asymmetric Diels–Alder reaction between furans and propiolates

Ogura A., Ito T., Moriya K., Horigome H., Takao K.

Tetrahedron Letters (Elsevier {BV})  72   153075 - 153075 2021.05

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  00404039

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We report the first asymmetric Diels–Alder reaction between furan and propiolates. Propiolate, a dienophile, was equipped with an Evans’ auxiliary and a sulfonyl group to control and facilitate diastereoselective cycloaddition. Treatment with furan as a diene and aluminium Lewis acid afforded a 7-oxabicyclo[2.2.1]heptadiene skeleton diastereoselectively. The origin of diastereoselectivity can be explained by chelation of aluminium center to carbonyl groups and oxygen of furan. Friedel–Crafts-type products were obtained when pyrrole was used as diene.

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Glycothermally Synthesized Carbon Dots with Narrow-Bandwidth and Color-Tunable Solvatochromic Fluorescence for Wide-Color-Gamut Displays

Taishu Yoshinaga, Momoka Shinoda, Yoshiki Iso, Tetsuhiko Isobe, Akihiro Ogura, Ken-ichi Takao

ACS Omega (American Chemical Society ({ACS}))  6 ( 2 ) 1741 - 1750 2021.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2470-1343

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Fluorescent carbon dots (CDs) represent a promising eco-friendly next-generation phosphor. However, most CDs exhibit broad photoluminescence (PL) spectra [full width at half-maximum (fwhm) over 60 nm]; few works on CDs with sharp PL spectra (fwhm less than 40 nm) have been reported. In addition, their syntheses and color tuning require harsh conditions of high temperatures, long reaction times, and high pressures with catalysts. Here, we successfully prepared narrow-bandwidth emissive CDs (fwhm of 27-40 nm) from phloroglucinol in a glycol solvent of 1,2-pentanediol at temperatures as low as 180 °C for a reaction duration of as short as 6 h under ambient conditions without any catalysts via an open reaction system in which dehydration and condensation reactions among phloroglucinol molecules were enhanced. We shifted the emission peak from 463 to 511 nm by selecting seven kinds of solvents with different polarities, that is, emission colors could be tuned from blue to green by taking advantage of fluorescence solvatochromism. The CD-dispersed polymer films showed a similar solvatochromic behavior and sharp PL spectra, verifying the feasibility of applying the CDs to displays with a wide color gamut.

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Red-Light-Mediated Barton–McCombie Reaction

Akihiro Ogura, Naoki Ichii, Kouhei Shibata, Ken-ichi Takao

Bulletin of the Chemical Society of Japan (The Chemical Society of Japan)  93 ( 7 ) 936 - 941 2020.07

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  00092673

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Stereoselective Synthesis of the Tricyclic Core of (-)-Callophycoic Acid A

Akihiro Sakama, Rika Kameshima, Yuko Motohashi, Wataru Sumida, Yuta Unno, Keisuke Yoshida, Akihiro Ogura, Ken Ichi Takao

Journal of Organic Chemistry (American Chemical Society ({ACS}))  85 ( 5 ) 3245 - 3264 2020.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00223263

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Identification of vibsanin A analog as a novel HSP90 inhibitor

Kazuki Miura, Wataru Matsuki, Akihiro Ogura, Ken-ichi Takao, Siro Simizu

Bioorganic & Medicinal Chemistry (Elsevier {BV})  28 ( 2 ) 115253 - 115253 2020.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09680896

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Identification of topoisomerases as molecular targets of cytosporolide C and its analog

Keisuke Otake, Kana Yamada, Kazuki Miura, Yukiko Sasazawa, So Miyazaki, Yuki Niwa, Akihiro Ogura, Ken-ichi Takao, Siro Simizu

Bioorganic & Medicinal Chemistry (Elsevier {BV})  27 ( 15 ) 3334 - 3338 2019.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09680896

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Total Syntheses of (+)‐Aquatolide and Related Humulanolides

Ken-ichi Takao, Hirotaka Kai, Ai Yamada, Yuuki Fukushima, Daisuke Komatsu, Akihiro Ogura, Keisuke Yoshida

Angewandte Chemie (Wiley)  131 ( 29 ) 9956 - 9960 2019.07

ISSN  1521-3757

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Total Syntheses of (+)-Aquatolide and Related Humulanolides

