| Project/Area Number |
16390032
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Drug development chemistry
|
|---|
| Research Institution | Tohoku Pharmaceutical University |
|---|
Principal Investigator |
ENDO Yasuyuki Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Professor (80126002)
|
|---|
| 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)
|
|---|
| Project Period (FY) |
2004 – 2007
|
| Project Status |
Completed (Fiscal Year 2007)
|
| Budget Amount *help |
¥15,100,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥900,000)
Fiscal Year 2007: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2006: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2005: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥4,600,000 (Direct Cost: ¥4,600,000)
|
|---|
| Keywords | medicinal drug design / nuclear receptor / estrogen receptor / androgen receptor / hydrophobic interaction / antagonist / boron cluster / molecular recognition / レチノイドX受容体 |
|---|
| 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.
|
