SAR study of oxidative DIMs analogs targeting the Nur77-mediated apoptotic pathway of cancer cells.

[Display omitted] • 35 New Ph-C-DIM+Cl- derivatives were designed and synthesized, and A11, B5 and B15 were identified as new Nur77 modulators. • A11, B5 and B15 showed excellent pro-apoptosis activity in colon cancer cell lines HCT116 and SW620, while showed non-significant cytotoxicity against normal colon cell line NCM460. • A11, B5 and B15 bind Nur77 with high affinity, with a K d of 34 nM, 19 nM and 16 nM, respectively. • A11, B5 and B15 induced apoptosis of cancer cells by activating the Nur77/Bcl-2 apoptotic pathway. Nur77, an orphan nuclear receptor, is implicated in regulating diverse cellular biological processes including apoptosis and inflammation. We previously identified BI1071 (DIM-C-pPhCF 3 +MeSO 3 -), an oxidized methanesulfonate salt of (4-CF 3 -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 K d 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. [ABSTRACT FROM AUTHOR]