Unified Total Synthesis and Structure-Activity Relationships of Marine Macrolide Natural Products of Cyanobacteria Origin

2013 Fiscal Year Final Research Report

• Project/Area Number: 23681045
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Living organism molecular science
• Research Institution: Tohoku University
• Principal Investigator: FUWA Haruhiko 東北大学, 生命科学研究科, 准教授 (90359638)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 海洋天然物 / 全合成 / 構造活性相関 / 生物活性分子の設計 / 細胞増殖阻害 / ミトコンドリア

Research Abstract

This project pursued unified total synthesis and structure-activity relationships of marine macrolide natural products of cyanobateria origin. Our concise synthesis of neopeltolide, a highly potent antiproliferative macrolide, enabled us to elucidate its pharmacophoric structural elements required for potent activity. Several truncated neopeltolide analogues with nanomolar activity were successfully designed on the basis of our pharmacophore model. Concise total synthesis of lyngbyaloside B, a moderately cytotoxic macrolide glycoside, and its 13-demethyl analogue was also achieved. Design, synthesis, and biological evaluation of chimeric macrolides were undertaken to show that polyketide macrolides offer unique structural motifs useful for the development of novel antiproliferative agents.

Research Products

• [Journal Article] Stereoselective synthesis of medium-sized cyclic ethers : Application of C-glycosylation chemistry to seven- to nine-membered lactone-derived thioacetals and their sulfone counterparts (2014)
  • Author(s): Y. Suga, H. Fuwa, M. Sasaki
  • Journal Title: J. Org. Chem Volume: 79 (Most Read Articles) Pages: 1656–1682
  • DOI: 10.1021/jo4025545
  • Peer Reviewed
• [Journal Article] Total synthesis and structure revision of didemnaketal B (2014)
  • Author(s): H. Fuwa, T. Muto, K. Sekine, M. Sasaki
  • Journal Title: Chem. Eur. J Volume: 20 (Frontispiece Article) Pages: 1848–1860
  • DOI: 10.1002/chem.201303713
  • Peer Reviewed
• [Journal Article] Total synthesis of the proposed structure of didemnaketal B (2013)
  • Author(s): H. Fuwa, K. Sekine, M. Sasaki
  • Journal Title: Org. Lett Volume: 15 Pages: 3970–3973
  • DOI: 10.1021/ol4017518
  • Peer Reviewed
• [Journal Article] Synthesis and biological evaluation of aspergillide A/neopeltolide chimeras (2013)
  • Author(s): H. Fuwa, K. Noto, M. Kawakami, M. Sasaki
  • Journal Title: Chem. Lett Volume: 42 Pages: 1020–1022
  • DOI: 10.1246/cl.2013.0322
  • Peer Reviewed
• [Journal Article] Concise synthesis and biological assessment of (+)-neopeltolide and a 16-member stereoisomer library of 8,9-dehydroneopeltolide : Identification of pharmacophoric elements (2013)
  • Author(s): H. Fuwa, M. Kawakami, K. Noto, T. Muto, Y. Suga, K. Konoki, M. Yotsu-Yamashita, M. Sasaki
  • Journal Title: Chem. Eur. J Volume: 19 Pages: 8100–8110
  • DOI: 10.1002/chem.201300664
  • Peer Reviewed
• [Journal Article] Total synthesis and biological evaluation of (−)-exiguolide analogues : Importance of the macrocyclic backbone (2013)
  • Author(s): H. Fuwa, K. Mizunuma, M. Sasaki, T. Suzuki, H. Kubo
  • Journal Title: Org. Biomol. Chem Volume: 11 (Inside Front Cover Article) Pages: 3442–3450
  • DOI: 10.1039/C3OB40131F
  • Peer Reviewed
• [Journal Article] Total synthesis of 13-demethyllyngbyaloside B (2013)
  • Author(s): H. Fuwa, N. Yamagata, A. Saito, M. Sasaki
