Design and Synthesis of Chloroalkene Dipeptide Isosteres as Ground State Peptidomimetics for drug discovery

• Project/Area Number: 24790107
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Shizuoka University (2013); Tokyo Medical and Dental University (2012)
• Principal Investigator: NARUMI Tetsuo 静岡大学, 工学(系)研究科(研究院), 准教授 (50547867)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: アミド結合等価体

Research Abstract

As part of a program aimed at acceleration of the peptide-lead drug discovery, synthetic studies and a structural analysis of a newly designed dipeptide bioisosteres possessing an E/Z-chloroalkene unit as the surrogate functionality of a peptide bond were investigated. In this study, practical and divergent methodologies for the synthesis of chloroalkenes dipeptide isosteres (CADIs) have been developed including large-scale synthesis of Xaa-Gly-type CADIs and highly diastereoselective synthesis of Xaa-Xaa-type CADIs. These studies should contribute to the development of alkene dipeptide isosteres-based medicinal chemistry.

Research Products

• [Journal Article] Imidazolium Salt-Catalyzed Friedel–Crafts-Type Conjugate Addition of Indoles : Analysis of Indole/Imidazolium Complex by High Level ab Initio Calculations (2014)
  • Author(s): Nar umi, T.; Tsuzuki, S.; Tamamura, H. Asian J.
  • Journal Title: Org. Chem Volume: 3(4) Pages: 497-503
  • Peer Reviewed
• [Journal Article] Development of the 8-aza-3-bromo-7-hydroxycoumarin-4-ylme thyl group as a new entry of photolabile protecting groups (2014)
  • Author(s): Takano, H.; Nar umi, T.; Takano, H.; Ohashi, N.; Suzuki, A.; Furuta, T.; Tamamura, H
  • Journal Title: Tetrahedron Volume: 70(29) Pages: 4400-4404
• [Journal Article] Isostere-Based Design of 8-Azacoumarin-Type Photolabile Protecting Groups : A Hydrophilicity-Increasing Strategy for Coumarin-4-ylmethyls (2014)
  • Author(s): Nar umi, T.; Takano, H.; Ohashi, N.; Suzuki, A.; Furuta, T.; Tamamura, H
  • Journal Title: Org. Lett Volume: 16(4) Pages: 1184-1187
  • Peer Reviewed
• [Journal Article] Isostere-Based Design of 8-Azacoumarin-Type Photolabile Protecting Groups: A Hydrophilicity-Increasing Strategy for Coumarin-4-ylmethyls (2014)
  • Author(s): Narumi, T., Takano, H., Ohashi, N., Suzuki, A., Furuta, T., Tamamura, H.
  • Journal Title: Org. Lett. Volume: 16 Issue: 4 Pages: 1184-1187
  • DOI: 10.1021/ol5000583
  • Peer Reviewed
• [Journal Article] Imidazolium Salt-Catalyzed Friedel-Crafts-Type Conjugate Addition via Cation-π Interaction of Imidazolium Cation with Indole: Analysis by High Level ab Initio Calculations (2014)
  • Author(s): Narumi, T.; Tsuzuki, S.; Tamamura, H.
  • Journal Title: Asian J. Org. Chem. Volume: 4 Issue: 4 Pages: 497-503
  • DOI: 10.1002/ajoc.201400026
  • Peer Reviewed
• [Journal Article] Development of the 8-aza-3-bromo-7-hydroxycoumarin-4-ylmethyl group as a new entry of photolabile protecting groups (2014)
  • Author(s): Takano, H., Narumi, T., Ohashi, N., Suzuki, A., Furuta, T., Nomura, W., Tamamura, H.
