American Chemical Society (ACS) Acta Medica Okayama 1554-8929 19 12 2024 Discovery of a Compound That Inhibits IRE1α S-Nitrosylation and Preserves the Endoplasmic Reticulum Stress Response under Nitrosative Stress 2429 2437 EN Haruna Kurogi Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Nobumasa Takasugi Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Sho Kubota Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ashutosh Kumar Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN Takehiro Suzuki Biomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science Naoshi Dohmae Biomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science Daisuke Sawada Department of Fine Organic Synthesis, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kam Y.J. Zhang Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN Takashi Uehara Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Inositol-requiring enzyme 1α (IRE1α) is a sensor of endoplasmic reticulum (ER) stress and drives ER stress response pathways. Activated IRE1α exhibits RNase activity and cleaves mRNA encoding X-box binding protein 1, a transcription factor that induces the expression of genes that maintain ER proteostasis for cell survival. Previously, we showed that IRE1α undergoes S-nitrosylation, a post-translational modification induced by nitric oxide (NO), resulting in reduced RNase activity. Therefore, S-nitrosylation of IRE1α compromises the response to ER stress, making cells more vulnerable. We conducted virtual screening and cell-based validation experiments to identify compounds that inhibit the S-nitrosylation of IRE1α by targeting nitrosylated cysteine residues. We ultimately identified a compound (1ACTA) that selectively inhibits the S-nitrosylation of IRE1α and prevents the NO-induced reduction of RNase activity. Furthermore, 1ACTA reduces the rate of NO-induced cell death. Our research identified S-nitrosylation as a novel target for drug development for IRE1α and provides a suitable screening strategy. No potential conflict of interest relevant to this article was reported.

American Chemical Society (ACS) Acta Medica Okayama 0163-3864 85 8 2022 First Total Synthesis of Reassigned Echinosulfonic Acid D 2122 2125 EN Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ren Nakajima Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Echinosulfonic acid D, a sponge metabolite whose structure was recently reassigned, was synthesized for the first time. The key step is the double indolization of dimethylbarbituric acid using the umpolung indole reagent, followed by a hydrolysis/decarboxylation/esterification sequence. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0947-6539 28 37 2022 Indole Editing Enabled by HFIP‐Mediated Ring‐Switch Reactions of 3‐Amino‐2‐Hydroxyindolines e202201113 EN Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaho Shimizu Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University We found the novel reactivity of hemiaminal as a precursor for indole editing at the multi-site. The HFIP-promoted indole editing of indoline hemiaminals affords 2-arylindoles through a ring-switch sequence. The key to success of this transformation is to use a cyclic hemiaminal as an a-amino aldehyde surrogate under transient tautomeric control. This transformation features mild reaction conditions and good yields with broad functional group tolerance. The utility of this transformation is presented through the one-pot protocol and the synthesis of isocryptolepine. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 2052-4129 9 7 2022 Synthesis of 2-monosubstituted indolin-3-ones by cine-substitution of 3-azido-2-methoxyindolines 1897 1903 EN Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University We report herein a formal cine-substitution/hydrolysis of 3-azidoindoles generated from 3-azido-2-methoxyindolines (AZINs). This protocol enables the introduction of various carboxylic acids and alcohols into indolin-3-ones at the C2-position, affording 2-monoacyloxy or alkoxy indolin-3-ones. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 1359-7345 57 2021 cis-3-Azido-2-methoxyindolines as safe and stable precursors to overcome the instability of fleeting 3-azidoindoles 13381 13384 EN Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Masaru Tanioka School of Pharmaceutical Sciences, Aichi Gakuin University Shinichiro Kamino School of Pharmaceutical Sciences, Aichi Gakuin University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Use of 3-azidoindoles in organic synthesis remains a difficult task owing to their instabilities. Herein, we report a general and concise approach for tackling this problem by using 3-azidoindole surrogates. The surrogates are bench-stable, presumably due to the observed intramolecular O-N-beta bonding. The resultant fleeting intermediates undergo capturing in situ to afford 3-substitued indoles through formal ipso-substitution of the azide group by nucleophiles. In these investigations, we found that the fleeting 3-azidoindoles show a C3-electrophilic character for the first time. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 1359-7345 57 61 2021 Synthesis of α-substituted indolylacetamide using acetonitriles as acetamide enolate equivalents through O-transfer reactions 7493 7496 EN Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kenta Noda Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University We introduce readily available ammonium hemiaminals as O-transfer reagents and commercially available acetonitriles as a primary amide enolate precursor. The combination serves as an amide enolate equivalent, thereby providing one-pot access to alpha-substituted indolylacetamides. A broad substrate scope and good functional group tolerance as well as gram-scale synthesis make this protocol highly attractive. Mechanistic experiments suggest that the cyano group is trapped by a hydroxy group of hemiaminals en route to the desired primary amides under metal-free conditions. No potential conflict of interest relevant to this article was reported.

PERGAMON-ELSEVIER SCIENCE Acta Medica Okayama 00404039 60 24 2019 Efficient and practical synthesis of N-acetyl enamides from ketoximes by unique iron catalytic system 1562 1565 EN Takahiro Kunishige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University A new procedure for the iron-catalyzed synthesis of enamides from ketoximes was developed, and its mechanism was proposed. A unique reduction system, with the concerted use of KI and Na2S2O4, was involved. The reaction exhibited a wide substrate scope and gave good yields in a short reaction time. The procedure is operationally simple and also applicable for the large-scale synthesis. No potential conflict of interest relevant to this article was reported.