  • Journal Title: Org. Lett Volume: 15 Pages: 1630–1633
  • DOI: 10.1021/ol400408w
  • Peer Reviewed
• [Journal Article] Total synthesis and biological evaluation of (+)-gambieric acid A and its analogues (2013)
  • Author(s): K. Ishigai, H. Fuwa, K. Hashizume, R. Fukazawa, Y. Cho, M. Yotsu-Yamashita, M. Sasaki
  • Journal Title: Chem. Eur. J Volume: 19 (V.I.P. (Very Important Paper)及びFront Cover Articleに選出,Most Accessed Articles in April, 2013, Chemistry Viewsやワイリー・サイエンスカフェで紹介。) Pages: 5276–5288
  • DOI: 10.1002/chem.201204303
  • Peer Reviewed
• [Journal Article] Total synthesis of tetrahydropyran-containing natural products exploiting intramolecular oxa-conjugate cyclization (2012)
  • Author(s): H. Fuwa
  • Journal Title: Heterocycles Volume: 85 (Invited personal account) Pages: 1255–1298
  • DOI: 10.3987/REV-12-730
  • Peer Reviewed
• [Journal Article] Effect of gambierol and its heptacylic and tetracyclic analogues in cultured cerebellar neurons. A structure–activity relationships study (2012)
  • Author(s): S. Perez, C. Vale, E. Alonso, H. Fuwa, M. Sasaki, Y. Konno, T. Goto, Y. Suga, M. R. Vieytes, L. M. Botana
  • Journal Title: Chem. Res. Toxicol Volume: 25 Pages: 1929–1937
  • DOI: 10.1021/tx300242m
  • Peer Reviewed
• [Journal Article] Tandem catalysis in domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization : Concise synthesis of 2,6-cis-substituted tetrahydroyran derivatives (2012)
  • Author(s): H. Fuwa T. Noguchi, K. Noto, M. Sasaki
  • Journal Title: Org. Biomol. Chem Volume: 10 Pages: 8108–8112
  • DOI: 10.1039/C2OB26189H
  • Peer Reviewed
• [Journal Article] Total synthesis and complete stereostructure of gambieric acid A (2012)
  • Author(s): H. Fuwa, K. Ishigai, K. Hashizume, M. Sasaki
  • Journal Title: J. Am. Chem. Soc Volume: 134 (Highlighted in SYNFACTS, 8, 1053 (2012). Most Read Articles in July 2012) Pages: 11984–11987
  • DOI: 10.1021/ja305864z
  • Peer Reviewed
• [Journal Article] A concise synthesis of the AB-ring fragment of (−)-gambierol (2012)
  • Author(s): H. Fuwa, K. Hirota, M. Sasaki
  • Journal Title: Heterocycles Volume: 86 Pages: 127–132
  • DOI: 10.3987/COM-12-S(N)21
  • Peer Reviewed
• [Journal Article] Stereoselective synthesis of the C1–C16 fragment of goniodomin A (2012)
  • Author(s): M. Nakajima, H. Fuwa, M. Sasaki
  • Journal Title: Bull. Chem. Soc. Jpn Volume: 85 (BCSJ Selected Paper) Pages: 948–956
  • DOI: 10.1246/bcsj.20120152
  • Peer Reviewed
• [Journal Article] Design and synthesis of skeletal analogues of gambierol : Attenuation of amyloid-βand tau pathology with voltage-gated potassium channel and N-methyl-D-aspartate receptor implications (2012)
  • Author(s): E. Alonso, H. Fuwa, C. Vale, Y. Suga, T. Goto, Y. Konno, M. Sasaki, F. M. LaFerla, M. R. Vieytes, L. Gimenez-Llort, L. M. Botana
  • Journal Title: J. Am. Chem. Soc Volume: 134 Pages: 7467–7479
  • DOI: 10.1021/ja300565t
  • Peer Reviewed
• [Journal Article] Stereoselective synthesis of 2,6-cis-substituted tetrahydropyrans : Brønsted acid-catalyzed intramolecular oxa-conjugate cyclization ofα,β-unsaturated ester surrogates (2012)
  • Author(s): H. Fuwa, N. Ichinokawa, K. Noto, M. Sasaki
  • Journal Title: J. Org. Chem Volume: 77 (JOC Featured Article及びFront Cover Articleに選定された。) Pages: 2588–2607
  • DOI: 10.1021/jo202179s
  • Peer Reviewed
• [Journal Article] Recent applications of the Suzuki–Miyaura coupling to complex polycyclic ether synthesis (2011)
