2. Academic Validation
  3. Synthesis and antiproliferative activity of 9-benzylamino-6-chloro-2-methoxy-acridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors

Synthesis and antiproliferative activity of 9-benzylamino-6-chloro-2-methoxy-acridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors

  • Eur J Med Chem. 2016 Jun 30:116:59-70. doi: 10.1016/j.ejmech.2016.03.066.
Wei Zhang 1,  Bin Zhang 2,  Wei Zhang 3,  Ti Yang 4,  Ning Wang 5,  Chunmei Gao 6,  Chunyan Tan 7,  Hongxia Liu 8,  Yuyang Jiang 9
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, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China; ShenzhenAnti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 2 ShenzhenAnti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China; ShenzhenAnti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 4 Tsinghua University, Department of Chemistry, Beijing 100084, PR China.
  • 5 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, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China.
  • 6 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, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
  • 7 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China.
  • 8 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China.
  • 9 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, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, 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: 27060757 DOI: 10.1016/j.ejmech.2016.03.066
Abstract

A series of 9-benzylamino acridine derivatives were synthesized as an extension of our discovery of acridine antitumor agents. Most of these acridine compounds displayed good antiproliferative activity with IC50 values in low micromole range and structure-activity relationships were studied. Topo I- and II- mediated relaxation studies suggested that all of our compounds displayed strong Topo II inhibitory activity at 100 μM, while only four exhibited moderate Topo I inhibitory activity. The typical compound 8p could penetrate A549 Cancer cells efficiently. Compound 8p could intercalate within the double-stranded DNA structure and induce DNA damage. Moreover, compound 8p could induce A549 cells Apoptosis through caspase-dependent intrinsic pathway and arrest A549 cells at the G2/M phase.

Keywords

Acridine derivatives; Antiproliferative activity; DNA damage; Topoisomerase II inhibitor.

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