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有機薬化学研究室

研究テーマ

創薬をめざしたリード化合物、機能性分子の合成および天然有機化合物の全合成

創薬のための基礎研究、医薬品の効率的合成法の開発、生物活性物質のデザイン、あるいは生命現象を解明するための機能性分子の合成について研究を行っています。
また、抗がん薬や糖尿病薬の開発を目指して、高い生理活性ポテンシャルを有する天然有機化合物あるいはその誘導体の高立体選択的全合成研究にも取り組んでいます。
 

キーワード

有機合成化学、天然有機化合物、全合成、生理活性物質、糖尿病薬、アミノボロン酸触媒、ピラゾール、オキサゾール、テトラゾール、トリアゾール、イミダゾール
 

配属学生

大学院生 0名
学部学生 6年次生：13名、5年次生：14名、4年次生：14名

所属教員

研究内容

（1）天然有機化合物および関連化合物の合成1-3)

抗がん薬や糖尿病薬の開発を目指し、高い生理活性ポテンシャルをもつ海洋天然有機化合物の全合成や、その誘導体の高立体選択的合成研究を行っている。これまでに構造未定の海洋微生物由来の天然物の全合成を達成し、それらの立体構造を明らかにした。また、類縁体の合成によって、より高い生理活性を示す化合物の創製に取り組んでいる。

（2）アゾールの新規合成反応の開発と生物活性物質への応用4-6)

五員環の中に窒素原子を含む複素環化合物はアゾールと呼ばれ、医薬品や天然物、農薬の重要構造として用いられている。カルボン酸から導くオキサゾール新規合成法、加熱を必要としないテトラゾール合成法、及びマイクロウェーブ加熱を利用したテトラゾールからピラゾールへの変換反応を開発した。

（3）天然に存在しないアミノ酸の効率的不斉合成法の確立7)

β-アミノ酸は非天然型アミノ酸であり、従来型の低分子医薬品を構成するだけでなく、新たな高分子医薬品に組み込まれることも期待できる。資源の乏しい我が国においては、廃棄物やエネルギー消費を抑えた直截的な合成手法の確立が求められており、アミノボロン酸を触媒とした反応開発によって、その実現を目指している。

参考論文

  1. Mar. Drugs, 18, 221, 2020; 20, 438 2022.
  2. Molecules, 25, 4634, 2020; 26, 3370, 2021
  3. Chirality. 34, 1320, 2022
  4. Tetrahedron, 82, 131914, 2021
  5. Tetrahedron Lett., 61, 151517, 2020; 61, 151983, 2020
  6. Inorg. Chem. 61, 12155, 2022
  7. Tetrahedron, 89, 132089, 2021

代表的論文

2023年

  1. Yoneyama, H., Adachi, M., Morita, A., Nakagawa, M., Yamawaki, K., Hayama, N., Harusawa, S., Usami, Y.: Synthesis of 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazoles and Homologs from 5- Substituted 2-(Alkynyl)tetrazoles avia Microwave-Induced Intramolecular Nitrile-Imine-Alkyne 1,3-Dipolar Cycloaddition, Synthesis, 55, 945-958 (2023).; DOI:10.1055/a-1961-8504

2022年

  1. Usami, Y., Nakamura, K., Mizobuchi, Y., Mizuki, K., Harusawa, S., Yoneyam, H., Yamada. T.: Enantiomeric composition of natural pericosine A derived from Periconia byssoides and α-glycosidase inhibitory activity of (−)-enantiomer, Chirality. 34, 1320–1327 (2022); DOI:10.1002/chir.23491
  2. Usami, Y., Mizobuchi, Y., Ijuin, M., Yamada, T., Morita, M., Mizuki, K., Yoneyama, H., Harusawa, S.: Synthesis of 6-Halo-Substituted Pericosine A and an Evaluation of Their Antitumor and Antiglycosidase Activities, Mar. Drugs 20, 438 (2022).; DOI:10.3390/md20070438
  3. Yoneyama, H., Hosohata, K., Jin, D., Yoshida, I., Toyoda, M., Kitamura, I., Takai, S., Usami, Y.: Design, synthesis, and evaluation of new vanin-1 inhibitors based on RR6, Bioorg. Med. Chem., 65, 116791 (2022).; DOI:10.1016/j.bmc.2022.116791
  4. Uemura, M., Hiramoto, K., Yoneyama, H., Harusawa, S., Komeda, S.: Introduction of Fluorine into Antitumor-Active Dinuclear Platinum(II) Complexes Leads to Modulation of In Vivo Antitumor Activity in Mice, Inorg. Chem. 61, 12155−12164 (2022); DOI:10.1021/acs.inorgchem.2c01126

