Structural evaluation of new 14-epimerized tachysterol analogs as hVDR agonists

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590015
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Okayama University (2013); Teikyo University (2011-2012)
• Principal Investigator: SAWADA Daisuke 岡山大学, 医歯(薬)学総合研究科, 教授 (00338691)
• Project Period (FY): 2011 – 2013
• Keywords: タキステロール / ビタミンD / 有機合成化学 / X線結晶構造解析

Research Abstract

I found that 14-epi-19-nortachysterol derivatives was able to be isolated by 14 epimerization. And I succeeded in their chemical synthesis and revealed their marked stability in comparison with natural tachysterol and they showed their potent VDR binding affinity. Also, X-ray co-crystallographic analyses were performed using their complex with the ligand binding domain of the human VDR, and surprisingly, they exhibited an unprecedented binding configurations, C5,6-s-trans and C7,8-s-trans triene configurations, which were opposite the natural C7,8-ene-configuration of vitamin D3.

Research Products

• [Journal Article] Synthesis and Biological Activity of 1α,2α,25-Trihydroxyvitamin D_3: Active Metabolite of 2α-(3-Hydroxypropoxy)-1α,25-dihydroxyvitami n D_3 by Human CYP3A4 (2014)
  • Author(s): Masashi Takano, Saori Ohya, Kaori Yasuda, Miyu Nishikawa, Akiko Takeuchi, Daisuke Sawada, Toshiyuki Sakaki, and Atsushi Kittaka
  • Journal Title: Chem. Pharm. Bull Volume: 62 (2) Pages: 182-184
  • DOI: 10.1248/cpb.c13-00646
  • Peer Reviewed
• [Journal Article] Synthesis of 2α-Heteroarylalkyl Active Vitamin D_3 with Therapeutic Effect on Enhancing Bone Mineral Density in vivo (2013)
  • Author(s): Miki Matsuo, Asami Hasegawa, Masashi Takano, Hiroshi Saito, Shinji Kakuda, Takayuki Chida, Ken-ichiro Takagi, Eiji Ochiai, Kyohei Horie, Yoshifumi Harada, Midori Takimoto-Kamimura, Kazuya Takenouchi, Daisuke Sawada, and Atsushi Kittaka
  • Journal Title: ACS Med. Chem. Lett Volume: 4 (7) Pages: 671-674
  • DOI: 10.1021/ml400098w
  • Peer Reviewed
• [Journal Article] Synthesis of 14-epi-2α-hydroxypropoxy-1α,25-dihydroxy-19- nortachysterol and its hVDR binding (2013)
  • Author(s): Daisuke Sawada, Yuya Tsukuda, Hiroshi Saito, Kenichiro Takagi, Shinji Kakuda, Midori Takimoto-Kamimura, Eiji Ochiai, Kazuya Takenouchi, and Atsushi Kittaka
  • Journal Title: J. Steroid Biochem. Mol. Biol Volume: 136 Pages: 27-29
  • Peer Reviewed
• [Journal Article] 14-エピ-タキステロール類の合成とVDR結合様式の解明 (2013)
  • Author(s): 澤田大介、堀江恭平、落合鋭士、竹内明子、角田真二、上村みどり、橘高敦史
  • Journal Title: ビタミン Volume: 87 (4) Pages: 220
• [Journal Article] 2α-アゾールエチル基を有する1α,25-ジヒドロキシビタミンD_3の合成と生物活性評価 (2013)
  • Author(s): 橘高敦史、松尾実紀、長谷川麻美、高野真史、澤田大介、齋藤博、角田真二、高木健一郎、落合鋭士、堀江恭平、上村みどり、竹之内一弥
  • Journal Title: ビタミン Volume: 87 (11) Pages: 652
• [Journal Article] Potent 19-Norvitamin D Analogs for Prostate and Liver Cancer Therapy (2012)
  • Author(s): Atsushi Kittaka, Akihiro Yoshida, Kun-Chun Chiang, Masashi Takano, Daisuke Sawada, Toshiyuki Sakaki, and Tai C. Chen
  • Journal Title: Future Med. Chem Volume: 4 (16) Pages: 2049-2065
  • DOI: 10.4155/fmc.12.130
  • Peer Reviewed
• [Journal Article] Synthesis and Biological Activities of 1α,4α,25- and 1α,4β,25-Trihydroxyvitamin D_3 and Their Metabolism by Human CYP24A1 and UDP-glucuronosyltransferase (2012)
