An efficient, convenient solid-phase synthesis of amino acid-modified peptide nucleic acid monomers and oligomers
An efficient, convenient solid-phase synthesis of amino acid-modified peptide nucleic acid monomers and oligomers
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DOI：
10.1021/bc0502208
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发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Lewis, MR
中科院分区：
文献类型：
--
作者：
Balaji, BS;Gallazzi, F;Lewis, MR
描述了一种高效且高度通用的合成氨基酸修饰肽核酸（PNA）单体的方法。通过使用固相Fmoc技术，这些单体可以很容易地以逐步的方式组装，并且以最少的纯化获得高收率。保护中性亲水性，酸性和碱性氨基酸偶联到2-氯三烷基氯树脂。在去除Fmoc之后，开发了关键步骤的创新条件，即n -Fmoc-氨基乙醛的还原烷基化，以避免先前报道的方法遇到的问题。嘧啶和嘌呤核碱基与仲胺的活化和偶联产生氨基酸修饰的PNA单体。所采用的温和反应条件与敏感和不稳定的官能团（如叔丁基醚和叔丁基酯）相容。PNA单体经裂解和纯化后，总产率为36-42%，纯度很高。使用标准固相Fmoc化学，其中两种单体以高偶联效率结合到各种修饰的PNA低聚物中，包括四种设计用于靶向bcl-2 mRNA的四聚体。这种改性低聚物具有提高水溶性和细胞可移植性的潜力，同时保持杂交亲和性和促进良好的生物分布特性。
An efficient and highly versatile method for the synthesis of amino acid-modified peptide nucleic acid (PNA) monomers is described. By using solid-phase Fmoc techniques, such monomers can be assembled readily in a stepwise manner and obtained in high yield with minimal purification. Protected neutral hydrophilic, acidic, and basic amino acids were coupled to 2-chlorotrityl chloride resin. Following Fmoc removal, innovative conditions for the key step, reductive alkylation with N-Fmoc-aminoacetaldehyde, were developed to circumvent problems encountered with previously reported methods. Activation and coupling of pyrimidine and purine nucleobases to the resulting secondary amines afforded amino acid-modified PNA monomers. The mild reaction conditions utilized were compatible with sensitive and labile functional groups, Such as tert-butyl ethers and tert-butyl esters. PNA monomers were obtained in 36-42% overall yield and very high purity, after cleavage and purification. Using standard solid-phase Fmoc chemistry, two of these monomers were incorporated with high coupling efficiency into a variety of modified PNA oligomers, including four tetradecamers designed to target bcl-2 mRNA. Such modified oligomers have the potential to enhance water solubility and cell portability, while maintaining hybridization affinity and promoting favorable biodistribution properties.