Design, synthesis and biological evaluation of sphingosine-1-phosphate receptor 2 antagonists as potent 5-FU-resistance reversal agents for the treatment of colorectal cancer

• Published in: European journal of medicinal chemistry 2021-12, Vol.225, p.113775, Article 113775
• Main Authors: Luo, Dongdong, Zhang, Yuhang, Yang, Shuang, Tian, Xiaochen, Lv, Yan, Guo, Zhikun, Liu, Xiaochun, Han, Gaitian, Liu, Shuai, Wang, Wenyu, Cui, Shuxiang, Qu, Xianjun, Wan, Shengbiao
• Format: Article
• Language: English
• Subjects: 5-FU-Resistance; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Colorectal cancer therapy; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Fluorouracil - chemical synthesis; Fluorouracil - chemistry; Fluorouracil - pharmacology; Humans; Molecular Structure; Mouse xenograft model; Pharmacokinetic properties; S1PR2 antagonists; Sphingosine-1-Phosphate Receptors - antagonists & inhibitors; Sphingosine-1-Phosphate Receptors - metabolism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113775

5-Fluorouracil (5-FU) and its prodrugs are the essential clinical drugs for colorectal cancer (CRC) treatment. However, the drug resistance of 5-FU has caused high mortality of CRC patients. Thus, it is urgent to develop reversal agents of 5-FU resistance. Sphingosine-1-phosphate receptor 2 (S1PR2) was proved to be a potential target for reversing 5-FU resistance, but the activity of known S1PR2 antagonists JTE-013 were weak in 5-FU-resistant cell lines. To develop more potent S1PR2 antagonists to treat 5-FU-resistant cancer, a series of JTE-013 derivatives were designed and synthesized. The most promising compound 40 could markedly reverse the resistance in 5-FU-resistant HCT116 cells and 5-FU-resistant SW620 cells via inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). The key was that compound 40 with improved pharmacokinetic properties significantly increased the inhibitory rate of 5-FU in the SW620/5-FU cells xenograft model with no observable toxicity by inhibiting the expression of DPD in tumor and liver tissues. Altogether, these results suggest that compound 40 may be a promising drug candidate to reverse 5-FU resistance in the treatment of CRC. [Display omitted] •A series of S1PR2 antagonists were designed, synthesized and most compounds showed potent binding abilities with S1PR2.•Most compounds showed potent 5-FU-resistance reversal activity in resistant cells.•Compound 40 showed the most potent binding ability (KD = 13.2 nM) with S1PR2.•Compound 40 has the most potent reversal activity (EC50