| Project/Area Number |
15590066
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Biological pharmacy
|
|---|
| Research Institution | Tohoku Pharmaceutical University |
|---|
Principal Investigator |
NUMAZAWA Mitsuteru Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (90006338)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
NAGAOKA Masao Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (00104084)
WATARI Yoko Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手
HANDA Wakako Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手
TAKAHASHI Madoka Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手
|
|---|
| Project Period (FY) |
2003 – 2005
|
| Project Status |
Completed (Fiscal Year 2005)
|
| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
|
|---|
| Keywords | Aromatase / Inhibitor / Anti-breast cancer agent / Hydroxylation / Stereochemistry / Structure-activity relationship / Suicidal substrate / Carbon -carbon bond cleavage reaction / 炭素-炭素結合切断 / 不活性化機構 / 阻害活性 / 19-置換3-デオキシアンドロゲン / 重水素標識 / 同位体効果 / 芳香核化反応 / ヒト胎盤ミクロゾーム / 3-デオキシアンドロゲン / トリチウム標識 |
|---|
| Research Abstract |
In order to gain insight into the aromatase reaction mechanisms, we explored aromatase reactions of the powerful aromatase inhibitors 3-deoxyandrogens, 3-deoxyandrostenedione (1)and 3-deoxydehydroepiandrosterone (2), in relation to the stereomechanisms of the 19-oxygenation and the C(10)-C(19)bond cleavage reaction.
1.Treatment of the 19-oxo derivatives of compounds 1 and 2, steroids 5 and 6, with NaB^2H_4 or NaB^3H_4 produced the corresponding [19,19^<-2>H_2] 19-ols 3 and 4 or [19R^<-3>H]-ols 3 and 4 as well as their [19S^<-3>H] isomers.
2.Incubation of [19, 19^<-2>H_4] 3 and 4 with human placental microsomes in the presence of NADPH produced the 19-oxo metabolites 5 and 6, respectively, where the deuterium isotope effect was not observed in each case.
3.[19R^<-3>H]- and [19S^<-3>H] 3 and 4 were also incubated with the microsomes described above, and ^3H_2O and ^3HCOOH released into the incubation mixtures were analyzed. The results indicate that a 19-pro-R hydrogen in stereospecifically eliminated in the conversion of Steroid 4 into the 19-oxo steroid 6 whereas a selectivity of 75 : 25 for pro-R : pro-S is observed in the case of steroid 3. In both cases, the C(10)-C(19) bond cleavage reaction, yielding ^3HCOOH, was established.
4.Structure-activity relationships of 4-substituted derivatives of inhibitor 1,2α-substituted ADs as well as 2, 4, or 6-substituted estrogens as aromatase inhibitors were also studied in relation to elucidate the spatial nature of the active site of aromatase.
|