  • Author(s): H. Fuwa, M. Ebine, M. Sasaki
  • Journal Title: J. Synth. Org. Chem. Jpn Volume: 69 (Special Issue In English) Pages: 1251–1262
  • DOI: 10.5059/yukigoseikyokaishi.69.1251
  • Peer Reviewed
• [Journal Article] Total synthesis of (−)-brevenal : A streamlined strategy for practical synthesis of polycyclic ethers (2011)
  • Author(s): M. Ebine, H. Fuwa, M. Sasaki
  • Journal Title: Chem. Eur. J Volume: 17 Pages: 13754–13761
  • DOI: 10.1002/chem.201101437
  • Peer Reviewed
• [Journal Article] Comparative cytotoxicity of gambierol versus other marine neurotoxins (2011)
  • Author(s): E. Cagide, M. C. Louzao, B. Espina, I. R. Ares, M. R. Vieytes, M. Sasaki, H. Fuwa, C. Tsukano, Y. Konno, M. Yotsu-Yamashita, L. A. Paquette, T. Yasumoto, L. M. Botana
  • Journal Title: Chem. Res. Toxicol Volume: 24 Pages: 835–842
  • DOI: 10.1021/tx200038j
  • Peer Reviewed
• [Journal Article] Studies toward the total synthesis of gambieric acids, potent antifungal polycyclic ethers : Convergent synthesis of a fully elaborated GHIJ-ring fragment (2011)
  • Author(s): K. Tsubone, K. Hashizume, H. Fuwa, M. Sasaki
  • Journal Title: Tetrahedron Volume: 67 Pages: 6600–6615
  • DOI: 10.1016/j.tet.2011.05.082
  • Peer Reviewed
• [Journal Article] A new strategy for the synthesis of substituted dihydropyrones and tetrahydropyrones via palladium-catalyzed coupling of thioesters (2011)
  • Author(s): H. Fuwa K. Mizunuma, S. Matsukida, M. Sasaki
  • Journal Title: Tetrahedron Volume: 67 Pages: 4995–5010
  • DOI: 10.1016/j.tet.2011.03.114
  • Peer Reviewed
• [Journal Article] Biosynthesis-inspired intramolecular oxa-conjugate cyclization ofα,β-unsaturated thioesters : Stereoselective synthesis of 2,6-cis-substituted tetrahydropyrans (2011)
  • Author(s): H. Fuwa, K. Noto, M. Sasaki
  • Journal Title: Org. Lett Volume: 13 Pages: 1820–1823
  • DOI: 10.1021/ol200333p
  • Peer Reviewed
• [Presentation] ネオペルトリド類縁体の作用解析研究 (2014)
  • Author(s): 佐藤みずほ,不破春彦,佐々木誠
  • Organizer: 日本化学会第94春季年会
  • Place of Presentation: 名古屋
  • Year and Date: 20140326-30
• [Presentation] ネオペルトリドの構造活性相関研究 : オキサゾール含有側鎖の重要性 (2014)
  • Author(s): 野口拓真,川上雅人,不破春彦,佐々木誠
  • Organizer: 日本化学会第94春季年会
  • Place of Presentation: 名古屋
  • Year and Date: 20140326-30
• [Presentation] リングビヤロシドBの全合成研究 (2014)
  • Author(s): 奥秋佑太,不破春彦,佐々木誠
  • Organizer: 日本化学会第94春季年会
  • Place of Presentation: 名古屋
  • Year and Date: 20140326-30
• [Presentation] ディデムナケタールBの全合成と完全立体構造決定 (2013)
  • Author(s): 武藤崇史,関根久美子,不破春彦,佐々木誠
  • Organizer: 第104回有機合成シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 20131106-07
• [Presentation] ディデムナケタールBの全合成と完全立体構造決定 (2013)
  • Author(s): 武藤崇史,関根久美子,不破春彦,佐々木誠
  • Organizer: 第55回天然有機化合物討論会
  • Place of Presentation: 京都
  • Year and Date: 20130918-20
• [Presentation] 海洋天然物の効率的全合成と高活性構造単純化類縁体の創出 (2013)
  • Author(s): 不破春彦
  • Organizer: 新学術領域研究「天然物ケミカルバイオロジー : 分子標的と活性制御」第四回領域公開シンポジウム
  • Place of Presentation: つくば
  • Year and Date: 20130528-29
• [Presentation] ネオペルトリド構造類縁体の設計・合成・活性評価 (2013)
  • Author(s): 川上雅人,武藤崇史,不破春彦,佐々木誠
  • Organizer: 日本化学会第93春季年会
  • Place of Presentation: 滋賀
  • Year and Date: 20130322-25
• [Presentation] リングビヤロシドB類縁体の合成と活性評価 (2013)
  • Author(s): 山縣直哉,不破春彦,佐々木誠
  • Organizer: 日本化学会第93春季年会
  • Place of Presentation: 滋賀
  • Year and Date: 20130322-25
• [Presentation] タンデム反応によるテトラヒドロピラン誘導体の合成 (2013)
  • Author(s): 野口拓真,能登健吉,不破春彦,佐々木誠
