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

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

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: lsshsl@mail.sysu.edu.cn.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China. Electronic address: ceshzs@mail.sysu.edu.cn.
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.

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