  • Journal Title: Tetrahedron Volume: XX Issue: 29 Pages: 4400-4404
  • DOI: 10.1016/j.tet.2014.04.063
  • Peer Reviewed
• [Journal Article] A CD4 Mimic as an HIV Entry Inhibitors : Pharmacokinetic (2013)
  • Author(s): Hashimoto, C.; Nar umi, T.; Otsuki, H.; Hirota, Y.; Arai, H.; Yoshimura, K.; Harada, S.; Ohashi, N.; Nomura, W.; Miura, T.; Igarashi, T.; Matsushita S.; Tamamura, H., Bioorg
  • Journal Title: Med. Chem Volume: 21(24) Pages: 7884-7889
  • Peer Reviewed
• [Journal Article] Generation of a Replication-competent Simian-human Immunodeficiency Virus, the Neutralisation Sensitivity of Which can be Enhanced in the Presence of a Small Molecule CD4 Mimic (2013)
  • Author(s): Otsuki, H.; Hishiki, T.; Miura, T.; Hashimoto, C.; Nar umi, T.; Tamamura, H.; Yoshimura, K.; Matsushita, S.; Igarashi, T
  • Journal Title: J. Gen. Virol Volume: 94(12) Pages: 2710-2716
  • Peer Reviewed
• [Journal Article] Peptide-based Ligand Screening and Functional Analysis of Protein Kinase C (2013)
  • Author(s): Ohashi, N.; Nomura, W.; Nar umi, T.; Tamamura, H., Biopolymers
  • Journal Title: Peptide Science Volume: 100(6) Pages: 118-124
  • Peer Reviewed
• [Journal Article] Low Molecular Weight CXCR4 Ligands with Variable Spacers (2013)
  • Author(s): Nar umi, T.; Aikawa, H.; Tanaka, T.; Hashimoto, C.; Ohashi, N., Nomura, W.; Kobayakawa, T.; Takano, H.; Hirota, Y.; Murakami, T.; Yamamoto, N.; Tamamura, H
  • Journal Title: ChemMedChem Volume: 8(1) Pages: 118-124
  • Peer Reviewed
• [Journal Article] CD4 Mimics as HIV Entry Inhibitors : Lead Optimization Studies of the Aromatic Substituents (2013)
  • Author(s): Nar umi, T.; Arai, H.; Yoshimura, K.; Harada, S.; Hirota, Y.; Ohashi, N.; Hashimoto, C.; Nomura, W.; Matsushita, S.; Tamamura, H
  • Journal Title: Bioorg. Med. Chem Volume: 21(9) Pages: 2518-2526
  • Peer Reviewed
• [Journal Article] Conjugation of Cell-penetrating Peptides Leads to Identification of Anti-HIV Peptides from Matrix Proteins (2013)
  • Author(s): Nar umi, T.; Komoriya, M.; Hashimoto, C.; Wu, H.; Nomura, W.; Suzuki, S.; Tanaka, T.; Chiba, J.; Yamamoto, N.; Murakami, T.; Tamamura, H., Bioorg
  • Journal Title: Med. Chem Volume: 20(4) Pages: 1468-1474
  • Peer Reviewed
• [Journal Article] CD4 Mimics as HIV Entry Inhibitors: Lead Optimization Studies of the Aromatic Substituents. (2013)
  • Author(s): Narumi, T., Arai, H., Yoshimura, K., Harada, S., Hirota, Y., Ohashi, N., Hashimoto, C.. Nomura, W., Matsushita, S. and Tamamura, H.
  • Journal Title: Bioorg. Med. Chem. Volume: 8 Issue: 9 Pages: 2518-2526
  • DOI: 10.1016/j.bmc.2013.02.041
  • Peer Reviewed
• [Journal Article] Peptide-based Ligand Screening and Functional Analysis of Protein Kinase C (2013)
  • Author(s): Ohashi, N., Nomura, W., Narumi, T., Tamamura, H.
  • Journal Title: Biopolymers: Peptide Science Volume: 100 Issue: 6 Pages: 613-620
  • DOI: 10.1002/bip.22324
  • Peer Reviewed
• [Journal Article] Generation of a replication-competent simianhuman immunodeficiency virus, the neutralisation sensitivity of which can be enhanced in the presence of a small molecule CD4 mimic. (2013)
  • Author(s): Otsuki, H., Hishiki, T., Miura, T., Hashimoto, C., Narumi, T., Tamamura, H., Yoshimura, K., Matsushita, S., and Igarashi, T.
  • Journal Title: J. Gen. Virol. Volume: 94 Issue: 12 Pages: 2710-2716
  • DOI: 10.1099/vir.0.055590-0
  • Peer Reviewed
• [Journal Article] A CD4 Mimic as an HIV Entry Inhibitors: Pharmacokinetics (2013)
  • Author(s): Hashimoto, C., Narumi, T., Otsuki, H., Hirota, Y., Arai, H., Yoshimura, K., Harada, S., Ohashi, N., Nomura, W., Miura, T., Igarashi, T., Matsuhita, S., Tamamura, H.
