Abstract

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 d  = 2.89 × 10 −6 M) with potent antiproliferative activity against human cancer cell lines (IC 50  ≈ 10 μM) and low toxic to normal LO2 and MRC-5 cells (IC 50  > 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- κ B signal pathway.