1. Academic Validation
  2. Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy

Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy

  • Eur J Med Chem. 2017 Sep 29:138:1135-1146. doi: 10.1016/j.ejmech.2017.07.050.
Zigao Yuan 1 Shaopeng Chen 2 Changjun Chen 2 Jiwei Chen 1 Chengken Chen 1 Qiuzi Dai 1 Chunmei Gao 3 Yuyang Jiang 4
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, The 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, 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, 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
  • 4 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The 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; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
Abstract

PARP-1 could repair the DNA damages induced by Topo inhibitors, therefore inhibiting Topo and PARP-1 simultaneously might be able to overcome resistance and improve outcomes. In this study a series of 4-amidobenzimidazole acridines were designed and synthesized as dual Topo and PARP-1 inhibitors. Compound 11l displayed good inhibitory activities against Topo and PARP-1, as well as significantly inhibited Cancer cells proliferation. Further mechanistic evaluations indicated that 11l treatment in MCF-7 cells induced accumulated DNA double-strand breaks, prompted remarkable Apoptosis, and caused prominent G0/G1 cell cycle arrest. Moreover, 11l greatly suppressed tumor growth in mice, and displayed favorable metabolic properties in liver microsomes. Our study suggested that single agents inhibiting Topo and PARP concurrently might be an alternative for Cancer therapy and 11l represented a potential lead compound for development of antitumor agents.

Keywords

Acridines; Antitumor bioactivity; Multitarget; PARP; Topo.

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