2021年

  1.  Usami, Y., Tatsui, Y.,Sumimoto, K., Yoneyama, H.,Harusawa, S.: 3-trifluoromethanesulfonyloxy-4,7-dihydropyrazolo [1,5-a]pyridine via ring-closing metathesis: Synthesis and transformation to withasomnine homologs, Heterocycles, 103, 284-299, (2021); DOI: 10.3987/COM-20-S(K)13
  2. Usami, Y., Kubo, Y., Takagaki, T., Kuroiwa, N., Ono, J., Nishikawa, K., Nakamizu, A., Tatsui, Y., Harusawa, S., Hayama, N., Yoneyama, H.: CuI-catalyzed coupling reactions of 4-iodopyrazoles and alcohols: Application toward withasomnine and Homologs, Molecules, 26, 3370, (2021).; DOI: 10.3390/molecules26113370
  3. Yoneyama, H., Takatsuji, K., Ito, A., Usami, Y., Harusawa, S.: Transformation of γ-ketoaldehyde acetals into 3-substituted-2-cyclopentenones via cyanophosphates under mild conditions, Tetrahedron, 82, 131914, (2021).; DOI: 10.1016/j.tet.2020.131914
  4. Hayama, N., Kobayashi, Y., Takemoto, Y.: Asymmetric hetero-Michael addition to α,β-unsaturated carboxylic acids using thiourea–boronic acid hybrid catalysts, Tetrahedron, 89, 132089, (2021).; DOI: 10.1016/j.tet.2021.132089

2020年

  1. Usami, Y., Tatsui, Y., Yoneyama, H., Harusawa, S.: C4-Alkylamination of C4-Halo-1H-1-tritylpyrazoles Using Pd(dba)2 or CuI, Molecules, 25, 4634, (2020); DOI: 10.3390/molecules25204634
  2. Usami, Y., Higuchi, M., Mizuki, K., Yamamoto, M., Kanki, M., Nakasone, C., Sugimoto, Y., Shibano, M., Uesawa, Y., Nagai, J., Yoneyama, H., Harusawa, S.: Syntheses and glycosidase inhibitory activities, and in silico docking studies of pericosine e analogs methoxy-substituted at C6, Marine Drugs, 18, 221, (2020); DOI: 10.3390/md18040221
  3. Usami, Y., Tsujiuchi, Y., Machiya, Y., Chiba, A., Ikawa, T., Yoneyama, H., Harusawa, S.: Synthetic challenges in the construction of 8- To 10-membered pyrazole-fused rings via ring-closing metathesis, Heterocycles, 101, 496-511, (2020); DOI: 10.3987/COM-19-S(F)32
  4. Yoneyama, H., Oka, N., Usami, Y., Harusawa, S.: A novel synthetic method of 2,4-disubstituted oxazoles using carboxylic acid-derived Bu2Sn[OC(O)R]2, Tetrahedron Letters, 61, 151983, (2020); DOI: 10.1016/j.tetlet.2020.151983
  5. Yoneyama, H., Oka, N., Usami, Y., Harusawa, S.: TMSN3-Bu2Sn(OAc)2: A modified and mild reagent system for Wittenberger tetrazole-synthesis, Tetrahedron Letters, 61, 151517, (2020); DOI: 10.1016/j.tetlet.2019.151517

