摘要/Abstract

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.
关键词: 拓扑异构酶IIα, 设计合成, 结构优化, 抗肿瘤活性
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.
Key words: topoisomerase IIα, design and synthesis, structure optimization, antitumor activity


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