  • Author(s): Daisuke Sawada, Yuya Tsukuda, Kaori Yasuda, Toshiyuki Sakaki, Hiroshi Saito, Ken-ichiro Takagi, Kazuya Takenouchi, Tai C. Chen, G. Satyanarayana Reddy, and Atsushi Kittaka
  • Journal Title: Chem. Pharm. Bull Volume: 60 Pages: 1343-1346
  • DOI: 10.1248/cpb.c12-00526
  • Peer Reviewed
• [Journal Article] The Difference between 14-Epi-previtamin D_3 and 14-Epi-19-norprevitmain D_3: Their Synthesis and Binding Affinity for Human VDR (2012)
  • Author(s): Daisuke Sawada, Tomoyuki Katayama, Yuya Tsukuda, Nozomi Saito, Hiroshi Saito, Shinji Kakuda, Midori Takimoto-Kamimura, Kazuya Takenouchi, and Atsushi Kittaka
  • Journal Title: Anticancer Res Volume: 32 Pages: 319-326
  • Peer Reviewed
• [Journal Article] C15-functionalized 16-Ene-1α,25-dihydroxyvitamin D_3 is a New Vitamin D Analog with Unique Biological Properties (2012)
  • Author(s): Go Kumagai, Masashi Takano, Kanako Shindo, Daisuke Sawada, Nozomi Saito, Hiroshi Saito, Shinji Kakuda, Ken-ichiro Takagi, Midori Takimoto-Kamimura, Kazuya Takenouchi, Tai C. Chen, Atsushi Kittaka
  • Journal Title: Anticancer Res Volume: 32 Pages: 311-318
  • Peer Reviewed
• [Journal Article] 2alpha-(3-ヒドロキシプロピル)-1alpha,25-ジヒドロキシ-19-ノルビタミンD_3(MART-10)とその類縁体の合成と制がん活性等 (2012)
  • Author(s): 高野真史、澤田大介、橘高敦史、高木健一郎、千田貴之、原田善文、齋藤博、山本恵子、榊利之、Kun-Chun Chiang、Shasha Zheng、John N. Flanagan、Tai C. Chen
  • Journal Title: ビタミン Volume: 86 (12) Pages: 694-696
• [Journal Article] ヒト由来CYP24A1抵抗性ビタミンD誘導体合成とATRA耐性APL細胞分化誘導 (2012)
  • Author(s): 高野真史、松本直樹、林恵子、生城真一、榊利之、角田真二、高木健一郎、落合鋭士、堀江恭平、上村みどり、澤田大介、野尻久雄、橘高敦史
  • Journal Title: ビタミン Volume: 86 (4) Pages: 243
• [Journal Article] 14-エピ-19-ノルタキステロールの合成とVDRリガンド骨格としての可能性 (2012)
  • Author(s): 澤田大介、佃勇也、橘高敦史、齋藤博、角田真二、上村みどり、竹之内一弥
  • Journal Title: ビタミン Volume: 86 (3) Pages: 181-182
• [Journal Article] A Multivalent Probe for AI-2 Quorum-Sensing Receptors (2011)
  • Author(s): Amanda L. Garner, Junguk Park, Joseph S. Zakhari, Colin A. Lowery, Anjali Kumari Struss, Daisuke Sawada, Gunnar F. Kaufmann, and Kim D. Janda
  • Journal Title: J. Am. Chem. Soc Volume: 133 Pages: 15934-15937
  • Peer Reviewed
• [Journal Article] New C15-Substituted Active Vitamin D_3 (2011)
  • Author(s): Kanako Shindo, Go Kumagai, Masashi Takano, Daisuke Sawada, Nozomi Saito, Hiroshi Saito, Shinji Kakuda, Ken-ichiro Takagi, Eiji Ochiai, Kyouhei Horie, Midori Takimoto-Kamimura, Seiichi Ishizuka, Kazuya Takenouchi, Atsushi Kittaka
  • Journal Title: Org. Lett Volume: 13 Pages: 2852-2855
  • Peer Reviewed
• [Journal Article] Development of 14-epi-19-Nortachysterol and Its Unprecedented Binding Configuration for the Human Vitamin D Receptor (2011)
  • Author(s): Daisuke Sawada, Yuya Tsukuda, Hiroshi Saito, Shinji Kakuda, Midori Takimoto-Kamimura, Eiji Ochiai, Kazuya Takenouchi, and Atsushi Kittaka
  • Journal Title: J. Am. Chem. Soc Volume: 133 Pages: 7215-7221
  • Peer Reviewed
• [Journal Article] Evaluation and characterization of 14-epi-19-nortachysterol analogs from 14-epi-19-norprevitamin D_3 (2011)
  • Author(s): Daisuke Sawada, Yuya Tsukuda, Hiroshi Saito, Ken-ichiro Takagi, Shinji Kakuda, Midori Takimoto-Kamimura, Kazuya Takenouchi, and Atsushi Kittaka
  • Journal Title: Anticancer Res Volume: 31 Pages: 1501
