| Project/Area Number |
16K21362
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Chemical pharmacy
Drug development chemistry
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| Research Institution | Keio University |
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Principal Investigator |
HANAYA Kengo 慶應義塾大学, 薬学部(芝共立), 助教 (50637262)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | プロドラッグ / スルホン酸エステル / 分子内環化 / γ-スルタム / 自己分解 / 刺激応答性リンカー / チオール / 1,4-付加 / 1，4-付加 / チオール応答性蛍光プローブ / スルタム / Thorpe-Ingold効果 / 薬学 |
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| Outline of Final Research Achievements |
Prodrugs are drug precursors which are designed to be activated through enzymatic or chemical transformation in vivo microenvironment. Fast reaction kinetics of activation reactions are required to exert maximum biological activity with fewer side effects. We have proposed the sulfonate-based prodrug strategy: prodrugs with sulfonylester-based self-immolative linkers release active drugs through enzymatic cleavage of trigger moieties and successive intramolecular nucleophilic attack of terminal amino group to sulfonylester. In this strategy, intramolecular cyclization had been revealed to be a rate limiting step.
In this study, various substituents were introduced on terminal amino group and/or alkyl chain of sulfonylester-based linker and reaction kinetics of intramolecular cyclization were evaluated. With the results in hand, photo- and oxidation-sensitive prodrugs were designed and their properties were examined.
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| Academic Significance and Societal Importance of the Research Achievements |
新薬の創出が難しくなっている昨今、既存の薬の有効性を最大限向上させ、かつ副作用を低減させるプロドラッグの開発は創薬において重要である。近年急速に開発が進んでいる抗体-薬物複合体（ADC）もプロドラッグの一種である。特定の化学的刺激に応答し、薬物分子を迅速に放出する刺激応答性リンカーはプロドラッグの開発に欠かせない。本研究では、刺激応答性アミノスルホン酸エステルリンカーの化学構造と薬物放出速度を明らかにし、実用的なプロドラッグの創製に寄与する知見を得ることができた。
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