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 <b>4a</b>-<b>4h</b>, <b>6a</b>-<b>6b</b>, <b>7c</b>-<b>7f</b>, and <b>7h</b>-<b>7i</b> inhibited 9-<i>cis</i>-retinoic acid-induced RXRα transactivation, while compounds <b>3b</b>, <b>4f</b>-<b>4h</b>, <b>7a</b>, <b>7c</b>, <b>7f</b>, and <b>7h</b>-<b>7i</b> 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 <b>7i</b> 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 <b>7i</b> 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 <b>7i</b> were RXRα-dependent. Cellular Thermal Shift Assay (CETSA) and molecular docking studies further confirmed that <b>7i</b> directly bound to RXRα, thereby mediating its anti-cancer efficacy.