Design, synthesis and biological evaluation of novel 7-alkylamino substituted benzo[a]phenazin derivatives as dual topoisomerase I/II inhibitors

  • Eur J Med Chem. 2015 Mar 6:92:540-53. doi: 10.1016/j.ejmech.2015.01.024.
Bing-Lei Yao  1 ,  Yan-Wen Mai  1 ,  Shuo-Bin Chen  1 ,  Hua-Ting Xie  1 ,  Pei-Fen Yao  1 ,  Tian-Miao Ou  1 ,  Jia-Heng Tan  1 ,  Hong-Gen Wang  1 ,  Ding Li  1 ,  Shi-Liang Huang  2 ,  Lian-Quan Gu  1 ,  Zhi-Shu Huang  3
Affiliations
  • 1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
  • 2. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China. Electronic address: [email protected].
  • 3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China. Electronic address: [email protected].
PMID: 25599951 DOI: 10.1016/j.ejmech.2015.01.024
Abstract

A novel series of benzo[a]phenazin derivatives bearing alkylamino side chains were designed, synthesized and evaluated for their topoisomerases inhibitory activity as well as cytotoxicity against four human Cancer cell lines (HL-60, K-562, HeLa, and A549). These compounds were found to be dual inhibitors of Topoisomerase (Topo) I and Topo II, and exhibited excellent antiproliferative activity, in particular against HL-60 cells with submicromolar IC50 values. Further mechanistic studies showed that this class of compounds acted as Topo I poisons by stabilizing the Topo I-DNA cleavage complexes and Topo II catalytic inhibitors by inhibiting the ATPase activity of hTopo II. Molecular docking studies revealed the binding modes of these compounds for Topo I and Topo II.

Keywords
ATPase catalytic inhibitor; Antitumor; Benzo[a]phenazin derivatives; Topoisomerase I; Topoisomerase II.