159178-03-7Relevant articles and documents
4-Aminopyridine derivatives with anticholinesterase and antiamnesic activity
Scipione, Luigi,De Vita, Daniela,Musella, Alessandra,Flammini, Lisa,Bertoni, Simona,Barocelli, Elisabetta
, p. 309 - 312 (2008)
Several carbamate derivatives of 4-aminopyridine were synthesized and their anticholinesterase activity was evaluated. Compound 4d showed the highest inhibitory effect blocking non-competitively acetylcholinesterase and competitively butyrylcholinesterase
Novel 5-fluorouracil sensitizers for colorectal cancer therapy: Design and synthesis of S1P receptor 2 (S1PR2) antagonists
Luo, Dongdong,Guo, Zhikun,Zhao, Xuecui,Wu, Lijuan,Liu, Xiaochun,Zhang, Yingzhi,Zhang, Yuhang,Deng, Zirong,Qu, Xianjun,Cui, Shuxiang,Wan, Shengbiao
, (2021/10/25)
Sphingosine-1-phosphate receptor 2 (S1PR2) has been identified as a brand-new GPCR target for designing antagonists to reverse 5-FU resistance. We herein report the structural optimization and structure-activity relationship of JTE-013 derivatives as S1PR2 antagonists. Compound 9d was the most potent S1PR2 antagonist (KD = 34.8 nM) among developed compounds. Here, compound 9d could significantly inhibit the expression of dihydropyrimidine dehydrogenase (DPD) to reverse 5-FU-resistance in HCT116DPD and SW620/5-FU cells. Further mechanism studies demonstrated that compound 9d not only inhibited S1PR2 but also affected the transcription of S1PR2. In addition, compound 9d also showed acceptable selectivity to normal cells (NCM460). Importantly, compound 9d with suitable pharmacokinetic properties could significantly reverse 5-FU-resistance in the HCT116DPD and SW620/5-FU xenograft models without obvious toxicity, in which the inhibition rates of 5-FU were increased from 23.97% to 65.29% and 27.23% to 60.81%, respectively. Further immunohistochemistry and western blotting analysis also demonstrated that compound 9d significantly decreases the expression of DPD in tumor and liver tissues. These results indicated that compound 9d is a promising lead compound to reverse 5-FU-resistance for colorectal cancer therapy.
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
Cui, Shuxiang,Guo, Zhikun,Han, Gaitian,Liu, Shuai,Liu, Xiaochun,Luo, Dongdong,Lv, Yan,Qu, Xianjun,Tian, Xiaochen,Wan, Shengbiao,Wang, Wenyu,Yang, Shuang,Zhang, Yuhang
, (2021/08/20)
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.
S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer
Zhang, Yu-Hang,Luo, Dong-Dong,Wan, Sheng-Biao,Qu, Xian-Jun
, (2020/02/29)
In this study, S1PR2 was reckoned as a brand-new GPCR target for designing inhibitors to reverse 5-FU resistance. Herein a series of pyrrolidine pyrazoles as the S1PR2 inhibitors were designed, synthesized and evaluated for their activities of anti-FU-resistance. Among them, the most promising compound JTE-013, exhibited excellent inhibition on DPD expression and potent anti-FU-resistance activity in various human cancer cell lines, along with the in vivo HCT116DPD cells xenograft model, in which the inhibition rate of 5-FU was greatly increased from 13.01percent–75.87percent. The underlying mechanism was uncovered that JTE-013 demonstrated an anti-FU-resistance activity by blocking S1PR2 internalization to the endoplasmic reticulum (ER), which inhibited the degradation of 5-FU into α-fluoro-β-alanine (FBAL) by downregulating tumoral DPD expression. Overall, JTE-013 could serve as the lead compound for the discovery of new anti-FU-resistance drugs. Significance: This study provides novel insights that S1PR2 inhibitors could sensitize 5-FU therapy in colorectal cancer.