• [Journal Article] Synthesis of C15-Modified 16-ene-active vitamin D_3 analogs for the receptor-ligand interaction studies (2011)
  • Author(s): Atsushi Kittaka, Go Kumagai, Masashi Takano, Daisuke Sawada, Hiroshi Saito, Shinji Kakuda, Ken-ichiro Takagi, Eiji Ochiai, Kyohei Horie, Kazuya Takenouchi, Midori Takimoto-Kamimura, and Tai C. Chen
  • Journal Title: Anticancer Res Volume: 31 Pages: 1500-1501
• [Journal Article] 2□位にアゾール環側鎖を有する活性型ビタミンD_3の合成と生物活性評価 (2011)
  • Author(s): 高野真史、松尾実紀、長谷川麻美、中村優子、齋藤博、角田真二、高木健一郎、落合鋭士、堀江恭平、上村みどり、竹之内一弥、澤田大介、橘高敦史
  • Journal Title: ビタミン Volume: 85 (4) Pages: 236
• [Journal Article] 変異VDR(Arg274Leu)に対するセコステロイドリガンドの設計と合成 (2011)
  • Author(s): 本澤忍、高橋尚志、山本康弘、荒井緑、高野真史、澤田大介、山下純、杉浦隆之、橘高敦史、角田真二、齋藤博、高木健一郎、上村みどり、石塚誠一、竹之内一弥、榊利之、加藤茂明、栗原正明
  • Journal Title: ビタミン Volume: 85 Pages: 166-167
• [Journal Article] Design and synthesis of 2α-(tetrazolylethyl)-1α,25-dihydroxyvitamin D_3 as a high affinity ligand for vitamin D receptor
  • Author(s): Miki Matsuo, Asami Hasegawa, Masashi Takano, Hiroshi Saito, Shinji Kakuda, Kenichiro Takagi, Eiji Ochiai, Kyohei Horie, Midori Takimoto-Kamimura, Kazuya Takenouchi, Daisuke Sawada, and Atsushi Kittaka
  • Journal Title: J. Steroid Biochem. Mol. Biol Volume: (in press)
  • DOI: 10.1016/j.jsbmb.2013.09.001
  • Peer Reviewed
• [Presentation] 14-エピ-8,9-ジヒドロ-1α,25-ジヒドロキシ-19-ノルタキステロールの合成 (2014)
  • Author(s): 澤田大介、他3名
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140327-30
• [Presentation] 14-epi-tachysterol類の合成、生物活性評価、及び受容体結合様式の解明 (2013)
  • Author(s): 澤田大介、他6名
  • Organizer: 第31回メディシナルケミストリーシンポジウム
  • Place of Presentation: 広島アステールプラザ
  • Year and Date: 20131120-22
• [Presentation] 7,8-cis-vitamin D_3類の合成、活性評価、及びVDR結合様式の解明 (2013)
  • Author(s): 澤田大介、他6名
  • Organizer: 第39回反応と合成の進歩シンポジウム
  • Place of Presentation: 九州大学
  • Year and Date: 20131105-06
• [Presentation] C5-C6 Coupling of MART-10 Synthesis and Its Clinical Implication in Cancer Treatment and Prevention (2013)
  • Author(s): Takano M.他11名内、Sawada D.含む
  • Organizer: 第10回カルボアニオン化学国際会議
  • Place of Presentation: ISCC-10、同志社大学
  • Year and Date: 20130923-26
• [Presentation] Synthesis of 14-Epi-19-Nortachysterol and Elucidation of Its Binding Affinity and Configuration for the Human Vitamin D Receptor (2013)
  • Author(s): Sawada D.他11名
  • Organizer: 14th Tetrahedron Symposium
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20130625-28
• [Presentation] DESIGN AND SYNTHESIS OF 2α-HETEROARALKYL-1α,25-DIHYDROXY VITAMIN D_3 ANALOGS AS STRONG LIGANDS FOR VITAMIN D RECEPTOR (2013)
  • Author(s): Matsuo M.他12名内、Sawada D.含む
  • Organizer: 16th Vitamin D Workshop
  • Place of Presentation: San Francisco, USA
  • Year and Date: 20130611-14
• [Presentation] 14-epi-tachysterol類の合成とVDR結合様式の解明 (2013)
  • Author(s): 澤田大介、他6名
  • Organizer: 日本ビタミン学会第65回大会
  • Place of Presentation: 東京
  • Year and Date: 20130517-18
• [Presentation] 7,8-cis-14-epi-19-Norvitamin D_3誘導体の合成と活性評価 (2013)
  • Author(s): 澤田大介、他4名
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 20130327-30
• [Presentation] 7,8-cis-1α,25(OH)_2-19-norvitamin D_3の合成と活性評価 (2013)
  • Author(s): 澤田大介、他6名
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 帝京大学
  • Year and Date: 2013-10-26
• [Presentation] Synthesis of 1α,2α,25-Trihydroxyvitamin D_3: Major Metabolite of 2α-(3-Hydroxypropoxy)-1α,25-dihydroxyvitami n D_3 by CYP3A4 (2012)
