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The chirality of metal complexes recognized by DNA and its significance towards biological activities

DNA识别的金属配合物的手性及其对生物活性的意义

基本信息

批准号：
03403009
负责人：
KURODA Reiko
金额：
$ 17.09万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1993
项目状态：
已结题

项目摘要

The modes of DNA-porphyrin interactions are multiple and depend on the central metal ions. We have found that iron-tatrakis(4-N-methylpyridiniumyl)porphyrin possesses surprisengly high sequence preference towards the minor groove of three contiguous A.T base paris from DNase I footprinting study and affinity cleavage experiments. By analyzing CD in the porphyrins's Soret band induced by the interaction with chiral DNA, we could estimate the preferred binding modes and sequences semi-quantitatively.A series of compounds which possess a second functional group at the end of a sidechain, as well as a compounds which possess a second functional group at the end of a sidechain, as well as a compound which substitutes a 4-N-methyl-pyridiniumyl by a tolyl group have been synthesized to study the origin of the sequence selectivity. Affinity cleavage experiments have shown that all the compounds exhibit the same high specificity and at maximum 3 positive charges are necessary for the recognition.Molecular dynamics has shown that the most stable interaction is the side on model in the minor groove, then the major groove binding and the face on model in the minor groove. Non-bonded rather than Coulombic energy seems to contribute the stability difference.A series of new complexes which contain a chiral ligand, [Cu(1,10-phenanthroline)(X-proline)]C1.3H_2O (X=D or L), have been synthesized and their DNA cleavage efficiency compared. The D-enantiomer cleaved DNA more efficiently than the L counterpart. The molecuar structure was determined by the single crystal X-ray diffractometry. A chiral amino acid, histidine, was introduced to the iron porphyrin. This is to study chiral recognition and the consequential difference in the DNA cleavage efficiency and base sequence specificity. The synthesis is near completion.

DNA与卟啉的相互作用模式是多种多样的，并依赖于中心金属离子。通过DNA酶I足迹法和亲和切割实验，我们发现铁-四（4-N-甲基吡啶）卟啉对三个相邻A.T碱基巴黎的小沟具有高度的序列选择性。通过分析卟啉与手性DNA相互作用的Soret带的CD，可以半定量地估计卟啉与手性DNA的优先结合模式和结合顺序。一系列在侧链末端具有第二官能团的化合物，以及一个在侧链末端具有第二官能团的化合物，以及用甲苯基取代4-N-甲基-吡啶鎓基的化合物，以研究序列选择性的起源。亲和切割实验表明，所有化合物都表现出相同的高特异性，最多需要3个正电荷才能识别，分子动力学表明，最稳定的相互作用是小沟中的侧对模型，然后是大沟结合和小沟中的面对模型。本文合成了一系列新的含手性配体[Cu（1，10-Phenanthroline）（X-proline）] C1. 3H_2O（X=D或L）的配合物，并比较了它们对DNA的切割效率。D-对映体比L对应物更有效地切割DNA。用单晶X射线衍射法测定了分子结构。将手性氨基酸组氨酸引入到铁卟啉中。这是为了研究手性识别以及由此导致的DNA切割效率和碱基序列特异性的差异。综合工作已接近完成。