  • Organizer: 日本化学会第93春季年会
  • Place of Presentation: 滋賀
  • Year and Date: 20130322-25
• [Presentation] Studies toward the total synthesis of iriomoteolide-2a (poster presentation) (2013)
  • Author(s): H. Fuwa
  • Organizer: The 2nd International Symposium on Chemical Biology of Natural Products : Target ID and Regulation of Bioactivity
  • Place of Presentation: Yokohama
  • Year and Date: 2013-10-28
• [Presentation] Total synthesis and biological evaluation of marine macrolide natural products (2013)
  • Author(s): H. Fuwa
  • Organizer: International Symposium for the 70th Anniversary of the Tohoku Branch of the Chemical Society of Japan
  • Place of Presentation: Sendai
  • Year and Date: 2013-09-29
• [Presentation] ガンビエル酸Aの全合成 (2012)
  • Author(s): 石貝和也,橋詰圭祐,不破春彦,佐々木誠
  • Organizer: 第102回有機合成シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 20121108-09
• [Presentation] ガンビエル酸Aの全合成と完全立体構造決定 (2012)
  • Author(s): 不破春彦,石貝和也,橋詰圭祐,佐々木誠
  • Organizer: 第54回天然有機化合物討論会
  • Place of Presentation: 東京
  • Year and Date: 20120918-20
• [Presentation] ガンビエロール構造単純化類縁体の設計・合成・評価 (2012)
  • Author(s): 菅悠人,不破春彦,後藤智見,今野悠,佐々木誠,Eva Alonso,Carmen Vale,Luis M. Botana
  • Organizer: 第7回日本ケミカルバイオロジー学会
  • Place of Presentation: 京都
  • Year and Date: 20120607-09
• [Presentation] ネオペルトリドの効率的全合成と立体構造活性相関 (2012)
  • Author(s): 川上雅人,能登健吉,斎藤麻美,菅悠人,不破春彦,佐々木誠
  • Organizer: 第101回有機合成シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 20120606-07
• [Presentation] 13-デメチルリングビヤロシドBの合成研究 (2012)
  • Author(s): 山縣直哉,不破春彦,佐々木誠
  • Organizer: 日本化学会第92春季年会
  • Place of Presentation: 横浜
  • Year and Date: 20120325-28
• [Presentation] ネオペルトリドの効率的全合成と構造類縁体ライブラリーの構築 (2012)
  • Author(s): 能登健吉,川上雅人,斎藤麻美,菅悠人,不破春彦,佐々木誠
  • Organizer: 日本化学会第92春季年会
  • Place of Presentation: 横浜
  • Year and Date: 20120325-28
• [Presentation] ガンビエル酸Aの全合成研究 (2012)
  • Author(s): 石貝和也,橋詰圭祐,不破春彦,佐々木誠
  • Organizer: 日本化学会第92春季年会
  • Place of Presentation: 横浜
  • Year and Date: 20120325-28
• [Presentation] Total synthesis and structure–activity relationships of marine macrolides and their analogues (2012)
  • Author(s): H. Fuwa
  • Organizer: The 1st International Symposium on Chemical Biology of Natural Products : Target ID and Regulation of Bioactivity
  • Place of Presentation: Kyoto
  • Year and Date: 2012-10-31
• [Presentation] 海洋天然物イグジグオリドの化学合成と抗腫瘍活性評価 (2012)
  • Author(s): 不破春彦
  • Organizer: 東北大学イノベーションフェア2012
  • Place of Presentation: 東京
  • Year and Date: 2012-03-15
• [Presentation] 微量複雑海洋天然物の全合成とケミカルバイオロジーへの展開 (2011)
  • Author(s): 不破春彦
  • Organizer: 東北大学グローバルCOEプログラム分子系高次構造体化学国際教育研究拠点シンポジウム2011
  • Place of Presentation: 仙台
  • Year and Date: 20111119-20
• [Presentation] 海洋天然物(−)-exiguolideの全合成と生物活性評価 (2011)
  • Author(s): 不破春彦
  • Organizer: 第10回化学系薬学若手研究者のセミナー
  • Place of Presentation: 仙台
  • Year and Date: 2011-08-27
• [Remarks]
  • URL: http://www.agri.tohoku.ac.jp/kanshoku/index.html
• [Patent(Industrial Property Rights)] 抗がん作用を有する複素環化合物 (2012)
  • Inventor(s): 不破春彦,佐々木誠
  • Industrial Property Rights Holder: 国立大学法人東北大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2012-235042
  • Filing Date: 2012-10-24
  • Overseas
• [Patent(Industrial Property Rights)] 抗がん作用を有するマクロライド 化合物 (2011)
  • Inventor(s): 不破春彦,佐々木誠,久保裕司,鈴木隆哉
  • Industrial Property Rights Holder: 国立大学法人東北大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: PCT/JP2011/006057
  • Filing Date: 2011-10-28
  • Overseas