2019年

  1. Usami, Y., Sumimoto, K., Kishima, A., Tatsui, Y., Yoneyama, H., Harusawa, S: Synthesis of dihydropyrano[3,2-c]pyrazoles via double bond migration and ring-closing metathesis., Molecules, Volume 24, 2019, Article number 296; DOI: 10.3390/molecules24020296
  2. Yoneyama, H., Usami, Y., Harusawa, S..: Efficient Synthesis of a 5α-Reductase Inhibitor, 3-(Tetrazol-5-yl)-3,5-pregnadien-20-one through Allylic Rearrangement of Cyanophosphates., Synthesis, Volume 51, 2019, Pages 1791-1794.; DOI: 10.1055/s-0037-1612060
  3. Komeda, S., Yoneyama, H., Uemura, M., Tsuchiya, T., Hoshiyama, M., Sakazaki, T., Hiramoto, K., Harusawa, S.: Synthesis and structure–activity relationships of tetrazolato-bridged dinuclear platinum(II) complexes: A small modification at tetrazole C5 markedly influences the in vivo antitumor efficacy,; J. Inorg. Biochem., Volume 192, 2019, Pages 82-86; DOI: 10.1016/j.jinorgbio.2018.12.009
  4. Komeda, S., Uemura, M., Yoneyama, H., Harusawa, S., Hiramoto, K.: In vitro cytotoxicity and in vivo antitumor efficacy of tetrazolato-bridged dinuclear platinum(II) complexes with a bulky substituent at tetrazole C5; Inorganics, 7, 5 (2019); DOI: 10.3390/inorganics7010005

2018年

  1. Yoneyama, H, Hikasa, F, Fujisue, D, Usami, Y, Zhao, Z.-Y., Harusawa, S: Synthesis of Triazol Cn-Ribonucleoside Phosphoramidites Using β-Ribofuranosyl-Cn-acetylenes for RNA Catalysis Probin., Heterocycles , Volume 96, Issue 1, 2018, Pages 106-126; DOI: 10.3987/COM-17-13837
  2. Usami, Y., Kohno, A., Yoneyama, H., Harusawa, S.: Synthesis of Dihydrooxepino[3,2-c]Pyrazoles via Claisen Rearrangement and Ring-Closing Metathesis from 4-Allyloxy-1H-pyrazoles., Molecules , Volume 23, Issue 3, 2018, Article number 592; DOI: 10.3390/molecules23030592
  3. Yoneyama, H., Uemura, K., Usami, Y., Harusawa, S: Syntheses of cyclopentyl nucleoside (−)-neplanocin A through tetrazole-fragmentation from cyanophosphates,; Tetrahedron , Volume 74, Issue 17, 26 April 2018, Pages 2143-2150; DOI: 10.1016/j.tet.2018.03.020
  4. Y. Yoneyama, S. Harusawa: Tetrazole-Fragmentation for the Generation of Alkylidene Carbenes from Cyanophosphates under Neutral Conditions and Its Application to Organic Synthesis; Heterocycles , 96, 2037-2078 (2018), DOI: 10.3987/REV-18-894

2017年

  1. Yoneyama H, Numata M, Uemura K, Usami Y, Harusawa S: Transformation of Carbonyl Compounds into Homologous Alkynes under Neutral Conditions: Fragmentation of Tetrazole Intermediates Derived from Cyanophosphates, J. Org. Chem., 82, 5538-5556; DOI 10.1021/acs.joc.7b00346.
  2. Usami Y, Mizuki K, Kawahata R, Shibano M, Sekine A, Yoneyama H, Harusawa S: Syntheses of Natural O-Linked Carba-disaccharide (+)- and (-)-Pericosine E and Its Analogues as α-Glucosisase Inhibitors., Mar. Drugs, 15, 22, 2017; doi:10.3390/md15010022.
  3. H. Yoneyama, K. Uemura, Y. Usami, S. Harusawa: Synthesis of five-membered unsaturated compounds from ketones via cyanophosphates under neutral conditions: [1,5]-C-H insertion of alkylidene carbenes generated by tetrazole fragmentation., Tetrahedron, 73, 6109-6117 (2017).
  4. S. Komeda, H. Yoneyama, M. Uemura, A. Muramatsu, N. Okamoto, H. Konishi, H. Takahashi, A. Takagi, W. Fukuda, T. Imanaka, T. Kanbe, S. Harusawa, Y. Yoshikawa, K. Yoshikawa: Specific Conformational Change in Giant DNA Caused by Anticancer Tetrazolato-bridged Dinuclear Pt(II) Complexes: Middle-Length Alkyl Substituents Exhibit Minimum Effect., Inorg. Chem., 56, 802-811 (2017).　 DOI:10.1021/acs.inorgchem.6b02239.

