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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.
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.
Afiliação
  • Luo D; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • Zhang Y; Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100034, China.
  • Yang S; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • Tian X; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • Lv Y; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • Guo Z; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.
  • Liu X; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • Han G; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • Liu S; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • Wang W; Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • Cui S; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.
  • Qu X; Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. Electronic address: quxj@ccmu.edu.cn.
  • Wan S; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China. Electronic address: biaowan@ouc.edu.cn.
Eur J Med Chem ; 225: 113775, 2021 Dec 05.
Article em En | MEDLINE | ID: mdl-34411894
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Desenho de Fármacos / Fluoruracila / Receptores de Esfingosina-1-Fosfato / Antineoplásicos Limite: Humans Idioma: En Revista: Eur J Med Chem Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Desenho de Fármacos / Fluoruracila / Receptores de Esfingosina-1-Fosfato / Antineoplásicos Limite: Humans Idioma: En Revista: Eur J Med Chem Ano de publicação: 2021 Tipo de documento: Article