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  3. Molecular design, synthesis and biological research of novel pyridyl acridones as potent DNA-binding and apoptosis-inducing agents

Molecular design, synthesis and biological research of novel pyridyl acridones as potent DNA-binding and apoptosis-inducing agents

  • Eur J Med Chem. 2015 Mar 26:93:214-26. doi: 10.1016/j.ejmech.2015.02.003.
Bin Zhang 1,  Kang Chen 1,  Ning Wang 1,  Chunmei Gao 2,  Qinsheng Sun 3,  Lulu Li 3,  Yuzong Chen 4,  Chunyan Tan 5,  Hongxia Liu 3,  Yuyang Jiang 6
Affiliations

Affiliations

  • 1 Tsinghua University, Department of Chemistry, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China.
  • 2 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China; Shenzhen Anti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
  • 3 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China.
  • 4 Bioinformatics and Drug Design Group, Department of Pharmacy, Centre for Computational Science and Engineering, 117543, Singapore.
  • 5 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China; Shenzhen Anti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 6 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China; Shenzhen Anti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Medicine, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 25686590 DOI: 10.1016/j.ejmech.2015.02.003
Abstract

A series of novel pyridyl acridone derivatives comprised of a pseudo-five-cyclic system to extend the π-conjugated acridone chromophore, were designed and synthesized as potent DNA binding antitumor compounds. Most synthesized compounds displayed good activity against human leukemia K562 cells in MTT tests, with compound 6d exhibiting the highest activity with IC50 value at 0.46 μM. Moreover, 6d showed potent activities against solid tumor cell lines (0.16-3.79 μM). Several experimental studies demonstrated that the antitumor mode of action of compound 6d involves DNA intercalation, Topoisomerase I inhibition, and Apoptosis induction through the mitochondrial pathway. In summary, compound 6d represents a novel and promising lead structure for the development of new potent Anticancer DNA-binding agents.

Keywords

Acridone; Antitumor; DNA; Molecular docking; Pyridyl; Topoisomerase I.

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