Ken-ichi Takao, Hirotaka Kai, Ai Yamada, Yuuki Fukushima, Daisuke Komatsu, Akihiro Ogura, Keisuke Yoshida

Angewandte Chemie International Edition (Wiley)  58 ( 29 ) 9851 - 9855 2019.06

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1433-7851

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Herein, the total syntheses of (+)-aquatolide, a humulane-derived sesquiterpenoid lactone, and five other related humulanolides are described. The key reactions in these syntheses are a cascade metathesis reaction of cyclobutenecar-boxylate to construct a γ-butenolide with an unsaturated aldehyde side chain, an intramolecular Nozaki-Hiyama-Takai-Kishi reaction to form an all-trans-humulene lactone skeleton, and a biosynthesis-inspired [2 + 2] photocycloaddition to provide a bridged 5/5/4/8-ring system. A cycloaddition giving a 5/4/4/7-ring system was also found. In addition, biological studies were conducted using the synthesized samples.

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Studies toward the Synthesis of Perforatumone: Synthesis of the 7-Oxabicyclo[4.2.1]nonane-8,9-dione Core

Ken-ichi Takao, Tatsuki Nakajima, Keita Takiguchi, Keisuke Yoshida, Akihiro Ogura

HETEROCYCLES (Japan Institute of Heterocyclic Chemistry)  99 ( 1 ) 661 - 668 2019

Research paper (scientific journal), Joint Work, Last author, Accepted,  ISSN  03855414

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Enantioselective Total Synthesis of (-)-Misramine

Keisuke Yoshida, Yuta Fujino, Yusei Takamatsu, Kohei Matsui, Akihiro Ogura, Yuri Fukami, Shinji Kitagaki, Ken Ichi Takao

Organic Letters (American Chemical Society ({ACS}))  20 ( 16 ) 5044 - 5047 2018.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15237060

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© 2018 American Chemical Society. The enantioselective total synthesis of an unusual pentacyclic proaporphine alkaloid, (-)-misramine, was achieved. The synthetic strategy relied on an enantioselective intramolecular Friedel-Crafts-type 1,4-addition using an asymmetric organocatalyst to construct a spiroindane skeleton containing an all-carbon quaternary stereocenter and a double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. This work is the first example of asymmetric synthesis of a proaporphine alkaloid.

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Total Synthesis of Clavilactones

Ken-ichi Takao, Kento Mori, Kenya Kasuga, Ryuki Nanamiya, Ayumi Namba, Yuuki Fukushima, Ryuichi Nemoto, Takuma Mogi, Hiroyuki Yasui, Akihiro Ogura, Keisuke Yoshida, Kin-ichi Tadano

JOURNAL OF ORGANIC CHEMISTRY (American Chemical Society ({ACS}))  83 ( 13 ) 7060 - 7075 2018.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00223263

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A viable strategy for screening the effects of glycan heterogeneity on target organ adhesion and biodistribution in live mice

Akihiro Ogura, Sayaka Urano, Tsuyoshi Tahara, Satoshi Nozaki, Regina Sibgatullina, Kenward Vong, Takehiro Suzuki, Naoshi Dohmae, Almira Kurbangalieva, Yasuyoshi Watanabe, Katsunori Tanaka

Chemical Communications (Royal Society of Chemistry ({RSC}))  54 ( 63 ) 8693 - 8696 2018

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  13597345

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Synthesis and evaluation of biological activities of vibsanin A analogs

Wataru Matsuki, So Miyazaki, Keisuke Yoshida, Akihiro Ogura, Yukiko Sasazawa, Ien-ichi Takao, Siro Simizu

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (PERGAMON-ELSEVIER SCIENCE LTD)  27 ( 19 ) 4536 - 4539 2017.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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Vibsanin A is an 11-membered vibsane diterpenoid and is reported to induce myeloid cell differentiation via activation of protein kinase C (PKC) without tumor-promoting activity. Therefore, vibsanin A is thought to be an attractive compound for acute myeloid leukemia (AML) therapy. In this study, we synthesized vibsanin A analogs and compared the activity of these compounds for PKC activation and myeloid cell differentiation. We found that the hydroxymethyl group in vibsanin A is an important substituent to induce differentiation of AML cells. Collectively, our results showed the biochemical features of vibsanin A and provided new insights into the development of new antileukemic drugs. (C) 2017 Elsevier Ltd. All rights reserved.

