| Project/Area Number |
22590102
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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 |
Drug development chemistry
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| Research Institution | Gifu Pharmaceutical University |
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Principal Investigator |
HARA Akira 岐阜薬科大学, 薬学部, 教授 (00094334)
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| Co-Investigator(Renkei-kenkyūsha) |
ENDO Satoshi 岐阜薬科大学, 薬学部, 助教 (60433207)
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| Research Collaborator |
TOYOOKA Naoki 富山大学, 工学部, 教授
KATO Atsushi 富山大学, 医学部, 准教授
EL-KABBANI Ossama Monash 大学, 薬学部, 准教授
MATSUNAGA Toshiyuki 岐阜薬科大学, 薬学部, 准教授
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2012: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2010: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
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| Keywords | 医薬品化学・医薬分子設計 / ヒドロキシステロイド脱水素酵素 / アルドーケト還元酵素 / 制癌剤 / 抗癌剤耐性 / 阻害剤 / 高次構造 / アルドース還元酵素 / 医薬品設計 |
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| Research Abstract |
Five aldo-keto reductases (AKR1C1, AKR1C3, AKR1C21, AKR1B1 andAKR1B10) are regarded as both diagnostic markers and therapeutic targets in the treatment of several types of cancer. We searched inhibitors of the enzymes, investigated selectivity determinants of the inhibitor-binding to the enzymes, and synthesized potent and selective inhibitors. (1) AKR1C1 inhibitor: Potent salicylic acid-based inhibitorswere synthesized based on the crystal structure of the enzyme. (2) AKR1C3 inhibitor: Among the inhibitors found, tolfenamic acid and baccharin were the most potent and selective inhibitors, respectively. A baccharin derivative with high inhibitory potency and selectivity was synthesized. (3) AKR1C21 inhibitor: Cholanic acid and its derivatives were found to be potent inhibitors. (4) AKR1B1 inhibitor: A selective and potent inhibitorwas synthesized based on the structure of an alkaloid rhetsinine. (4) AKR1B10 inhibitor:Some drugs (such as mefenamic acid) and natural products (mangostin, oleanolic acid,caffeic acid phenethyl ester) were found to be selective inhibitors. A caffeic acid phenethyl ester derivative with high inhibitory potency and selectivity was synthesized.
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