Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: Structural features and biological implications
Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: Structural features and biological implications
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DOI：
10.1016/j.ijbiomac.2014.02.028
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发表时间：
2014-05-01
影响因子：
8.2
通讯作者：
Tajmir-Riahi, Heidar-Ali
中科院分区：
文献类型：
--
作者：
Agudelo, Daniel;Bourassa, Philippe;Tajmir-Riahi, Heidar-Ali
使用 FTIR、CD、荧光光谱方法和分子模型研究了抗肿瘤药物阿霉素 (DOX) 及其类似物 N-(三氟乙酰基)阿霉素 (FDOX) 与 DNA 双链体的嵌入。 DOX和FDOX均插入DNA双链体中，DOX-DNA的自由结合能为-4.99 kcal，FDOX-DNA加合物的自由结合能为-4.92 kcal，并且阿霉素NH2基团和胞嘧啶-19之间存在氢键网络。光谱结果显示，FDOX 与 KDOX-DNA = 2.5(+/- 0.5) x 10(4) M-1 和 KDOX-DNA = 3.4(+/- 0.7) x 10(4) M-1 形成比 DOX 更稳定的复合物。每个 DNA 结合的药物分子数 (n) 对于 DOX 为 1.2，对于 FDOX 为 0.6。通过 DOX 插入，观察到 DNA 结构的主要改变，部分 B 到 A-DNA 转变，而 FDOX 相互作用时没有发生 DNA 构象变化。这项研究进一步证实了未修饰的道诺胺氨基对于与 DNA 实现最佳相互作用的重要性。对 SKC01 结肠癌进行的体外 mrr 测定结果证实了观察到的 DNA 相互作用。这种 DNA 结构变化可能与阿霉素抗肿瘤活性有关，阿霉素抗肿瘤活性可防止 DNA 复制。 (C) 2014 Elsevier B.V. 保留所有权利。
The intercalation of antitumor drug doxorubicin (DOX) and its analogue N-(trifluoroacetyl) doxorubicin (FDOX) with DNA duplex was investigated, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Both DOX and FDOX were intercalated into DNA duplex with the free binding energy of -4.99 kcal for DOX-DNA and -4.92 kcal for FDOX-DNA adducts and the presence of H-bonding network between doxorubicin NH2 group and cytosine-19. Spectroscopic results showed FDOX forms more stable complexes than DOX with KDOX-DNA = 2.5(+/- 0.5) x 10(4) M-1 and KDOX-DNA = 3.4(+/- 0.7) x 10(4) M-1. The number of drug molecules bound per DNA (n) was 1.2 for DOX and 0.6 for FDOX. Major alterations of DNA structure were observed by DOX intercalation with a partial B to A-DNA transition, while no DNA conformational changes occurred upon FDOX interaction. This study further confirms the importance of unmodified daunosamine amino group for optimal interactions with DNA. The results of in vitro mrr assay carried out on SKC01 colon carcinoma corroborate the observed DNA interactions. Such DNA structural changes can be related to doxorubicin antitumor activity, which prevents DNA duplication. (C) 2014 Elsevier B.V. All rights reserved.