Discovery and radiosensitization research of ursolic acid derivatives as SENP1 inhibitors

• Published in: European journal of medicinal chemistry 2022-01, Vol.227, p.113918, Article 113918
• Main Authors: Wei, Huiqiang, Guo, Jianghong, Sun, Xiao, Gou, Wenfeng, Ning, Hongxin, Fang, Zhennan, Liu, Qiang, Hou, Wenbin, Li, Yiliang
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Molecular Structure; Radiosensitization; Semi-synthesis; SENP1; Structure modification; Structure-Activity Relationship; Triterpenes - chemical synthesis; Triterpenes - chemistry; Triterpenes - pharmacology; Ursolic Acid
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113918

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. [Display omitted] •A total of 53 ursolic acid (UA) derivatives were designed and synthesized as SENP1 inhibitors.•Ten derivatives exhibited better SENP1 inhibitory activities (inhibitory ratios over 93.89% at 2 μM) than UA.•Compound 36 was low-cytotoxic and 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.