期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 163, 期 -, 页码 690-709出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.12.009
关键词
Antitumor; PLK1; Structure-activity relationships
资金
- Program for Innovative Research Team of the Ministry of Education
- Program for Liaoning Innovative Research Team in University [IRT1073]
- National Natural Science Foundation of China [81628012]
- Fund for long-term training of young teachers in Shenyang Pharmaceutical University [ZQN2015002]
- National Natural Science Foundation of Liaoning province [20170540854]
- Training Program Foundation for the Distinguished Young Scholars of University in Liaoning Province [LJQ2015109]
To develop novel therapeutic agents with anticancer activities, two series of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivatives were designed and synthesized. All compounds were tested for anti-proliferative activities against five cancer cell lines. The structure-activity relationships (SARs) studies were conducted through the variation in two regions, the moiety of A ring and the terminal aniline B on pteridinone core. 1-Methyl-1,2,4-triazole derivative L-7 with 2,6-dimethylpiperazine showed the most potent antiproliferative activity against A549, PC-3, HCT116, MCF-7 and MDA-MB-231 cell lines with IC50 values of 0.16 mu M, 0.30 mu M, 0.511 mu M, 0.30 mu M, and 0.70 mu M, respectively. Combined with the results of the molecular docking and enzymatic studies, the PLK1 was very likely to be one of the drug targets of compound L7. Furthermore, to clarify the anticancer mechanism of compound L7, further explorations in the bioactivity were conducted. The results showed that compound L7 obviously inhibited proliferation of A549 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, suppressed the migration of tumor cells, and arrested G1 phase of A549 cells. (C) 2018 Elsevier Masson SAS. All rights reserved.
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