1996 Fiscal Year Final Research Report Summary
Activation Mechanism of Prodrugs Releasing 5-Fluorouracil by Radiolytic Reduction
| Project/Area Number |
07455339
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
工業物理化学
|
|---|
| Research Institution | Kyoto University |
|---|
Principal Investigator |
NISHIMOTO Sei-ichi Kyoto University Energy and Hydrocarbon Chemistry Professor, 工学研究科, 教授 (10115909)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OHOTANI Bunsho Instructor, 工学研究科, 助手 (80176924)
KITAGAWA Toshikazu Kyoto University Energy and Hydrocarbon Chemistry Lecturer, 工学研究科, 講師 (20183791)
FUJITA Shin-ichi University of Osaka Prefecture Research Institute of Advanced Technology Associa, 先端科学研究所, 助教授 (60100210)
TAKEUCHI Kenichi Kyoto University Energy and Hydrocarbon Chemistry Professor, 工学研究科, 教授 (50026358)
|
|---|
| Project Period (FY) |
1995 – 1996
|
| Keywords | Radiation-Activating Prodrugs / Radiolytic Reduction / 5-Fluorouracil / N (1) -C (5) -Linked Dimer / Electrochemical Synthesis / 2-Oxo Compounds / pi^<**>-sigma^<**>Orbital Overlap / Pulse Radiolysis |
|---|
| Research Abstract |
Various 1- (5FU) -substituted compounds possessing alpha-carbonyl group were synthesized to study activation mechanism via radiolytic reduction and structural effects on the rate selectivity of 5-fluorouracil (5FU) releasing reaction. The following results were obtained.
(1) Investigation the effect of reducting additives (aromatic amines and low valent transition metal ions) on the radiolytic reduction reactivity of homo-and hetero-dimers of 5FU,we concluded activation mechanism by which dimer radical anions release F^-ions preferentially to form oxidizing 5-yl radicals that undergo hydrolysis to release 5FU.
(2) Various 2-oxo compounds bearing releasing 5FU were synthesized to correlate the nucleophilic substitution by S_<RN>^1 mechanism with the activation mechanism of 5FU releasing via radiolytic reduction.
(3) X-Ray crystallography of 1- (5FU)-substituted compounds demonstrated degree of overlapping between carbonyl pi^<**>-orbital and sigma^<**>-orbital of C-N bond. This structural characteristics was correlated with one-electron reduction potential and activation mechanism of 5FU releasing.
(4) In the case of 4-substituted cyclohexanone derivatives possessing 2-oxo group the pi^<**>-sigma^<**> orbital overlapping is significantly different between cis and trans isomers, thereby the 5FU releasing reactivity was critically altered.
(5) The 5FU/uracil dimer released 5FU by OH radical reaction in the sonolysis of aqueous solution.
(6) On the basis of theoretical organic chemistry, the quantitative structure-activity relationship was characterized to get insight into molecular design of radiation activating prodrugs that is able to release antitumor 5FU via one-electron reduction.
|
