Cysteine-responsive, cyano-functionalized acenaphthopyrazine derivative for tumor microenvironment modulation-based chemotherapy sensitization and side effect reduction†

Abstract

Drug resistance and serious side effects are persistent obstacles in chemotherapy. Tumor microenvironment modulation is an emerging strategy to sensitize chemotherapy; however, the relevant side effects caused by chemotherapeutic drugs remain non-negligible. Herein, we constructed a cysteine-reactive, cyano-functionalized acenaphthopyrazine derivative for cisplatin sensitization and side effect reduction by regulating the tumor microenvironment. The developed cyano-functionalized acenaphthopyrazine derivative exhibited appropriate reactivity toward cysteine via an addition reaction. The incorporation of the cyano group not only improved the cellular uptake efficiency of cisplatin but also suppressed the drug inactivation behavior of tumor cells by reducing the expression of GSH within tumor cells. Moreover, selective inhibition of tumor cells was achieved due to the differing GSH dependence between normal and tumor cells. Most importantly, in vivo experiments revealed that the combination of the cyano-functionalized acenaphthopyrazine derivative with cisplatin could efficiently reduce liver and kidney damage during treatment. Our results demonstrated that cysteine consumption could serve as a general strategy for chemotherapy sensitization.