Synthesis and properties of novel artificial nucleic acid analogs having chiral backbones

肽核酸（PNA）是一种寡核苷酸模拟物，具有非手性聚酰胺主链，核碱基附着在主链上。由于PNA与单链DNA和RNA以及双链DNA结合，因此被认为是反义策略的潜在有用分子。众所周知，PNA-DNA和PNA-RNA双链比相应的DNA-DNA和DNA-RNA双链更稳定。然而，最近通过核磁共振对PNA-DNA和PNA-RNA双链的结构研究表明，由于PNA的螺旋间距比DNA和RNA大得多，PNA在这类复合物中的构象并不是最优RNA。在这项研究中，我试图合成一种新型的DNA类似物，来自l -丝氨酸与酯键，丝氨酸基核碱基连接聚酯（SNE）。与PNA相比，目前具有聚酯骨架的DNA类似物预计具有更短的螺旋节距，这与互补核酸杂交是相同的。我开发了一种合成由N-（胸腺素-1-酰基）乙酰l -丝氨酸组成的聚酯型核酸类似物的新策略。以l -丝氨酸乙酯为原料，经三步反应合成了胸腺碱单体，产率高，不发生外消旋。发现3-硝基-1,2,4-三唑-1-基-三（吡咯烷-1-基）六氟磷酸磷（PyNTP）在不外消旋的情况下快速形成酯键非常有效。采用2-苯基-2-（三甲基硅基）乙基作为羧基保护基团，成功地进行了液相合成。通过使用一种新型的连接剂和可以在温和的中性条件下去除的氨基保护基团，实现了SNE的固相合成。

Peptide nucleic acid(PNA), an oligonucleotide mimic, has an achiral polyamide backbone, to which nucleobases are attached. Since PNA binds to single stranded DNA and RNA as well as to double stranded DNA, it is regarded as a potentially useful molecule for antisense strategy. It is well known that the PNA-DNA and PNA-RNA duplexes are more stable than the corresponding DNA-DNA and DNA-RNA duplexes. However, the recent structural studies on PNA-DNA and PNA-RNA duplexes by NMR indicated that the conformation of PNA in such complexes was not optimal RNA because the helical pitch of PNA is much larger than that of DNA and RNA. In this study, I tried to synthesize a new type of DNA analog derived from L-serine with ester linkages, serine-based nucleobase-linked polyester (SNE). The present DNA analog bearing a polyester backbone is expected to have a shorter helical pitch compared with that of PNA, which is identical for the hybridization with complementary nucleic acids. I developed a new strategy for the synthesis of a polyester-type nucleic acid analog consist of N-(thymin-1-yl)acetyl L-serine. The monomer unit bearing thymine base was synthesized from L-serine ethyl ester by a three-step reaction in good yield without racemization. 3-Nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP) was found to be highly effective for the rapid ester bond formation without racemization. 2-Phenyl-2-(trimethylsilyl)ethyl group was successfully employed as a carboxyl protecting group in solution-phase synthesis. Solid-phase synthesis of SNE was achieved by using a novel type of linker and amino-protecting groups that can be removed under mild neutral conditions.