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Total Synthesis and Structural Revision of ClavilactoneD

Takao, Ken-ichi, Nemoto, Ryuichi, Mori, Kento, Namba, Ayumi, Yoshida, Keisuke, Ogura, Akihiro

CHEMISTRY-A EUROPEAN JOURNAL (WILEY-V C H VERLAG GMBH)  23 ( 16 ) 3828 - 3831 2017.03

Research paper (scientific journal), Joint Work, Last author, Accepted,  ISSN  0947-6539

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A structural revision of clavilactoneD, a potent inhibitor of protein tyrosine kinases, was achieved by total syntheses of two newly proposed structures. The syntheses relied on ring-opening/ring-closing metathesis, which transformed a cyclobutenecarboxylate into a -butenolide. The syntheses confirmed that the correct structure of clavilactoneD has an amino group at C-3 instead of a hydroxy group at C-2 in the originally proposed structure.

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In Vivo Gold Complex Catalysis within Live Mice

Kazuki Tsubokura, Kenward K. H. Vong, Ambara R. Pradipta, Akihiro Ogura, Sayaka Urano, Tsuyoshi Tahara, Satoshi Nozaki, Hirotaka Onoe, Yoichi Nakao, Regina Sibgatullina, Almira Kurbangalieva, Yasuyoshi Watanabe, Katsunori Tanaka

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (WILEY-V C H VERLAG GMBH)  56 ( 13 ) 3579 - 3584 2017.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1433-7851

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Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin-Au-III complex was designed and developed that enables organ-specific, localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5- and TAMRA-linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.

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Sequential Double "Clicks" toward Structurally Well-Defined Heterogeneous N-Glycoclusters: The Importance of Cluster Heterogeneity on Pattern Recognition In Vivo

Liliya Latypova, Regina Sibgatullina, Akihiro Ogura, Katsumasa Fujiki, Alsu Khabibrakhmanova, Tsuyoshi Tahara, Satoshi Nozaki, Sayaka Urano, Kazuki Tsubokura, Hirotaka Onoe, Yasuyoshi Watanabe, Almira Kurbangalieva, Katsunori Tanaka

ADVANCED SCIENCE (WILEY)  4 ( 2 ) 1600394 - 1600394 2017.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2198-3844

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Exploring the glycan interaction in vivo: Future prospects of neo-glycoproteins for diagnostics

Akihiro Ogura, Almira Kurbangalieva, Katsunori Tanaka

GLYCOBIOLOGY (OXFORD UNIV PRESS INC)  26 ( 8 ) 804 - 812 2016.08

Accepted,  ISSN  0959-6658

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Herein the biodistributions and in vivo kinetics of chemically prepared neoglycoproteins are reviewed. Chemical methods can be used to conjugate various mono- and oligosaccharides onto a protein surface. The kinetics and organ-specific accumulation profiles of these glycoconjugates, which are introduced through intravenous injections, have been analyzed using conventional dissection studies as well as noninvasive methods such as single photon emission computed tomography, positron emission tomography and fluorescence imaging. These studies suggest that glycan-dependent protein distribution kinetics may be useful for pharmacological and diagnostic applications.

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Glycan multivalency effects toward albumin enable N-glycan-dependent tumor targeting

Ogura, Akihiro, Tahara, Tsuyoshi, Nozaki, Satoshi, Onoe, Hirotaka, Kurbangalieva, Almira, Watanabe, Yasuyoshi, Tanaka, Katsunori

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (PERGAMON-ELSEVIER SCIENCE LTD)  26 ( 9 ) 2251 - 2254 2016.05

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  0960-894X

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Multivalent interactions play an essential role in molecular recognition in living systems. These effects were employed to target tumor cells using albumin clusters bearing similar to 10 molecules of asparagine-linked glycans (N-glycans). Noninvasive near-infrared fluorescence imaging clearly revealed A431 tumors implanted in BALB/cA-nu/nu mice after 1 h in an N-glycan structure-dependent manner, thereby demonstrating the efficient use of glycan multivalency effects for tumor targeting in vivo. (C) 2016 Elsevier Ltd. All rights reserved.

