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Citation: Dai Qiuzi, Chen Jiwei, Gao Chunmei, Qinsheng Sun, Yuan Zigao, Yuyang Jiang. Design, synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents[J]. Chinese Chemical Letters, ;2020, 31(2): 404-408. doi: 10.1016/j.cclet.2019.06.019 shu

Design, synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents

Dai Qiuzi ^a,b,1 ,
Chen Jiwei ^b,1 ,
Gao Chunmei ^b,c ,
Qinsheng Sun ^b ,
Yuan Zigao ^b,*, ,
Yuyang Jiang ^b,d,*,

a.
Department of Chemistry, Tsinghua University, Beijing 100084, China
b.
The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
c.
College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518060, China
d.
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China

^*

yzg12@tsinghua.org.cn

jiangyy@sz.tsinghua.edu.cn

¹

Received Date: 24 April 2019
Revised Date: 6 June 2019
Accepted Date: 10 June 2019
Available Online: 11 June 2019

Figures(7)

In this study, we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors. MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation. In addition, all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L, and also possessed good PARP-1 inhibitory activities. Subsequent mechanistic studies showed that compound 9a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells. Our study suggested that 9a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.
- Topo,
- PARP,
- Multitarget,
- Acridines,
- Antitumor bioactivity
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