Agudelo Daniel, Bourassa Philippe, Bérubé Gervais, Tajmir-Riahi Heidar-Ali
Department of Chemistry, Biochemistry and Physics, University of Québec at Trois-Rivières, C.P. 500, Trois-Rivières G9A 5H7 Québec, Canada.
Department of Chemistry, Biochemistry and Physics, University of Québec at Trois-Rivières, C.P. 500, Trois-Rivières G9A 5H7 Québec, Canada.
Int J Biol Macromol. 2014 May;66:144-50. doi: 10.1016/j.ijbiomac.2014.02.028. Epub 2014 Feb 20.
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)× 10(4)M(-1) and KFDOX-DNA=3.4(± 0.7)× 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 MTT 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.
采用傅里叶变换红外光谱（FTIR）、圆二色光谱（CD）、荧光光谱法以及分子模拟技术，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双链的嵌入作用。DOX和FDOX均嵌入到DNA双链中，DOX - DNA加合物的自由结合能为 - 4.99千卡，FDOX - DNA加合物的自由结合能为 - 4.92千卡，并且阿霉素的NH2基团与胞嘧啶 - 19之间存在氢键网络。光谱结果表明，FDOX与DNA形成的复合物比DOX更稳定，KDOX - DNA = 2.5（±0.5）×10⁴M⁻¹，KFDOX - DNA = 3.4（±0.7）×10⁴M⁻¹。每个DNA结合的药物分子数（n），DOX为1.2，FDOX为0.6。DOX嵌入导致DNA结构发生主要改变，伴有部分B型向A型DNA的转变，而FDOX与DNA相互作用时未发生DNA构象变化。该研究进一步证实了未修饰的柔红糖胺氨基对于与DNA实现最佳相互作用的重要性。对SKC01结肠癌进行的体外MTT试验结果证实了所观察到的DNA相互作用。这种DNA结构变化可能与阿霉素的抗肿瘤活性有关，阿霉素可阻止DNA复制。