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Visualizing Trimming Dependence of Biodistribution and Kinetics with Homo- and Heterogeneous N-Glycoclusters on Fluorescent Albumin

Ogura, Akihiro, Tahara, Tsuyoshi, Nozaki, Satoshi, Morimoto, Koji, Kizuka, Yasuhiko, Kitazume, Shinobu, Hara, Mitsuko, Kojima, Soichi, Onoe, Hirotaka, Kurbangalieva, Almira, Taniguchi, Naoyuki, Watanabe, Yasuyoshi, Tanaka, Katsunori

SCIENTIFIC REPORTS (NATURE PUBLISHING GROUP)  6   273 - 279 2016.02

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  2045-2322

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A series of N-glycans, each sequentially trimmed from biantennary sialoglycans, were homo-or heterogeneously clustered efficiently on fluorescent albumin using a method that combined strain-promoted alkyne-azide cyclization and 6p-azaelectrocyclization. Noninvasive in vivo kinetics and dissection analysis revealed, for the first time, a glycan-dependent shift from urinary to gall bladder excretion mediated by sequential trimming of non-reducing end sialic acids. N-glycoalbumins that were trimmed further, in particular, GlcNAc-and hybrid biantennary-terminated congeners, were selectively taken up by sinusoidal endothelial and stellate cells in the liver, which are critical for diagnosis and treatment of liver fibrillation. Our glycocluster strategy can not only reveal the previously unexplored extracellular functions of N-glycan trimming, but will be classified as the newly emerging glycoprobes for diagnostic and therapeutic applications.

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In vivo imaging of advanced glycation end products (AGEs) of albumin: first observations of significantly reduced clearance and liver deposition properties in mice

Tsutsui, Ayumi, Ogura, Akihiro, Tahara, Tsuyoshi, Nozaki, Satoshi, Urano, Sayaka, Hara, Mitsuko, Kojima, Soichi, Kurbangalieva, Almira, Onoe, Hirotaka, Watanabe, Yasuyoshi, Taniguchi, Naoyuki, Tanaka, Katsunori

ORGANIC & BIOMOLECULAR CHEMISTRY (ROYAL SOC CHEMISTRY)  14 ( 24 ) 5755 - 5760 2016

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  1477-0520

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Advanced glycation end products (AGEs) are associated with various diseases, especially during aging and the development of diabetes and uremia. To better understand these biological processes, investigation of the in vivo kinetics of AGEs, i.e., analysis of trafficking and clearance properties, was carried out by molecular imaging. Following the preparation of Cy7.5-labeled AGE-albumin and intravenous injection in BALB/cA-nu/nu mice, noninvasive fluorescence kinetics analysis was performed. In vivo imaging and fluorescence microscopy analysis revealed that non-enzymatic AGEs were smoothly captured by scavenger cells in the liver, i.e., Kupffer and other sinusoidal cells, but were unable to be properly cleared from the body. Overall, these results highlight an important link between AGEs and various disorders associated with them, which may serve as a platform for future research to better understand the processes and mechanisms of these disorders.

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Azaelectrocyclization on cell surface: convenient and general approach to chemical biology research

Ogura, Akihiro, Tanaka, Katsunori

TETRAHEDRON (PERGAMON-ELSEVIER SCIENCE LTD)  71 ( 26-27 ) 4518 - 4521 2015.07

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  0040-4020

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Convenient and general method for live cell surface labeling was established. Azide-containing fluorescences were initially conjugated with the unsaturated ester aldehyde containing the dibenzocyclooctyne (DIBO), by the strain-promoted click reaction. The resulting probes were then treated with the live cells in one-pot process, efficiently labeling the surface lysines by azaelectrocyclization under the mild conditions. (C) 2015 Elsevier Ltd. All rights reserved.

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Microfluidic Mixing of Polyamine with Acrolein Enables the Detection of the [4+4] Polymerization of Intermediary Unsaturated Imines: The Properties of a Cytotoxic 1,5-Diazacyclooctane Hydrogel

Pradipta, Ambara R., Tsutsui, Ayumi, Ogura, Akihiro, Hanashima, Shinya, Yamaguchi, Yoshiki, Kurbangalieva, Almira, Tanaka, Katsunori

SYNLETT (GEORG THIEME VERLAG KG)  25 ( 17 ) 2442 - 2446 2014.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0936-5214

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The [4+4] polymerization of an unsaturated imine, generated from the condensation of a polyamine and excess acrolein, was investigated. The polyamine was added by micropipet to acrolein, immediately yielding a mixture of the immiscible polymeric material. Microfluidic mixing was used to gradually form the soluble diazacyclooctane polymers. The polymerization reaction ultimately gave an insoluble cationic hydrogel that adhered strongly to anionic compounds on cell surfaces, including sialoglycan, and displayed a high cytotoxicity.

