2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivative as potent antitumor agents

Design, synthesis and biological evaluation of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivative as potent antitumor agents

  • Eur J Med Chem. 2019 Feb 1:163:690-709. doi: 10.1016/j.ejmech.2018.12.009.
Yunlei Hou 1,  Liangyu Zhu 1,  Zhiwei Li 1,  Qi Shen 1,  Qiaoling Xu 1,  Wei Li 1,  Yajing Liu 2,  Ping Gong 3
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: lyjpharm@126.com.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: gongpinggp@126.com.
PMID: 30572179 DOI: 10.1016/j.ejmech.2018.12.009
Abstract

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 L7 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 μM, 0.30 μM, 0.51 μM, 0.30 μM, and 0.70 μM, 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.

Keywords

Antitumor; PLK1; Structure-activity relationships.

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