2000 Fiscal Year Final Research Report Summary
Practical access to asymmetric synthesis of vitamin D derivatives based on ene reaction
| Project/Area Number |
10555319
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B).
|
| Allocation Type | Single-year Grants |
|---|
| Section | 展開研究 |
|---|
| Research Field |
Synthetic chemistry
|
|---|
| Research Institution | Tokyo Institute of Technology |
|---|
Principal Investigator |
MIKAMI Koichi Tokyo Inst. Tech., Fac. Eng., Prof., 大学院・理工学研究科, 助教授 (10157448)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OKANO Toshio Kobe Pharm. Univ., Fac. Pharm. Prof., 薬学部, 教授
|
|---|
| Project Period (FY) |
1998 – 2000
|
| Keywords | Vitamin D / Ene reaction / Asymmetric catalysis / Vitamin D derivatives / Asymmetric synthesis / Biological activity / Differentiation |
|---|
| Research Abstract |
Growing interests have been focused on the development of hybrid-analogs with modifications of the A-ring and the side chain of 1α, 25-dihydroxyvitamin D_3 [1α, 25(OH)_2D_3]. An exocyclic methylene group at C-10, a hydroxy group at C-1 and a hydroxy group at C-3 play a crucial role in the expression of biological activities of 1α, 25(OH)_2D_3. However, relationship between the functional groups and activities has not been fully understood. We have synthesized and evaluated biological activities of several singly dehydrated A-ring analogs of 19-nor-1α, 25(OH)_2D_3 and 19-nor-22-oxa-1α, 25(OH)_2D_3. All of them have an extremely low binding affinity for vitamin D receptor (VDR). Some of them lack the 1a-hydroxy group that is considered to be essential for VDR-mediated gene expression, have greater or equivalent potencies to 1α, 25(OH)_2D_3 for inducing differentiation and cell cycle G0-G1 arrest of human promyelocytic leukemia cells as well as for the transactivation of target genes including a rat 25-hydroxyvitamin D3-24-hydroxylase gene promoter and a human osteocalcin gene promoter in transfected mammalin cells. The assessment of a ligand/VDR/Retinoid X receptor complex formation using a two-hybrid luciferase assay revealed that the liganded VDR has high potency to form a heterodimer, but this could not explain the high biological potency of the 19-nor analogs. Other reasons including an interaction with transcriptional cofactors should be considered to explain the mechanism of action of 19-nor analogs.
|
