Synthesis and Biological Evaluation of Marine-Inspired Benzothiazole Derivatives as Retinoid X Receptor-α Antagonists with Anti-Cancer Activities

Retinoid X receptor α (RXRα) plays a vital role in multiple biological and pathological processes and represents a promising therapeutic target for anti-tumor drug design. Inspired by the marine-derived RXRα Antagonist meroterpenthiazole A, 21 undescribed benzothiazole derivatives were designed and synthesized. The inhibitory effects of 21 derivatives on RXRα transactivation and their anti-tumor activities against MDA-MB-231 cells were evaluated. Compounds 4a-4h, 6a-6b, 7c-7f, and 7h-7i inhibited 9-cis-retinoic acid-induced RXRα transactivation, while compounds 3b, 4f-4h, 7a, 7c, 7f, and 7h-7i exhibited inhibitory effects on the proliferation of MDA-MB-231 cells. Meanwhile, the structure-activity relationships governing both the RXRα Antagonist effects and the anti-proliferative activities against MDA-MB-231 cells were discussed. Compound 7i exhibited the most potent inhibitory effects on the proliferation of MDA-MB-231 cells with an IC₅₀ value of 16.5 μM. Further mechanism studies revealed that compound 7i induced G2/M phase arrest in MDA-MB-231 cells, accompanied by dose-dependent downregulation of Cyclin B1 and CDK1 protein expression. However, these effects were abolished in RXRα-knockout MDA-MB-231 cells, indicating that the anti-proliferative and cell cycle arrest activities of 7i were RXRα-dependent. Cellular Thermal Shift Assay (CETSA) and molecular docking studies further confirmed that 7i directly bound to RXRα, thereby mediating its anti-cancer efficacy.

RXRα; anti-cancer activity; benzothiazole derivatives; mechanism; structure–activity relationship.