2004 Fiscal Year Final Research Report Summary
Design and Synthesis of Vitamin D Receptor Antagonists : Remedy for Pagets Desease
| Project/Area Number |
15590021
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Teikyo University |
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Principal Investigator |
KITTAKA Atsushi Teikyo University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00214833)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Nozomi Teikyo University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (80349258)
HONZAWA Shinobu Teikyo University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (90311547)
ARAI Midori Teikyo University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (40373261)
SUGIYAMA Toru The University of Tokyo, Department of Life Sciences, Research Associate, 大学院・総合文化研究科, 助手 (40242036)
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| Project Period (FY) |
2003 – 2004
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| Keywords | vitamin D receptor (VDR) / active vitamin D_3 / antagonist / agonist / TEI-9647 / Paget's disease / HL-60 cells / structure activity relationship |
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| Research Abstract |
Recently, compounds with vitamin D receptor (VDR) antagonistic activity have received considerable attention because of their possibility to treat for Paget's disease, which is the second most common bone disease after osteoporosis in Anglo-Saxons. It is known that 1α-hydroxyvitamin D_3-26,23-lactone (TEI-9647) shows VDR antagonistic activity (IC_<50> 8.3 nM), while this compound has low affinity for the VDR and instability in blood. We investigated to enhance the affinity for the VDR and stability in blood by modifying C2α and C24 positions of TEI-9647. In this project, we have developed the short step synthesis of the new CD-ring lactone parts of 24,24-dimethylated TEI-9647 using low-valent Cr-mediated allylation and 24,24-ethano TEI-9647 with a spiro-structure using Ru-catalyzed intermolecular enyne metathesis between alkynone and ethylene to give dienone followed by regioselective cyclopropanation. Stereochemistry at the C23 position on the new side chains of 24,24-dimethyl and 24,24-ethano lactone was determined based on their X-ray crystallographic analyses.
It was found that the synthesized 24,24-dimethylated TEI-9647 showed more than 12 fold higher anti-D activity than that of the first reported VDR-antagonist TEI-9647. Moreover, double modification at both C2α and C24 with methyl groups showed 89 times more potent antagonistic activity (IC_<50> 0.093 nM) than that of TEI-9647. As far as we know, this 2α,24,24-trimethyl analog of TEI-9647 is the most potent VDR-antagonist so far. 2α-Methyl-24,24-ethano analog of TEI-9647 showed more than 19 fold higher anti-D activity than that of TEI-9647.
We believe these analogs with potent anti-D activity would contribute to understanding the mechanisms involved in the expression of antagonistic activity on the VDR as well as to finding the seeds of new medicines for treating patients of Paget's disease.
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[Journal Article] Design and Efficient Synthesis of 2α-(ω-Hydroxyalkoxy)-lα, 25-dihydroxyvitamin D_3 Including 2-epi-ED-71 and Its 20-Epimers with HL-60 Cell Differentiation Activity2004
Author(s)
Nozomi Saito, Yoshitomo Suhara, Masaaki Kurihara, Toshie Fujishima, Shinobu Honzawa, Hitoshi Takayanagi, Toshiro Kozono, Masahiko Matsumoto, Masayuki Ohmori, Naoki Miyata, Hiroaki Takayama, Atsushi Kittaka
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Journal Title
J Org.Chem. 69(22)
Pages: 7463-7471
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] 24, 24-Dimethylvitamin D_3-26, 23-lactones and Their 2α-Functionalized Analogues as Highly Potent VDR Antagonists2004
Author(s)
Nozomi Saito, Manami Masuda, Toshihiro Matsunaga, Hiroshi Saito, Miyuki Anzai, Kazuya Takenouchi, Daishiro Miura, Seiichi Ishizuka, Midori Kamimura, Atsushi Kittaka
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Journal Title
Tetrahedron 60 (36)
Pages: 7951-7961
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] 2,2-Functionalized Analogues of 1α, 25-Dihydroxyvitamin D_3, The Potent Inducers of Cell Differentiation2004
Author(s)
Toshie Fujishima, Atsushi Kittaka, Masaaki Kurihara, Nozomi Saito, Shinobu Honzawa, Seishi Kishimoto, Takayuki Sugiura, Keizo Waku, Hiroaki Takayama
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Journal Title
J.Steroid Biochem.Mol.Biol. 89-90 (May)
Pages: 89-92
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Synthesis of Novel 1α, 25-Dihydroxy-19-norvitamin D_3 with an Amide Conjugate2004
Author(s)
Yoshitomo Suhara, Keiichiro Ono, Akihiro Yoshida, Toshie Fujishima, Nozomi Saito, Shinobu Honzawa, Seishi Kishimoto, Takayuki Sugiura, Keizo Waku, Hiroaki Takayama, Atsushi Kittaka
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Journal Title
Heterocycles 62(1)
Pages: 423-436
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Dramatic Enhancement of Antagonistic Activity on Vitamin D Receptor : A Double Functionalization of 1α-Hydroxyvitamin D3-26,23-Lactones2003
Author(s)
Nozomi Saito, Hiroshi Saito, Miyuki Anzai, Kazuya Takenouchi, Daishiro Miura, Seiichi Ishizuka, Toshie Fujishima, Akihiro Yoshida, Hiroaki Takayama, Atsushi Kittaka
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Journal Title
Org.Lett. 5 (25)
Pages: 4859-4862
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Remarkable Effect of 2α-Modification on the VDR Antagonistic Activity of 1α-Hydroxyvitamin D_3-26,23-Lactones2003
Author(s)
Nozomi Saito, Toshihiro Matsunaga, Toshie Fujishima, Miyuki Anzai, Hiroshi Saito, Kazuya Takenouchi, Daishiro Miura, Seiichi Ishizuka, Hiroaki Takayama, Atsushi Kittaka
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Journal Title
Org.Biomol.Chem. 1(24)
Pages: 4396-4402
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Synthesis of 2-Modified 1α,25-Dihydroxy-19-norvitamin D_3 with Julia Olefination: High Potency in Induction of Differentiation on HL-60 Cells2003
Author(s)
Keiichiro Ono, Akihiro Yoshida, Nozomi Saito, Toshie Fujishima, Shinobu Honzawa, Yoshitomo Suhara, Seishi Kishimoto, Takayuki Sugiura, Keizo Waku, Hiroaki Takayama, Atsushi Kittaka
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Journal Title
J.Org.Chem. 68(19)
Pages: 7407-7415
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Concise Synthesis and Biological Activities of 2α-Alkyl-and 2α-(ω-Hydroxyalkyl)-20-epi-1α,25-Dihydroxyvitamin D_32003
Author(s)
Shinobu Honzawa, Yoshitomo Suhara, Ken-ichi Nihei, Nozomi Saito, Seishi Kishimoto, Toshie Fujishima, Masaaki Kurihara, Takayuki Sugiura, Keizo Waku, Hiroaki Takayama, Atsushi Kittaka
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Journal Title
Bioorg.Med.Chem.Lett. 13(20)
Pages: 3503-3506
Description
「研究成果報告書概要(欧文)」より
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