DNA binding properties of 9-substituted harmine derivatives
DNA binding properties of 9-substituted harmine derivatives
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DOI：
10.1016/j.bbrc.2005.10.121
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发表时间：
2005-12-23
影响因子：
3.1
通讯作者：
Xu, AL
中科院分区：
文献类型：
--
作者：
Cao, RH;Peng, WL;Xu, AL
β-咔啉生物碱是一类潜在的抗肿瘤药物。通过DNA结合实验和拓扑异构酶（Topo）抑制实验研究了去氢骆驼蓬碱及其衍生物的作用机制。同时，通过DNA光裂解实验和体外细胞毒性实验，考察了这些化合物的DNA光裂解能力和细胞毒性。去氢骆驼蓬碱及其衍生物表现出显著的DNA嵌入能力和显著的Topo I抑制活性，但对Topo II无影响。在β-咔啉核的9位引入适当的取代基，可增强药物对DNA的亲和力，从而产生显著的Topo Ⅰ抑制作用。这些结果表明，这些化合物作为嵌入剂和Topo I抑制剂的能力与抗肿瘤活性有关。此外，这些显示细胞毒性与Topo I抑制或DNA结合能力之间的相关性的数据是非常重要的，因为它们强烈地表明Topo I介导的DNA切割测定和DNA结合测定可用作设计和开发抗肿瘤活性的上级类似物的指导。(c)2005年爱思唯尔公司All rights reserved.
The beta-carboline alkaloids have been characterized its a group of potential antitumor agents. The underlying mechanisms of harmine and its derivatives were investigated by DNA binding assay and Topoisomerase (Topo) inhibition assay. Meanwhile, the DNA photocleavage potential of these compounds and their cytotoxicity were also examined by DNA photocleavage assay and cytotoxicity assay in vitro. Harmine and its derivatives exhibited remarkable DNA intercalation capacity and significant Topo I inhibition activity but no effect with Topo II. Introducing in appropriate substituent into position-9 of beta-carboline nucleus enhanced the affinity of the drug to DNA resulting in remarkable Topo I inhibition effects. These results Suggested that the ability of these compounds to act as intercalating agents and Topo I inhibitors was related to the antitumor activity. Moreover, these data showing a correlation between cytotoxicity and Topo I inhibition or DNA binding capacity are very important as they strongly suggested that the Topo I-mediated DNA cleavage assay and DNA binding assay Could be used as a guide to design and develop superior analogues for antiturrior activities. (c) 2005 Elsevier Inc. All rights reserved.