Design, Synthesis and Evaluation of S1PR2 Antagonists for Reversing 5-FU Resistance in Colorectal Cancer

To develop novel 5-fluorouracil (5-FU) resistance reversal agents against 5-FU resistance in colorectal cancer cells (HT29, SW620). Based on the mechanism that the S1PR2 antagonist JTE-013 reverses 5-FU resistance via downregulating dihydropyrimidine dehydrogenase (DPD) expression and reducing 5-FU degradation, 19 structurally novel JTE-013 derivatives were designed and synthesized. Their 5-FU resistance reversal activities were systematically assessed in two 5-FU-resistant colorectal cancer cell lines (HT29/5FU, SW620/5FU). Compound 12j showed a single-agent IC₅₀ of (255.80±0.91) μmol/L in HT29/5FU cells, and an EC₅₀ of (12.12±0.34) μmol/L when combined with 20 μmol/L 5-FU. Its 5-FU resistance reversal activity was approximately 5.7-fold higher than that of the lead compound JTE-013 (EC₅₀=(68.62±1.34) μmol/L). Moreover, under the combined administration of 20 μmol/L 12j and 5-FU, the 5-FU resistance reversal folds reached 72.6 in SW620/5FU cells and 39.7 in HT29/5FU cells, respectively. In this study, compound 12j displays markedly better 5-FU resistance reversal efficacy than JTE-013, offering a promising lead structure for overcoming 5-FU resistance in colorectal cancer.