  • Journal Title: Bioorg. Med. Chem. Volume: 21 Issue: 24 Pages: 7884-7889
  • DOI: 10.1016/j.bmc.2013.10.005
  • Peer Reviewed
• [Journal Article] Synthetic C34 Trimer of HIV-1 gp41 Shows Significant Increase of Inhibition Potency (2012)
  • Author(s): Nomura, W.; Hashimoto, C.; Ohya, A.; Miyauchi, K.; Urano, E.; Tanaka, T.; Nar umi, T., Nakahara, T.; Komano, J. A.; Yamamoto, N.; Tamamura, H
  • Journal Title: ChemMedChem Volume: 7(2) Pages: 205-208
  • Peer Reviewed
• [Journal Article] Evaluation of a Synthetic C34 Trimer of HIV-1 gp41 as AIDS Vaccines (2012)
  • Author(s): Hashimoto, C.; Nomura, W.; Ohya, A.; Urano, E.; Miyauchi, K.; Nar umi, T.; Aikawa, H.; Komano J. A.; Yamamoto, N.; Tamamura, H
  • Journal Title: Bioorg. Med. Chem Volume: 20(15) Pages: 3287-3291
  • Peer Reviewed
• [Journal Article] Pharmacophore-Based Small Molecule CXCR4 Ligands (2012)
  • Author(s): Nar umi, T.; Tanaka, T.; Hashimoto, C.; Nomura, W.; Aikawa, H.; Sohma, A.; Itotani, K.; Kawamata, M.; Murakami, T.; Yamamoto, N.; Tamamura, H
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 22(12) Pages: 4169-4172
  • Peer Reviewed
• [Journal Article] Stereoselective Formation of Trisubstituted (Z)-Chloroalkenes Adjacent to a Tertiary Carbon Stereogenic Center by Organocuprate-Mediated Reduction/ Alkylation (2012)
  • Author(s): Nar umi, T.; Kobayakawa, T.; Aikawa, H.; Seike, S.; Tamamura, H
  • Journal Title: Org. Lett Volume: 14(17) Pages: 4490-4493
  • Peer Reviewed
• [Journal Article] Stereoselective Formation of Trisubstituted (Z)-Chloroalkenes Adjacent to a Tertiary Carbon Stereogenic Center by Organocuprate-Mediated Reduction/Alkylation (2012)
  • Author(s): Narumi, T.; Kobayakawa, T.; Aikawa, H.; Seike, S.; *Tamamura, H.
  • Journal Title: Org. Lett. Volume: 14 Issue: 17 Pages: 4490-4493
  • DOI: 10.1021/ol301988d
  • Peer Reviewed
• [Presentation] 1,4−遠隔不斉誘起によるジアスエテレオ選択的アリル位アルキル化反応の開発 (2014)
  • Author(s): 鳴海哲夫、小早川拓也、玉村啓和
  • Organizer: 日本薬学会第134回年会
  • Place of Presentation: 熊本
  • Year and Date: 2014-03-28
• [Presentation] 1,4－遠隔不斉誘起によるジアスエテレオ選択的アリル位アルキル化反応の開発 (2014)
  • Author(s): 鳴海哲夫, 小早川拓也, 玉村啓和
  • Organizer: 日本薬学会 第134年会
  • Place of Presentation: 熊本大学（熊本）
• [Presentation] Development of 8-Azacoumarin-type Photolabile Protecting Groups that Efficiently React under Aqueous Milieu Based on Amide-Alkene Isosterism (2013)
  • Author(s): Takano, H., Nar umi, T.,他3名
  • Organizer: The 17th Korean Peptide Protein Society Symposium
  • Place of Presentation: Seoul (Korea)
  • Year and Date: 2013-11-29
• [Presentation] 他HIV活性を有するCD4ミミック誘導体の構造活性相関研究 : インドール型誘導体の設計合成とその生物活性評価 (2013)
  • Author(s): 廣田雄樹、鳴海哲夫
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-26
• [Presentation] FRETを基盤とするPKCリガンドスクリーニング法の開発 (2013)
  • Author(s): 大橋南美、鳴海哲夫、他3名
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-26
• [Presentation] クロロアルケン型ジペプチドイソスターのラージスケール合成法の開発 (2013)
  • Author(s): 小早川拓也、鳴海哲夫、玉村啓和
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-26
• [Presentation] 水性環境下で効率的に反応する8-アザクマリニルメチル型光分解性保護基の開発 (2013)
  • Author(s): 高野皓、鳴海哲夫、他3名
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-26
• [Presentation] Design and Synthesis of Chloroalkene Dipeptide Isosoteres as Ground State Peptidomimetics (2013)
  • Author(s): Nar umi, T., Kobayakawa, T., Tamamura, H.
