Synthesis and Biological Evaluation of Peripheral HTR2A Antagonists for Colorectal Cancer

Colorectal cancer is a prevalent and prominent contributor to global cancer-related fatalities with challenges in drug resistance and metastasis. Recent research highlights the potential relationship between serotonin and cancer. 5-Hydroxytryptamine receptor 2A (HTR2A) mRNA expression in colorectal cancer cells was found to be notably elevated compared to that in normal colon cells. We therefore attempted to synthesize and evaluate HTR2A antagonists to find peripherally acting anticancer agents. Among them, 15f showed good in vitro activity (IC₅₀: 42.79 nM). 15f revealed good liver microsomal stability, without significant CYP inhibition and limited blood-brain barrier penetration. 15f also exerted selective cytotoxic effects against various colorectal cancer cells but not normal cells. 15f induced sub-G1 cell cycle arrest and apoptosis in colorectal cancer cells via the activation of p53/p21/caspase 3 signaling. In vivo treatment with 15f led to a marked delay in tumor growth in a colorectal cancer model in a dose-dependent manner.