Design, synthesis and biological evaluation of tetrazole-containing RXRα ligands as anticancer agents

Nuclear receptor RXR alpha plays an important role in many biological and pathological processes. The nongenomic action of RXR alpha is implicated in many cancers. K-8008, a non-canonical RXR alpha ligand derived from sulindac, inhibits the INF alpha-activated PI3K/AKT pathway by mediating the interaction between a truncated form of RXR alpha (tRXR alpha) and the p85 alpha regulatory subunit of PI3K and exerts potent anticancer activity in animal model. Herein we report our studies of a novel series of K-8008 analogs as potential anticancer agents targeting RXR alpha. Two compounds 8b and 18a were identified to have slightly stronger binding to RXR alpha and improved apoptotic activities in breast cancer cells. (C) 2018 Elsevier Masson SAS. All rights reserved.