Binding of a non-ionic pyrenylisoxazolidine derivative to double-stranded polynucleotides: spectroscopic and molecular modelling studies
Binding of a non-ionic pyrenylisoxazolidine derivative to double-stranded polynucleotides: spectroscopic and molecular modelling studies
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DOI：
10.1039/b517150d
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发表时间：
2006-04-01
影响因子：
3.3
通讯作者：
Sortino, S
中科院分区：
文献类型：
--
作者：
Rescifina, A;Chiacchio, U;Sortino, S
采用紫外-可见吸收光谱和发射光谱相结合的方法，研究了具有潜在抗癌活性的非离子型芘衍生物[（3RS，5SR）-2-甲基-3-芘-1-基异恶唑烷-5-基]甲醇（MPIM）与小牛胸腺DNA（ct-DNA）及人工合成的双链多核苷酸poly-d（AT）（2）和poly-d（GC）（2）在中性pH下的相互作用。荧光猝灭实验和分子模拟研究。在MPIM与多核苷酸结合时观察到伴随着紧密等吸光点形成的减色效应。通过吸光度数据的半倒数图评价的相关结合常数，ct-DNA、poly-d（AT）（2）和poly-d（GC）（2）分别为6.8 x 10（3）M-1、6.0 x 10（3）M-1和1.5 x 10（3）M-1。MPIM的荧光发射强度被ct-DNA轻微淬灭，基本上不受poly-d（AT）（2）的影响，并被poly-d（GC）（2）有效抑制。总体结果支持在ct-DNA和polyd（AT）2的情况下芘衍生物的嵌入结合模式，而浅嵌入似乎涉及poly-d（GC）（2）。对接的研究同意实验观察到的复杂的稳定秩序，并揭示了一个共同的结合模式，这意味着生色团插入之间的桩碱基对和isoxazolidine环躺沿着的主要沟。在任何情况下，在MPIM甲醇部分的羟基和磷酸基团的氧之间形成稳定氢键。MPIM的优先结合选择性嵌入AT丰富的地区可能是由于空间位阻之间的N-甲基和4-氨基的胞嘧啶在GC网站。
The binding of [(3RS,5SR)-2-methyl-3-pyren-1-ylisoxazolidin-5-yl]methanol (MPIM), a non-ionic pyrene derivative with potential anticancer activity, to calf-thymus DNA (ct-DNA) and the synthetic double-strand polynucleotides poly-d(AT)(2) and poly-d(GC)(2) was investigated at neutral pH through the combination of UV-Vis absorption and emission spectroscopy, fluorescence quenching experiments and molecular modelling studies. Hypochromic effects accompanied by the formation of tight isosbestic points were observed upon binding of MPIM to polynucleotides. The related binding constants, evaluated by the half-reciprocal plots of the absorbance data, were 6.8 x 10(3) M-1, 6.0 x 10(3) M-1 and 1.5 x 10(3) M-1 for ct-DNA, poly-d(AT)(2) and poly-d(GC)(2), respectively. The fluorescence emission intensity of MPIM was slightly quenched by ct-DNA, basically unaffected by poly-d(AT)(2) and efficiently suppressed by poly-d(GC)(2). The overall results support an intercalative binding mode of the pyrene derivative in the case of ct-DNA and polyd(AT)2, whereas a shallow intercalation seems to be involved with poly-d(GC)(2). Docking studies agree with the experimentally observed complex stability order and reveal a common binding mode implying that the chromophore intercalates between the staked base pairs and the isoxazolidine ring lying along the major groove. In any case a stabilizing hydrogen bond is formed between the hydroxyl group of the MPIM methanol moiety and the oxygen of a phosphate group. The preferential binding selectivity of MPIM for intercalation in AT-rich regions is probably attributable to steric hindrance between the N-methyl group of MPIM and the 4-amino one of the cytosine in the GC sites.