Synthetic Studies on a Neuroexcitotoxic Amino Acid, Dysiherbaine
| Project/Area Number |
09680563
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Bioorganic chemistry
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
SASAKI Makoto The University of Tokyo, School of Science, Assistant, 大学院・理学系研究科, 助手 (80235267)
|
|---|
| Project Period (FY) |
1997 – 1998
|
| Project Status |
Completed (Fiscal Year 1998)
|
| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥2,200,000 (Direct Cost: ¥2,200,000)
|
|---|
| Keywords | Dysiherbaine / Neuroexcitotoxin / Amino Acid / Glutamate / Agonist / 全合成 |
|---|
| Research Abstract |
Dysiherbaine 1, recently isolated as a neuroexitotoxin from a Micronesian marine sponge Dysidea herbacea, is a potent agonist of non-NMDA (N-methyl-D-aspartate) subtype glutamate receptors in the central nervous system. The structure of 1 was determined to be an unprecedented diamino dicarboxylic acid, which consists of a structurally novel cis-fused hexahydrofuro [3,2-b] pyran ring system containing a glutamate substructure. Due to its unique skeletal structure and potent neuroexitatory activity, 1 may become a useful leading compound for development of selective and powerful agonists or antagonists of glutamate receptors ; however, its supply from natural source is very limited.
In the course of our studies directed toward total synthesis of 1, we have accomplished a synthesis of the structurally simplified model compound A, which lacks the hydroxyl and methylamino groups on the tetrahydropyran ring, and its C4 diastereomer B.Stereoselective synthesis of the fully fuctionalized bicyclic core of 1 was also achieved.
The toxicity of model compounds A and B was tested on mice as a preliminary investigation. Intracerebral injection of A (20 mg/mouse) in mice induced typical convulsive behaviors such as violent scratching, which was also observed for dysiherbaine (10-40 pmol/mouse). Interestingly, however, mice became hypoactive and rigid with occasional scratching behavior and eventually went into a deep sleeplike state. All mice recovered from these symptoms gradually and behaved apparently normal on the next day. Diastereomeric compound B did not induce neither typical convulsive behavior nor "sleeper" activity, suggesting that the stereochemistry at C4 quaternary carbon is important for this activity.
|
Report
(3 results)
Research Products
(3 results)