  • Organizer: The 10^<th> Australian Peptide Conference
  • Place of Presentation: Penang (Malaysia)
  • Year and Date: 2013-09-11
• [Presentation] HIV外被タンパク質gp120を分指標的とするインドール型低分子CD4ミミックの構造活性相関研究 (2013)
  • Author(s): 廣田雄樹、鳴海哲夫、他7名
  • Organizer: 日本ケミカルバイオジー研究会第8回年会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-21
• [Presentation] 有機銅試薬によるクロロアルケン類の立体選択的合成法の開発 (2013)
  • Author(s): 小早川拓也、鳴海哲夫、他2名
  • Organizer: 日本ケミカルバイオジー研究会第8回年会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-21
• [Presentation] 水性環境下で効率的に反応する8-アザクマリニルメチル型光分解性保護基の開発 (2013)
  • Author(s): 高野皓、鳴海哲夫、他3名
  • Organizer: 日本ケミカルバイオジー研究会第8回年会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-21
• [Presentation] 2価結合型リガンドのケモカインレセプターCXCR4の発現認識と細胞移動阻害活性に関する研究 (2013)
  • Author(s): 野村渉、鳴海哲夫、他3名
  • Organizer: 日本ケミカルバイオジー研究会第8回年会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-20
• [Presentation] FRETを用いたPKCリガンド結合性評価法の開発研究 (2013)
  • Author(s): 大橋南美、鳴海哲夫、他4名
  • Organizer: 日本ケミカルバイオジー研究会第8回年会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-20
• [Presentation] カチオン-π相互作用を利用したインドール類のFriedel-Crafts型共役付加反応の開発 (2013)
  • Author(s): 鳴海哲夫、相川春夫、玉村啓和
  • Organizer: 日本ケミカルバイオジー研究会第8回年会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-20
• [Presentation] 能性アゾリウム塩によるインドール類のFriedel-Crafts型共役付加反応機 (2013)
  • Author(s): 鳴海哲夫、相川春夫、玉村啓和
  • Organizer: 日本薬学会第133回年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-30
• [Presentation] E型クロロアルケン骨格の立体選択的合成法の開発 (2013)
  • Author(s): 小早川拓也、鳴海哲夫、他2名
  • Organizer: 日本薬学会第133回年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-30
• [Presentation] HIV外被タンパク質gp120を標的としたインドール型低分子CD4ミミックの創製 (2013)
  • Author(s): 廣田雄樹、鳴海哲夫、他3名
  • Organizer: 日本薬学会第133回年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-29
• [Presentation] 水性環境下で効率的に反応する8-アザクマリニルメチル型光分解性保護基の開発 (2013)
  • Author(s): 高野皓、鳴海哲夫、他3名
  • Organizer: 日本薬学会第133回年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-28
• [Presentation] 水性環境下で効率的に反応する8-アザクマリニルメチル型光分解性保護基の開発 (2013)
  • Author(s): 高野 皓, 鳴海哲夫, 野村渉, 古田寿昭, 玉村啓和
  • Organizer: 日本ケミカルバイオロジー学会 第8回年会
  • Place of Presentation: 東京医科歯科大学（東京都）
• [Presentation] 有機銅試薬によるクロロアルケン類の立体選択的合成法の開発 (2013)
  • Author(s): 小早川拓也, 鳴海哲夫, 相川春夫, 玉村啓和
  • Organizer: 日本ケミカルバイオロジー学会 第8回年会
  • Place of Presentation: 東京医科歯科大学（東京都）
• [Presentation] Design and Synthesis of Chloroalkene Dipeptide Isosteres as Ground State Peptidomimetics (2013)
  • Author(s): Tetsuo Narumi, Takuya Kobayakawa, Hirokazu Tamamura
  • Organizer: The 10th Australian Peptide Conference
  • Place of Presentation: Shangri-La Golden Sands Resort（Penang, Malaysia）
• [Presentation] 水性環境下で効率的に反応するアザクマリン型光感受性保護基の開発 (2013)
  • Author(s): 高野 皓, 鳴海哲夫, 野村渉, 古田寿昭, 玉村啓和
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 帝京大学板橋キャンパス（東京）
• [Presentation] クロロアルケン型ジペプチドイソスターのラージスケール合成法の開発 (2013)
  • Author(s): 小早川拓也, 鳴海哲夫, 玉村啓和
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 帝京大学板橋キャンパス（東京）
• [Presentation] Development of 8-Azacoumarin-type Photolabile Protecting Groups that Efficiently React under Aqueous Milieu Based on Amide-Alkene Isosterism (2013)
  • Author(s): Hikaru Takano, Tetsuo Narumi, Nami Ohashi, Toshiaki Furuta, Hirokazu Tamamura
  • Organizer: The 17th Korean Peptide Protein Society Symposium
