Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Chemistry and Chemical Engineering, Xiamen University, South Xiang-An Road, Xiamen 361102, China.
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Chemistry and Chemical Engineering, Xiamen University, South Xiang-An Road, Xiamen 361102, China.
Bioorg Chem. 2021 Aug;113:104961. doi: 10.1016/j.bioorg.2021.104961. Epub 2021 May 5.
In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (K = 2.89 × 10 M) with potent antiproliferative activity against human cancer cell lines (IC ≈ 10 μM) and low toxic to normal LO2 and MRC-5 cells (IC > 50 μM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.
在本研究中，我们合成了一系列新型查尔酮 adamantly 视黄醇类（chalcone AdArs），它们衍生自 RAR 拮抗剂 MX781，并对其进行了体外生物学活性评价。通过对目标化合物的抗增殖活性和 RXRα 结合亲和力的研究，发现了一个先导化合物（WA15），它是一种良好的 RXRα 结合剂（K=2.89×10^-5 M），对人癌细胞系具有很强的抗增殖活性（IC≈10 μM），对正常 LO2 和 MRC-5 细胞的毒性较低（IC>50 μM）。与 MX781 不同，WA15 消除了 RARα 拮抗剂活性，但以剂量依赖的方式抑制 9-顺式-RA 诱导的 RXRα 反式激活活性。研究发现，WA15 是一种有效的诱导多种癌细胞凋亡的化合物，能以 RXRα 非依赖的方式促进细胞凋亡。此外，WA15 还能诱导蛋白酶体依赖的 RXRα 降解，这可能增强了 WA15 诱导的凋亡。最后，免疫印迹表明，WA15 可以抑制 TNFα 诱导的 IKK 激活和 IκBα 降解，提示 WA15 的抗癌活性可能与抑制 IKK/NF-κB 信号通路有关。
