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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Self-association and unique DNA binding properties of the anti-cancer agent TAS-103, a dual inhibitor of topoisomerases I and II
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Self-association and unique DNA binding properties of the anti-cancer agent TAS-103, a dual inhibitor of topoisomerases I and II

机译：TAS-103（拓扑异构酶I和II的双重抑制剂）抗癌剂TAS-103的自缔合和独特的DNA结合特性

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摘要

The objective of our study was to investigate the self-association and DNA-binding properties of the DNA topoisomerases I (Topo I) and II (Topo II) dual inhibitor: (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[1,2-c]quinoline-7-one dihydrochloride (TAS-103), by means of ~1H-NMR and ~(31)P-NMR spectroscopy, structure computation techniques, thermal melting study, and UV-visible spectroscopy. In aqueous solution, all chemical shifts of TAS-103 underwent upfield shifts depending with an increase in concentration. The two-dimensional (2D)-NMR spectra and structure computations indicated that TAS-103 self-associated through π-π stacking and hydrophobic interactions of the aromatic chromophores. Thermal melting indicated that the binding of TAS-103 to DNA with a potency equal to that of ethidium bromide (EtBr). The UV-Visible spectra of TAS-103 titrated by several DNA exhibited hypochromic and hypsochromic effects. The ~(31)P-NMR spectrum of the 6:1 TAS-103/d(CGCGAATTCGCG)_2 complex showed two broadening signals. 2D-NMR spectra of the 1:1 TAS-103/d(CGCGAATTCGCG)_2 complex indicated that the chemical shift differences of the DNA are very small. However, those of the terminal region are relatively large. The chemical shift differences of TAs-103 showed that the proton resonances except H2 underwent downfield shifts. From these observations, we conclude that TAS-103 binds to DNA by two modes. The major binding mode is on the surface (outside binding) and the minor binding mode by intercalation.
机译：我们研究的目的是研究DNA拓扑异构酶I（Topo I）和II（Topo II）双重抑制剂（6-[[[2-（二甲基氨基）乙基]氨基]-的自缔合和DNA结合特性。 3-羟基-7H-茚并[1,2-c]喹啉-7-二盐酸盐（TAS-103），通过〜1H-NMR和〜（31）P-NMR光谱，结构计算技术，热熔研究在水溶液中，TAS-103的所有化学位移都随浓度的增加而发生高场位移，二维（2D）-NMR光谱和结构计算表明，TAS-103通过芳香族发色团的π-π堆积和疏水相互作用。热融解表明TAS-103与DNA的结合力与溴化乙锭（EtBr）相等。TAS-103的紫外可见光谱由数个DNA滴定TAS-103 / d（CGCGAATTCGCG）_2配合物的〜（31）P-NMR谱图显示出两个扩大信号。 1：1 TAS-103 / d（CGCGAATTCGCG）_2配合物的2D-NMR光谱表明，DNA的化学位移差异非常小。然而，末端区域的那些相对较大。 TAs-103的化学位移差异表明除H2以外的质子共振经历了场下位移。从这些观察结果，我们得出结论，TAS-103通过两种模式与DNA结合。主要的结合方式是在表面上（外部结合），次要的结合方式是通过插入。

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