標的部位の微小環境に由来する化学的な刺激に応答し、薬物を放出するプロドラッグの開発は、薬の有効性の向上、および副作用の低減、の両面で重要である。化学的刺激への応答速度が速ければ、狙った場所でのみプロドラッグを活性化することができる。本研究課題では、刺激応答性アミノスルホン酸エステルリンカーを開発し、その化学構造と薬物の放出速度の関係を明らかにした。そしてその結果をふまえ新たな化学構造を持つプロドラッグの開発を試みた。
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.

研究種目 : 若手研究(B)
研究期間 : 2016～2018
課題番号 : 16K21362
研究分野 : 生物有機化学