(E)-N-(4-苯乙烯基)丙烯酰胺类DNA拓扑异构酶IIα抑制剂的合成及抗肿瘤活性研究
收稿日期: 2021-05-06
修回日期: 2021-06-06
网络出版日期: 2021-06-29
基金资助
国家重点基础研究发展计划(973计划, No. 2010CB833802); 国家自然科学基金(81273384); 国家自然科学基金(90913024); 国家自然科学基金(91313303); 长江学者和创新团队发展计划(IRT_17R68); 国家杰出青年科学基金(30325044)
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)
人DNA拓扑异构酶IIα (topoisomerase IIα, Topo IIα)是重要的抗肿瘤药物靶标之一. 为发现新的高效、低毒Topo IIα抑制剂, 本研究通过对先导化合物CL-2进行骨架跃迁, 设计合成了18个(E)-N-(4-苯乙烯基)丙烯酰胺衍生物(A1~A9, B1~B9). 18个化合物对人三阴性乳腺癌MDA-MB-231细胞和人急性骨髓性白血病KG1细胞生长的抑制实验结果表明, (E)-N-(4-((E)-3,5-二羟基苯乙烯基)苯基)-3-(邻-甲苯基)丙烯酰胺(B1)和(E)-N-(4-((E)-3,5-二羟基苯乙烯基)苯基)-3-(4-硝基苯基)丙烯酰胺(B9)抑制KG1细胞生长的IC50分别为0.43和0.5 μmol/L; (E)-N-(4-((E)-3,5-二羟基苯乙烯基)苯基)-3-(2-羟基苯基)丙烯酰胺(B4)对MDA-MB-231细胞的生长抑制作用(IC50=0.82 μmol/L)超过阳性对照VP16 (IC50=6.62 μmol/L). (E)-N-(4-((E)-3,5-二甲氧基苯乙烯基)苯基)-3-(邻-甲苯基)丙烯酰胺(A1)、B1、(E)-N-(4-((E)-3,5-二甲氧基苯乙烯基)苯基)-3-(2-甲氧苯基)丙烯酰胺(A4)、B4、(E)-N-(4-((E)-3,5-二甲氧基苯乙烯基)苯基)-3-(噻吩-3-基)丙烯酰胺(A9)和B9体外抑制Topo IIα介导的DNA松弛作用. 研究结果为发现新骨架Topo IIα抑制剂提供了新方向.
尹丽君 , 李超群 , 吴晓霞 , 徐广森 , 李志颖 , 沈月毛 . (E)-N-(4-苯乙烯基)丙烯酰胺类DNA拓扑异构酶IIα抑制剂的合成及抗肿瘤活性研究[J]. 有机化学, 2022 , 42(1) : 293 -301 . DOI: 10.6023/cjoc202105008
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.
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