| Project/Area Number |
09672246
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Tohoku College of Pharmacy |
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Principal Investigator |
NUMAZAWA Mitsuteru Tohoku College of Pharmacy, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (90006338)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Keiko Tohoku College of Pharmacy, Faculty of Pharmaceutical Sciences, Assistant Profes, 薬学部, 助手
YOSHIMURA Akiko Tohoku College of Pharmacy, Faculty of Pharmaceutical Sciences, Assistant Profes, 薬学部, 助手
橘 美伊 東北薬科大学, 薬学部, 助手
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | Aromatase Inhibitor / 6-Alkyl steroid / 3-Deoxy steroid / Aromatization / 19-Oxygenation / Gas chromatography / Mass spectrometry / Breast cancer / アロマターゼ / 阻害剤 / 6-アルキルアンドロゲン / 芳香核化反応 / 乳ガン化学療法剤 |
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| Research Abstract |
We have obtained the following results by the project carried out at 1997 and 1998
1. Kinetics of aromatization of suicide substrates of aromatase, DELTA^<1_>, DELTA^<6_> and DELTA^<1.6_> androstenediones (AD) and their 6-alkyl analogs, with human placental aromatase was analyzed by GC-MS.DELTA^<1_>-AD was a good substrate for the enzyme and its aromatization rate was comparable with that of AD, in contrast, DELTA^<6_> and DELTA^<1.6_>-AD's were the poor substrates. The stereochemistry and length of the 6-alkyl group affected the aromatization to a different extent in each series. There was no direct correlation etween the K_i and K_m values for the inhibitors but the aromatization of DELTA^<1_> and DELTA^<1.6_> AD analogs correlated well to their inactivation reactions.
2. [19^<_3>H, 4-^<_14>C]-DELTA^<1_>-AD synthesized chemically, was aromatized accompanying with the release of ^3H_20 and ^3HCOOH, indicating that DELTA^1-AD aromatizes via the same mechanism involved in the AD aromatization.
3. Structure-activity relationships of 6-phenylaliphatic AD's as well as their DELTA^<1_>, DELTA^<6_>, and DELTA^<1.6_> analogs as aromatase inhibitors inactivators showed new aspects for a binding manner of the inhibitors to the active site.
4. Three regioisomers of AD having a double-bond in A, B-ring system as well as 3-deoxy steroids was oxygenated at C-19 position with aromatase.
5.19-Oxygenated 4beta, 5beta-epoxy AD's were aromatized to estrone with aromatiase.
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