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In vivo kinetics and biodistribution analysis of neoglycoproteins: effects of chemically introduced glycans on proteins

Akihiro Ogura, Almira Kurbangalieva, Katsunori Tanaka

GLYCOCONJUGATE JOURNAL (SPRINGER)  31 ( 4 ) 273 - 279 2014.05

Accepted,  ISSN  0282-0080

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Biodistribution and in vivo kinetics analysis of chemically prepared neoglycoproteins are reviewed. Various mono- and oligosaccharides were conjugated onto the protein surface by use of chemical methods. Their kinetic and organ-specific accumulation have extensively been studied after intravenous injection and analyzed by conventional dissection studies, as well as noninvasive methods, such as SPECT, PET, or fluorescence imaging. These studies clearly show the glycan-structure dependency on protein kinetics, which will provide promising possibilities for pharmacological and diagnostic applications.

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Total Synthesis of (-)-Anisatin

Ogura, Akihiro, Yamada, Kohei, Yokoshima, Satoshi, Fukuyama, Tohru

ORGANIC LETTERS (AMER CHEMICAL SOC)  14 ( 6 ) 1632 - 1635 2012.03

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  1523-7060

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A novel synthetic route to (-)-anisatin has been developed. Our synthesis features a rhodium-catalyzed 1,4-addition of an arylboronic acid, an intramolecular Diels Alder reaction of an ortho-quinone monoketal, a stereoselective [2,3]-Wittig rearrangement, and construction of the oxabicyclo [3.3.1] skeleton via cleavage of an epoxide by a primary amide.

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Total Synthesis of Anisatin

Yamada Kohei, Ogura Akihiro, Yokoshima Satoshi, Fukuyama Tohru

Symposium on the Chemistry of Natural Products, symposium papers (Symposium on the chemistry of natural products)   ( 52 ) 127 - 132 2010.09

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Anisatin (1), isolated as a toxic component of Japanese Star Anise, is a sesquiterpene characterized by eight contifuous stereogenic centers, oxabicyclo[3.3.1] skeleton, and spiro β-lactone. Its challenging structure, as well as the stron bioactivity as a GABA antagonist, has attracted many synthetic organic chemists. Despite numerous synthetic studies reported to date, only one total synthesis has been achieved. Inspired by its challenging structure, we also initiated our own research program directed toward a total synthesis of thi sinteresting molecule. Our synthesis commenced with the synthesis of phenol 7 from the known mono-protected catechol in seven steps. Oxidation of 7 with iodobenzene diacetate yielded orthoquinone monoketal, which upon heating underwent intramolecular Diels-Alder reaction to privide tetracyclic compound 14. After a three-step conversion, the resulting ether 16 was treated with methyllithium in the presence of HMPA, which induced diastereoselective [2,3]-sigmatropic rearrangement. Thus, the quaternary carbon was constructed with complete stereoselectivity. Selective cleavage of the trisubstituted souble bond of 17 by careful ozonolysis, followed by treatment with potassium carbonate provided 19. After a six-step conversion, iodide 22 was subjected to halogen-lithium exchange, which caused intramolecular addition to ketone to provide bicylco[4.3.0] skeleton. The enol ether moiety of 23 was oxidized to α-hydroxylactone, and the allyl alcohol moiety was converted to epoxide to provide 27. Upon ammonolysis of the lactone moiety, intramolecular S_N2 reaction to epoxide took place to give, after acid treatment, the desired lactone 29. Removal of the primary hydroxy group and protection of the resultin g tertiary alcohol afforded 31. The vinyl group of 31 was converted to carboxylic acid, followed by deprotection of the primary hydroxy group. Crucial lactonization was performed with MNBA to yield desired β-lactone successfully. A three-step sequence involving dihydroxylation of the trisubstituted olefin afforded 1. Having achieved total synthesis of racemic anisatin, we turned our attention to asymmetric synthesis. Phenol 35 and epoxyalcohol 36 were condensed by Mitsunobu reaction. Resulting ether 37 was subjected to halogen-lithium exchange. Bis(diethylaluminium)sulfate facilitated intramolecular S_N2 reaction to afford 38. HPLC analysis revealed that 38 was enantiomerically pure. Further synthetic studies toward asymmetric synthesis are currently under way.

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