2007 Fiscal Year Final Research Report Summary
Development and Application of Novel 3-Dimensional Hydrophobic Structures for Drug Design, Which Are Focused on Molecular Recognition between Ligand and Receptor
| Project/Area Number |
16390032
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Tohoku Pharmaceutical University |
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Principal Investigator |
ENDO Yasuyuki Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Professor (80126002)
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| Co-Investigator(Kenkyū-buntansha) |
INOMATA Kohei Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Lecturer (60221785)
OHTA Kiminori Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant Professor (90347906)
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| Project Period (FY) |
2004 – 2007
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| Keywords | medicinal drug design / nuclear receptor / estrogen receptor / androgen receptor / hydrophobic interaction / antagonist / boron cluster / molecular recognition |
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| Research Abstract |
Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having globular shape, remarkable thermal stability and hydrophobic character. In this study, we applied their molecular shape and hydrophobic surface of the molecules to design and synthesis of nuclear receptor ligands. Hydrophobic and hydrogen bonding interaction of carborane derivatives, and synthetic methods of carborane derivatives for analysis and preparation of various carborane-containing compounds were also investigated. The results were summarized as follows.
1. Candidate estrogen receptor ligands with two phenolic residues on a 3-dimensional hydrophobic core structure (carborane, bicyclo[2, 2, 2]octane, adamantane) were synthesized and biologically evaluated. Amog the carborane-containing compounds, a dynamic change of agonist/antagonist balance was observed depending on the direction and the distance of the two phenolic groups.
2. Candidate androgen receptor ligands bearing carborane as a hydrophobic pharmacophore were designed based on testosterone and aromatic anti-estrogen agents, and synthesized, biologically evaluated. Novel potent non-steroidal androgen antagonists BA321, BA341 were found.
3. Intramolecular hydrogen bonding on 2-(2-hydroxyphenyl)-o-carborane and 2-(2-hydroxyphenyl)-p-carborane were observed on H-NMR study. The intranolecular hydrogen bonding was confirmed by X-ray, IR and DFT calculation.
4. A few synthetic method of carborane derivatives, such as regioselective iodination reaction on the carborane cage, facile hydroxylation of a carbon on, the carborane cage were developed.
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[Journal Article] Identification of an Intermediate in the Deboronation of ortho-Carborane : an Adduct of ortho-Carborane with Two Mucleophiles on One Boron Atom2008
Author(s)
Taoda, Y., Sawabe, T., Endo, Y.*, Yamaguchi, K., Fujii, S., Kagechika, H.*
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Journal Title
Chem. Commun
Pages: 2049-2051
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Proton-Driven Conformational Change in a 2-Aryl-p-carborane Constrained by an Intramolecular C-H-O Hydrogen Bond2007
Author(s)
K. Ohta, K., Yamazaki, H., Kawahata, M., Yamaguchi, K., Pichierri, F., Endo. Y.*
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Journal Title
Tetrahedron. Lett 48
Pages: 5231-5234
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Solid-state Supramolecular Array through Cooperative tt-it Interactions of -(2-Methoxyphenyl)-o-carborane2007
Author(s)
Ohta, K., Yamazaki, H., Pichierri, F., Kawahata, M., Yamaguchi, K., Endo, Y.*
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Journal Title
Tetrahedron 63
Pages: 12160-12165
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] m-Carborane Bisphenol Structure as a Pharmacophore for Selective Estrogen Receptor Modulators2006
Author(s)
Ogawa, T., Ohta K, Yoshimi, T., Yamazaki, H., Suzuki, T., Ohta, S., Endo, Y.*
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Journal Title
Bioorg. Med. Chem. Lett 16
Pages: 3943-3946
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Genetic and Pharmacological Evidence that a Retinoic Acid Cannot be the RXR-activating Ligand in Mouse Epidermis Keratinocytes2006
Author(s)
Calleja, C., Messaddeq, N., Chapellier, B., Yang, H., Krezel, W., Li, M., Metzger, D., Marcrez, B., Ohta, K., kagechika H, Endo, Y., Mark, M., Ghyselinck, N. B., Chambon, P.*
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Journal Title
Genes Dev 20
Pages: 1525-1538
Description
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[Journal Article] A Distorted Benzene Bearing Two Bulky Substituents on Adjacent Positions : Structure of 1, 2-Bis(I, 2-Dicarba-closo-dodecaboran-1-yl)benzene2005
Author(s)
Endo, Y.*, Songkram, C., Ohta, K., Kaszynski, P., Yamaguchi, K
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Journal Title
Tetrahedron Lett 46
Pages: 699-702
Description
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[Journal Article] Potent Androgen Antagonists Based on Carborane As a Hydrophobic Core Structure.2005
Author(s)
Fujii, S., Goto, T., Ohta, K., Hashimoto, Y., Suzuki, T., Ohta, S., Endo, Y.*
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Journal Title
J. Med. Chem 48
Pages: 4654-4662
Description
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[Journal Article] A comparison of Mesogenic Properties of p-Carborane-1, 12-dicarbaldehyde Schiff Bases with Their Terephthaldehyde Analogues2005
Author(s)
Nagamine, T., Januszko, A., Ohta, K., Kaszynski, P., Endo, Y
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Journal Title
Liq. Cryst 32
Pages: 985-995
Description
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[Journal Article] Structural Effects in Three-Ring Mesogenic Derivatives of p-Carborane and Their Hydrocarbon Analogs2004
Author(s)
Ohta, K., Januszko, A., Kaszynski, P., Nagamine, T., Sasnouski, G., Endo, Y
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Journal Title
Liq. Cryst 31
Pages: 1-12
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A New Application of Inorganic Cluster, Carboranes for Medicinal Drug Design and Molecular Construction2004
Author(s)
Endo, Y.*, Ohta, K., Yoshimi, T., Yamaguchi, K
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Journal Title
Phosphorous, Sulfur, and Silicon 179
Pages: 799-802
Description
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[Presentation] Potent Estrogen Receptor Modulators Based on 3-Dimensional Hydrophobic Core Structure2006
Author(s)
Endo, Y., Ogawa, T., Yoshimi, T., Ohta, K., Suzuki, T., Ohta, S
Organizer
The 30th National Medicinal Chemistry Symposium
Place of Presentation
Seattle, WA, US
Year and Date
20060600
Description
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[Presentation] Structure-activity study of nuclear androgen receptor(AR) antagonistd bearing carborane as a hydrophobic pharmacophore2005
Author(s)
Goto, T., Ohta, K., Endo, Y., Suzuki, T., Ohta, S
Organizer
The 12th International Conference on Boron Chemistry
Place of Presentation
Sendai, Japan
Year and Date
20050900
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Design, Synthesis and biological evaluation of estrogen receptor modulators with m-carborane as a hydrophobic pharmacophore2005
Author(s)
Ogawa, T., Ohta, K., Endo, Y., Suzuki, T., Ohta, S
Organizer
The 12th International Conference on Boron Chemistry
Place of Presentation
Sendai, Japan
Year and Date
20050900
Description
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