Chinese Journal of Organic Chemistry >
Synthesis of (E)-N-(4-Styrene) Acrylamides for DNA Topoisomerase IIα Inhibitors and Antitumor Agents
Received date: 2021-05-06
Revised date: 2021-06-06
Online published: 2021-06-29
Supported by
National Basic Research Program of China (973 Program, No. 2010CB833802); National Natural Science Foundation of China(81273384); National Natural Science Foundation of China(90913024); National Natural Science Foundation of China(91313303); Program for Changjiang Scholars and Innovative Research Team in University(IRT_17R68); Distinguished Young Scholars Grant(30325044)
Human DNA topoisomerase IIα (Topo IIα) is one of the important targets of antitumor drugs. In this study, eighteen (E)-N-(4-styrene) acrylamide derivatives (A1~A9, B1~B9) were designed and synthesized through skeleton hopping of the lead compound CL-2 for the discovery of new high-efficient and low-toxic Topo IIα inhibitors. In vitro growth inhibition experiments of human triple negative breast cancer MDA-MB-231 cells and human acute myeloid leukemia KG1 cells were carried out for these eighteen compounds. Amongst, (E)-N-(4-((E)-3,5-dihydroxystyryl)phenyl)-3-(o-tolyl) acrylamide (B1) and (E)-N-(4-((E)-3,5-dihydroxystyryl)phenyl)-3-(4-nitrophenyl) acrylamide (B9) showed evident cytotoxicity against the KG1 cells with the IC50 values of 0.43 and 0.5 μmol/L, respectively. (E)-N-(4-((E)-3,5-dihydroxyphenyl)phenyl)-3-(2- hydroxyphenyl) acrylamide (B4) showed stronger growth inhibitory effect (IC50=0.82 μmol/L) against the MDA-MB-231 cells than that of the positive control VP16 (IC50=6.62 μmol/L). (E)-N-(4-((E)-3,5-Dimethoxystyryl)phenyl)-3-(o-tolyl)- acrylamide (A1)、B1、(E)-N-(4-((E)-3,5-dimethoxystyryl)phenyl)-3-(2-methoxyphenyl)acrylamide (A4)、B4、(E)-N-(4-((E)- 3,5-dimethoxystyryl)phenyl)-3-(thiophen-3-yl)acrylamide (A9) and B9 inhibited Topo IIα-mediated DNA relaxation in vitro. These results provide a new direction for the discovery of new skeleton Topo IIα inhibitors.
Lijun Yin , Chaoqun Li , Xiaoxia Wu , Guangsen Xu , Zhiying Li , Yuemao Shen . Synthesis of (E)-N-(4-Styrene) Acrylamides for DNA Topoisomerase IIα Inhibitors and Antitumor Agents[J]. Chinese Journal of Organic Chemistry, 2022 , 42(1) : 293 -301 . DOI: 10.6023/cjoc202105008
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