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
  • 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: [email protected].
  • 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: [email protected].
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.