Highly Efficient Synthesis of Artificial Nucleic Acids Having New Functions

开发了高效合成可用作药物或功能材料的人造核酸的新方法。硼磷酸盐DNA被认为是潜在的有用的反义分子或稳定的核酸功能材料。基于一种新的硼磷酰化反应(硼磷三酯法)，我们开发了一种合成硼磷酸盐DNA的新方法。我们还开发了一种新的反应来将硼磷酸DNA转化为相应的H-磷酸DNA，这些DNA是合成各种骨架修饰的DNA类似物的有用中间体。在这些DNA类似物中，硫代硫代DNA是迄今为止应用最广泛的反义药物。然而，由于磷的手性，目前使用的硫代DNA是非对映异构体的随机混合物。我们开发了一种以3‘-恶唑磷烷为单体的核苷类化合物立体控制合成硫代磷酸DNA的新方法(恶唑磷烷方法)。该方法被成功地应用于硫代磷酸核糖核酸和其他骨架修饰的核酸类似物的立体控制合成。

New methods for the highly efficient synthesis of artificial nucleic acids, which are useful as drugs or functional materials, were developed. Boranophosphate DNAs are regarded as potentially useful antisense molecules or stable nucleic acid-based functional materials. We developed a new method for the synthesis of the boranophosphate DNAs on the basis of a new boranophosphorylation reaction (boranophosphotriester approach). We also developed a new reaction for the transformation of the boranophosphate DNAs into the corresponding H-phosphonate DNAs, which are useful intermediates for the synthesis of a wide variety of backbone-modified DNA analogs. Among these DNA analogs, phosphorothioate DNAs are most widely used for antisense drugs to date. However, the currently used phosphorothioate DNAs are random mixtures of diastereomers owing to the phosphorous chirality. We developed a new method for the stereocontrolled synthesis of phosphorothioate DNAs by the use of nucleoside 3'-oxazaphospholidine derivatives as monomers (oxazaphospholidine approach). The method was successfully applied to the stereocontrolled synthesis of phosphorothioate RNAs as well as other backbone-modified nucleic acid analogs.