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  3. Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors

Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors

  • Bioorg Med Chem. 2017 Jul 1;25(13):3437-3446. doi: 10.1016/j.bmc.2017.04.030.
Dan Li 1,  Zigao Yuan 1,  Shaopeng Chen 2,  Cunlong Zhang 3,  Lu Song 1,  Chunmei Gao 4,  Yuzong Chen 2,  Chunyan Tan 2,  Yuyang Jiang 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 2 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 4 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
  • 5 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 28511910 DOI: 10.1016/j.bmc.2017.04.030
Abstract

DNA and DNA-related Enzymes are one of the most effective and common used intracellular Anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0.57μM against U937 cells, which was slightly better than m-AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC50 of which was more than 3 times lower than m-AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50μM. The representative compound 9 could bind with DNA and induce U937 Apoptosis through the exogenous pathway.

Keywords

Antiproliferative activity; Azaacridine derivatives; DNA binding; Molecular docking; Topoisomerase II inhibitor.

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