  • Author(s): Takano M.他12名内、Sawada D.含む
  • Organizer: チトクロームP450発見50周年記念シンポジウム
  • Place of Presentation: 九州大学医学部コラボレーション
  • Year and Date: 20121202-03
• [Presentation] Synthesis Of New C15-Substituted 16-Ene-1α,25-dihydroxyvitamin D_3 Analogs and The Receptor-ligand Interaction Studies (2012)
  • Author(s): Kittaka A.他14名内、Sawada D.含む
  • Organizer: 13th Tetrahedron Symposium
  • Place of Presentation: 台北
  • Year and Date: 20121127-30
• [Presentation] 2α-アルコキシ置換活性型ビタミンD_3誘導体の代謝と合成研究 (2012)
  • Author(s): 高野真史、他6名内、澤田大介含む
  • 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: タワーホール船堀
  • Year and Date: 20121105-06
• [Presentation] 14-epi-1α,25-dihydroxytachysterolの合成と生物活性評価 (2012)
  • Author(s): 澤田大介、他5名
  • Organizer: 第38回反応と合成の進歩シンポジウム
  • Place of Presentation: タワーホール船堀
  • Year and Date: 20121105-06
• [Presentation] 2α-ヘテロアラルキル活性型ビタミンD3の合成と生物活性:2α側鎖長の研究 (2012)
  • Author(s): 高野真史、他12名内、澤田大介含む
  • Organizer: 第42回複素環化学討論会
  • Place of Presentation: 京都テルサ
  • Year and Date: 20121011-13
• [Presentation] 14-epi-19-Nortachysterol as a New Lead Compound in Vitamin D Family and Its Unprecedented Binding Configuration for the Human Vitamin D Receptor (2012)
  • Author(s): Sawada D.他7名
  • Organizer: XXIInd International Symposium on Medicinal Chemistry
  • Place of Presentation: ISMC 2012, Berlin, Germany
  • Year and Date: 20120902-06
• [Presentation] REVISITING THE MINOR VITAMIN D FAMILY : A NEW TACHYSTEROL ANALOG AND ITS UNPRESEDENTED BINDING CONFIGURATION FOR THE HUMAN VITAMIN D RECEPTOR (2012)
  • Author(s): Sawada D.他8名
  • Organizer: 15th Vitamin D Workshop
  • Place of Presentation: Houston Intercontinental Hotel, USA
  • Year and Date: 20120620-22
• [Presentation] 1α,4,25-トリヒドロキシビタミンD_3の合成とヒト水酸化酵素による代謝に関する研究 (2012)
  • Author(s): 澤田大介、他7名
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 20120329-31
• [Presentation] 2alpha-(3-ヒドロキシプロピル)-1alpha,25-ジヒドロキシ-19-ノルビタミンD_3(MART-10)とその類縁体の合成と制がん活性等 (2012)
  • Author(s): 橘高敦史、他12名内、澤田大介含む
  • Organizer: 第336回脂溶性ビタミン総合研究委員会
  • Place of Presentation: 東京農業大学
  • Year and Date: 2012-09-28
• [Presentation] New Skeleton in Vitamin D Family : 14-epi-19-Nortachysterol and Its Unprecedented Binding Configuration for the Human Vitamin D Receptor (2011)
  • Author(s): Sawada D.他7名
  • Organizer: AIMECS-11
  • Place of Presentation: 8th AFMC International Medicinal Chemistry Symposium, Tokyo
  • Year and Date: 20111129-1202
• [Presentation] 14-epi-19-Nortachysterol類の合成と受容体結合様式の解明 (2011)
  • Author(s): 澤田大介、他6名
  • Organizer: 第37回反応と合成の進歩シンポジウム
  • Place of Presentation: 徳島
  • Year and Date: 20111107-08
• [Presentation] Evaluation and characterization of 14-epi-19-nortachysterol analogs from 14-epi-19-norprevitamin D_3 (2011)
  • Author(s): Sawada D.他7名
  • Organizer: 4th Symposium Vitamin D Analogs in Cancer Prevention and Therapy
  • Place of Presentation: Homburg, Germany
  • Year and Date: 20110520-21
• [Presentation] 14-エピ-19-ノルタキステロールの合成とVDRリガンド骨格としての可能性 (2011)
  • Author(s): 澤田大介、他6名
  • Organizer: 第332回脂溶性ビタミン総合研究委員会
  • Place of Presentation: 昭和薬科大学
  • Year and Date: 2011-09-30
• [Remarks]
  • URL: http://www.pharm.teikyo-u.ac.jp
• [Remarks]
  • URL: http://www.pharm.okayama-u.ac.jp/department/post-116.html