Open AccessSynthesis and radioprotective effects of novel hybrid compounds containing edaravone analogue and 3‐ n ‐butylphthalide ring‐opening derivatives
Author(s) -
Li Xuejiao,
Wang Xinxin,
Miao Longfei,
Liu Yahong,
Lin Xiaona,
Guo Yuying,
Yuan Renbin,
Tian Hongqi
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16557
Subject(s) - edaravone , in vivo , apoptosis , progenitor cell , pharmacology , stem cell , haematopoiesis , chemistry , oxidative stress , caspase 3 , dna damage , in vitro , cancer research , microbiology and biotechnology , biochemistry , biology , programmed cell death , dna
Abstract As the potential risk of radiation exposure is increasing, radioprotectors studies are gaining importance. In this study, novel hybrid compounds containing edaravone analogue and 3‐ n ‐butylphthalide ring‐opening derivatives were synthesized, and their radioprotective effects were evaluated. Among these, compound 10a displayed the highest radioprotective activity in IEC‐6 and HFL‐1 cells. Its oral administration increased the survival rates of irradiated mice and alleviated total body irradiation (TBI)‐induced hematopoietic damage by mitigating myelosuppression and improving hematopoietic stem/progenitor cell frequencies. Furthermore, 10a treatment prevented abdominal irradiation (ABI)‐induced structural damage to the small intestine. Experiment results demonstrated that 10a increased the number of Lgr5 + intestinal stem cells, lysozyme + Paneth cells and Ki67 + transient amplifying cells, and reduced apoptosis of the intestinal epithelium cells in irradiated mice. Moreover, in vitro and in vivo studies demonstrated that the radioprotective activity of 10a is associated to the reduction of oxidative stress and the inhibition of DNA damage. Furthermore, compound 10a downregulated the expressions of p53, Bax, caspase‐9 and caspase‐3, and upregulated the expression of Bcl‐2, suggesting that it could prevent irradiation‐induced intestinal damage through the p53‐dependent apoptotic pathway. Collectively, these findings demonstrate that 10a is beneficial for the prevention of radiation damage and has the potential to be a radioprotector.