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Development of the Efficient Synthetic Method for Nucleosides labeled with Stable Isotopes and Their Application to Structural Analysis of the Complex of a DNA with a Drug

稳定同位素标记核苷高效合成方法的建立及其在DNA与药物复合物结构分析中的应用

基本信息

批准号：
11672117
负责人：
KAWASHIMA Etsuko
金额：
$ 1.73万
依托单位：
Tokyo University of Pharmacy and Life Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

For the elucidation of the recognition mechanism of a DNA with a drug, the studies were performed as follows ; 1. the structural analysis of the complex of a [5'-^<13>C]DNA with Tallimustine (distamycin analogue) by NMR spectroscopy and 2. the development of the efficient methodology for the synthesis of 2'-deoxyribonucleosides site-specifically and diastereoselectivly labeled with ^<13>C and/or ^2H at their 5'- or 3'-positions. On the first study, the analysis of a d(C^*G^*C^*G^*A^*A^*T^*T^*C^*G^*C^*G)_2 {N^* : [5'-^<13>C]nucleotide} provided us with the correlation between C5'(i)-C6H(i-1) or -C8H(i), the sequential NOEs and unambiguous assignment of all the signals. We extend these results to NMR study of the complex of [5'-^<13>C]DNA with Tallimustine (distamycin analogue). The structural information on surrounded by H5' protons in a complex of these drug with a DNA has not been obtained, because of the difficulty of the assignment for H5' proton signals. We have overcome this problem by NMR analysis of a complex of [5'-^<13>C]DNA with a drug. Information obtained from our studies should aid in the investigation of sequence-specific DNA-protein or -drug recognition processes.On the second studies, we achieved the development of the efficient methodology for the synthesis of (2'R)-2'-deoxy[2-^2H]guanosine and D-[5-^2H]ribofuranose derivative. Moreover, we found that a significant role of the phenylcarbamoyl protecting group in the asymmetric dihydroxylation reaction of the unsubstituted allyl alcoholic system using AD-mix-α and -β was confirmed to afford remarkably high enantioselectivity (>99% ee).

为了阐明DNA与药物的识别机制，研究进行如下：1. [5'-^<13>C]DNA与他莫司汀（二霉素类似物）配合物的核磁共振结构分析。开发了合成2'-脱氧核糖核苷的有效方法，并在5'-或3'-位置上以^<13>C和/或^2H进行非对映选择性标记。在第一项研究中，对a d(C^*G^*C^*G^* a ^* a ^*T^*C^*G^*C^*G)_2 {N^*: [5'-^<13>C]核苷酸}的分析为我们提供了C5'(i)- c6h （i-1）或- c8h (i)之间的相关性，序列NOEs和所有信号的无二义分配。我们将这些结果扩展到[5'-^<13>C]DNA与他莫司汀（双霉素类似物）复合物的核磁共振研究。由于H5′质子信号的分配困难，这些药物与DNA复合物中被H5′质子包围的结构信息尚未得到。我们通过核磁共振分析[5'-^<13>C]DNA与药物的复合物，克服了这个问题。从我们的研究中获得的信息应该有助于研究序列特异性dna -蛋白质或药物识别过程。在第二项研究中，我们开发了合成(2' r)-2'-脱氧[2-^2H]鸟苷和D-[5-^2H]核糖呋喃糖衍生物的高效方法。此外，我们发现苯基氨基甲酰保护基团在AD-mix-α和-β的非取代烯丙基醇体系的不对称二羟基化反应中发挥了重要作用，证实了它具有非常高的对映选择性（>99% ee）。