Design, synthesis and biological evaluation of 2-pyrrolone derivatives as radioprotectors
Design, synthesis and biological evaluation of 2-pyrrolone derivatives as radioprotectors
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DOI：
10.1016/j.bmc.2022.116764
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发表时间：
2022-05-27
影响因子：
3.5
通讯作者：
Aoki，Shin
中科院分区：
文献类型：
--
作者：
Satoh，Hidetoshi;Ochi，Shintaro;Aoki，Shin
已知p53是一种重要的转录因子，在电离辐射（IR）诱导的DNA损伤反应如细胞周期阻滞、DNA修复和凋亡中起核心作用。我们以前报道过调节p53蛋白是通过减少放射治疗的急性副作用来调节细胞命运的有效策略。在此，我们报告的发现STK 160830作为一种新的辐射防护剂从化学图书馆在东京大学和设计，合成和生物学评价其衍生物。STK 160830本身及其衍生物的辐射防护活性，在这项工作中合成的评价使用白血病细胞系，MOLT-4细胞作为正常细胞的模型，表达p53蛋白的结构-活性关系（SAR）的研究。实验结果表明，这些STK 160830衍生物对p53表达水平的抑制作用与其辐射防护活性之间存在直接关系，STK 160830衍生物对p53的抑制有助于保护MOLT-4细胞免于因辐射暴露而诱导的凋亡。
It is known that p53 is an important transcription factor and plays a central role in ionizing radiation (IR)-induced DNA damage responses such as cell cycle arrest, DNA repair and apoptosis. We previously reported that regulating p53 protein is an effective strategy for modulating cell fate by reducing the acute side effects of radiation therapy. Herein, we report on the discovery of STK160830 as a new radioprotector from a chemical library at The University of Tokyo and the design, synthesis and biological evaluation of its derivatives. The radioprotective activity of STK160830 itself and its derivatives that were synthesized in this work was evaluated using a leukemia cell line, MOLT-4 cells as a model of normal cells that express the p53 protein in a structure–activity relationships (SAR) study. The experimental results suggest that a direct relationship exists between the inhibitory effect of these STK160830 derivatives on the expression level of p53 and their radioprotective activity and that the suppression of p53 by STK160830 derivatives contribute to protecting MOLT-4 cells from apoptosis that is induced by exposure to radiation.