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Discovery and radiosensitization research of ursolic acid derivatives as SENP1 inhibitors
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2021-10-14 , DOI: 10.1016/j.ejmech.2021.113918
Huiqiang Wei 1 , Jianghong Guo 1 , Xiao Sun 2 , Wenfeng Gou 1 , Hongxin Ning 1 , Zhennan Fang 1 , Qiang Liu 1 , Wenbin Hou 1 , Yiliang Li 1
Affiliation  

SUMOylation and deSUMOylation plays an important role in DNA damage response and the formation of radiotherapy resistance. SENP1 is the main specific isopeptidase to catalyze deSUMOylation modification. Inhibiting SENP1 upregulates cancer cell radiosensitivity and it becomes a promising target for radiosensitization. Herein, based on the structure of ursolic acid (UA), a total of 53 pentacyclic triterpene derivatives were designed and synthesized as SENP1 inhibitors. Ten derivatives exhibited better SENP1 inhibitory activities than UA and the preliminary structure-activity relationship was discussed. Most of the UA derivatives were low-cytotoxic, among which compound 36 showed the best radiosensitizing activity with the SER value of 1.45. It was the first study to develop small molecular SENP1 inhibitors as radiosensitizers.



中文翻译:


SENP1抑制剂熊果酸衍生物的发现及放射增敏研究



SUMO化和去SUMO化在DNA损伤反应和放疗抵抗的形成中发挥着重要作用。 SENP1是催化去SUMO化修饰的主要特异性异肽酶。抑制 SENP1 会上调癌细胞的放射敏感性,使其成为放射增敏的有希望的靶标。在此,基于熊果酸(UA)的结构,总共设计并合成了53个五环三萜衍生物作为SENP1抑制剂。十种衍生物表现出比UA更好的SENP1抑制活性,并讨论了初步的构效关系。大多数UA衍生物的细胞毒性较低,其中化合物36的放射增敏活性最好, SER值为1.45。这是第一项开发小分子 SENP1 抑制剂作为放射增敏剂的研究。

更新日期:2021-10-21
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