6313-57-1Relevant academic research and scientific papers
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.
Amino containing isonicotinic acid derivatives
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, (2008/06/13)
Compounds of formula STR1 wherein X represents chlorine, bromine or iodine, R1 represents a C1 -C12 -alkyl group optionally substituted by hydroxy, C1 -C4 -alkoxy, amino or mono- or di-C1 -C2 -alkylamino; or a C3 -C4 -alkenyl group, C3 -C8 -cycloalkyl group, benzyl group, p-acetylbenzyl group or phenethyl group, and R2 represents hydrogen or a C1 -C4 -alkyl group or a C3 -C4 -alkenyl group, or R1 and R2 together represent a 5- to 7-membered heterocyclic group, which optionally can additionally contain an oxygen atom, As well as their salts with organic and inorganic bases which are useful as bactericides and fungicides.