  • Place of Presentation: Hanwha Resort (Seoul, Korea)
• [Presentation] E型クロロアルケン骨格の立体選択的合成法の開発 (2013)
  • Author(s): 小早川拓也，鳴海哲夫，相川春夫，玉村啓和
  • Organizer: 日本薬学会第133年会（横浜）
  • Place of Presentation: 横浜
• [Presentation] 有機銅試薬によるクロロアルケン類の立体選択的合成法の開発 (2013)
  • Author(s): 小早川拓也，鳴海哲夫，相川春夫，玉村啓和
  • Organizer: 日本ケミカルバイオロジー研究会第８回年会
  • Place of Presentation: 東京
• [Presentation] 低分子型CD4ミミック : HIV外被タンパク質の構造変化を促すHIV侵入阻害剤 (2012)
  • Author(s): 鳴海哲夫、廣田雄樹、他5名
  • Organizer: 第30回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-11-28
• [Presentation] HIV外被タンパク質gp120を標的とするインドール型低分子CD4ミミックの創製研究 (2012)
  • Author(s): 廣田雄樹、鳴海哲夫、他10名
  • Organizer: 第26回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京
  • Year and Date: 2012-11-26
• [Presentation] HIV-1 MA, CAタンパク質を基にした新規抗HIV-1剤の創製研究 (2012)
  • Author(s): 高野皓、鳴海哲夫、他7名
  • Organizer: 第26回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京
  • Year and Date: 2012-11-25
• [Presentation] ペプチドミメティック型インテグラーゼ阻害剤の構造活性相関研究 (2012)
  • Author(s): 相川春夫、鳴海哲夫、他11名
  • Organizer: 第26回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京
  • Year and Date: 2012-11-24
• [Presentation] Development of Cell-Penetrating ZIP Tag-Probe Systems for Fluorescent Imaging of Protein Dynamics in Cells (2012)
  • Author(s): 野村渉、鳴海哲夫、他2名
  • Organizer: 第49回ペプチド討論会
  • Place of Presentation: 鹿児島
  • Year and Date: 2012-11-08
• [Presentation] 有機銅試薬によるアリル位アルキル化反応を基軸とするZ型クロロアルケン骨格の立体選択的合成法の開発 (2012)
  • Author(s): 小早川拓也、鳴海哲夫、他2名
  • Organizer: 第38回反応と合成の進歩シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-11-06
• [Presentation] アゾリウム塩を酸触媒とするインドール類のFriedel-Crafts型共役付加反応の開発 (2012)
  • Author(s): 鳴海哲夫、他2名
  • Organizer: 第38回反応と合成の進歩シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-11-06
• [Presentation] 二核亜鉛錯体型CXCR4アンタゴニストの創製 (2012)
  • Author(s): 紺野誠、鳴海哲夫、他2名
  • Organizer: 第56回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-13
• [Presentation] 高活性イミダゾールカルベンの創製を目指した構造活性相関研究 (2012)
  • Author(s): 鳴海哲夫、他2名
  • Organizer: 第56回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-13
• [Presentation] Stereoselective Formation of Trisubstituted (Z)-Chloroalkenes Flanking Two Stereogenic Centers by Organocopper-Mediated Reduction/ Alkylation (2012)
  • Author(s): Nar umi, T.; Seike, S.,他2名
  • Organizer: 244^<th> American Chemical Society National Meeting & Exposition
  • Place of Presentation: Philadelphia (USA)
  • Year and Date: 2012-08-21
• [Presentation] Isostere Chemistry : ペプチド結合等価体の合成と応用 (2012)
  • Author(s): 鳴海哲夫
  • Place of Presentation: 東京理科大学
  • Year and Date: 2012-05-30
• [Presentation] Stereoselective Formation of Trisubstituted (Z)-Chloroalkenes Flanking Two Stereogenic Centers by Organocopper-Mediated Reduction/Alkylation of Allylic gem-Dichlorides (2012)
  • Author(s): Tetsuo Narumi, Shunsuke Seike, Haruo Aikawa and Hirokazu Tamamura
  • Organizer: 244th ACS National Meeting in Philadelphia
  • Place of Presentation: philadelphia
• [Presentation] Isostere Chemistry：ペプチド結合等価体の合成と応用 (2012)
  • Author(s): 鳴海哲夫
  • Organizer: 東京理科大学化学特別講義
  • Place of Presentation: 東京
  • Invited
• [Book] 最新ペプチド合成技術とその創薬研究への応用 (2012)
  • Author(s): 鳴海哲夫, Jeffrey W. Bode
  • Total Pages: 8
  • Publisher: 株式会社 メディカル ドゥ (大阪)
• [Remarks]
  • URL: http://www.ipc.shizuoka.ac.jp/~ttnarum/