2016年

  1. Harusawa S, Shioiri T: Diethyl Phosphorocyanidate (DEPC): a versatile reagent for organic synthesis., Tetrahedron,72:8125-8200, 2016
  2. Sato K, Sandford G, Shimizu K, Akiyama S, Lancashire M. J, Yufita D. S, Tarui A, Omote M, Kumadaki I, Harusawa S, Ando A: Synthesis of fluorinated isoxazoles using SelectfluorTM: preparation and characterization of 4-fluoroisoxazole, 4,4,5-trifluoroisoxazoline and 4,4-difluoro-5-hydroxyisoxazoline systems from one-pot and multi-step processes., Tetrahedron, 72:1690-1698, 2016.
  3. Tanaka S, Sakaguchi M, Yoneyama H, Usami Y, Harusawa S: Histamine H3 receptor antagonist OUP-186 attenuates the proliferation of cultured human brest cancer cell lines., Biochem. Biophys. Res., Commun., 480:479-485, 2016.
  4. 米山弘樹, 山本大助，大和谷厚，春沢信哉: イソチオウレア合成法の開発と新規ヒスタミンH3 受容体アンタゴニストへの応用., YAKUGAKU ZASSHI, 136:1217-1232, 2016.
  5. 宇佐美吉英, 水木晃治: 海洋天然物を中心とする生理活性化合物の全合成研究., 有機合成化学協会誌, 74: 172-1181, 2016.
  6. 水木晃治, 宇佐美吉英: Pericosine E 及び類縁化合物の合成に関する研究., 大阪薬科大学紀要, 10: 51-66, 2016.
  7. Harusawa S: Mitsunobu Reaction in My Chemistry: Lecture at VU Study Tour., Bull. Osaka Univ. Pharm. Sci., 10:75-85, 2016.

2015年

  1. Yoneyama H, Magata T, Uemura K, Usami Y, Tanaka S, Takaoka M, Harusawa S: Efficient Synthesis of N-​[4-​(4-​Chlorophenyl)​butyl]​-​S-​(3-​piperidinopropyl)​isothiourea (OUP-​186) and Its Analogues Using 2-​Nitrophenylacetyl Isothiocyanate., Synthesis, 47:1291-1302, 2015.

2014年

  1. Mizuki K, Iwahashi K, Murata N, Ikeda M, Nakai Y, Yoneyama H, Harusawa S, Usami Y: Synthesis of marine natural product (-)-pericosine E., Org. Lett.,16:3760-3763, 2014.
  2. Mizuki K, Yoneshige Y, Kawahata R, Yoneyama H, Harusawa S, Usami Y: MICROWAVE-AIDED ONE-POT DEHYDRATION OF THE ALCOHOL DERIVED FROM (-)-SHIKIMIC ACID FOR EFFICIENT SYNTHESIS OF PERICOSINES., Heterocycles, 89:2161-2167, 2014.
  3. Harusawa S, Yoneyama H, Usami Y, Yamamoto D, Zhao Z: Synthesis of C4-Linked C0- and C2-Imidazole 2’-Deoxyribonucleoside Phosphoramidites and Imidazole., Synthesis, 46:2815-2825, 2014.
  4. Usami Y.: Synthesis of Marine-Drived Carbasugar Pericosines In "Studies in Natural Products Chemistry" (Bioactive Natural Products) edited by Atta-ur-Rahman, Pergamon Science Publishers, Netherland, vol. 41, pp. 287-319, 2014.
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