SAR study of oxidative DIMs analogs targeting the Nur77-mediated apoptotic pathway of cancer cells.
Bioorganic chemistry(2022)
摘要
Nur77, an orphan nuclear receptor, is implicated in regulating diverse cellular biological processes including apoptosis and inflammation. We previously identified BI1071 (DIM-C-pPhCF3+MeSO3-), an oxidized methanesulfonate salt of (4-CF3-Ph-C-DIM), was a direct ligand of Nur77, which could activate the Nur77-Bcl-2 apoptotic pathway. To obtain more effective compounds targeting the Nur77-mediated apoptotic pathway, we designed and synthesized a series of BI1071 analogs by introducing various substituent groups in the indolyl-rings of BI1071. Structure-activity relationship study identified A11, B5 and B15 as improved analogs with stronger binding affinity to Nur77 and enhanced apoptotic activity compared to BI1071. Nur77-binding studies demonstrated that A11, B5 and B15 bind to Nur77 with a Kd of 34 nM, 19 nM and 16 nM, respectively. Furthermore, mechanism studies showed that A11, B5 and B15 induced apoptosis through utilizing the Nur77-Bcl-2 pathway.
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