2000 Fiscal Year Final Research Report Summary
De novo design and synthesis of aromatic vitamain D analogs having rigid three-dimensional structure and differential activity
| Project/Area Number |
11694253
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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 |
医薬分子機能学
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
YAMADA Sachiko Tokyo Medical and Dental University, Institute of Biomaterials and Bioengineering Professor, 生体材料工学研究所, 教授 (10014078)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Keiko Tokyo Medical and Dental University, Institute of Biomaterials and Bioengineering Research Associate, 生体材料工学研究所, 助手 (90147017)
SHIMIZU Masato Tokyo Medical and Dental University Institute of Biomaterials and Bioengineering Associate Professor, 生体材料工学研究所, 助教授 (50126231)
REISCHL Wolfgang University of Vienna Institute of Organic Chemistry Associate Professor
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| Project Period (FY) |
1999 – 2000
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| Keywords | Vitamin D / Nuclear receptor / Homology modeling / Analogs / Non-steroid vitamin D / Differential action / Structure-function relationship / Three-dimensional structure |
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| Research Abstract |
1) Three-dimensional structure of vitamnin D receptor ligand-binding domain (VDR-LBD) was homology modeled based on the crystal structure of LBD of human retinoic acid receptor g (hRAR g). The natural ligand, 1,25-(OH) 2D3, was docked in the VDR-LBD and amino acid residues facing ligand binding pocket (LBP) and interacting with the ligand were identified. The model structure was substantiated by alanine scanning mutation analysis of the putative key amino acids interacting with ligand The model structure and ligand-docking manner were essentially the same as the crystal structure of VDR-LBD deletion mutant (VDR D 165-215) which was disclosed simultaneously.
2) Based out the VDR model, some ten non-steroid vitamnin D analogs having aromatic rings for the CD-and A-ring systems were designed and synthesized. The aromatic CD-and A-rings were successfully coupled by using Suzuki method. Biological activities of these compounds are now under examination. Fluorinated A-ring analogs were also synthesized. Also new stereoselective synthetic method for A-ring synthon of 19-norvitamin D derivatives was established starting from D-glucose.
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Research Products
(44 results)
