Synthesis of Bifacial Peptide Nucleic Acids with Diketopiperazine Backbones.
Synthesis of Bifacial Peptide Nucleic Acids with Diketopiperazine Backbones.
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DOI：
10.1055/a-1802-6873
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发表时间：
2022-06
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--
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我们报道了一种具有新的二酮哌嗪（DKP）骨架的双面肽核酸（bPNA）的合成，该骨架显示非天然的三聚氰胺（M）碱基以及天然碱基。为了研究DKP bPNAs的结构-功能范围，我们通过使用二氨基丙酸、二氨基丁酸、鸟氨酸和赖氨酸衍生物来显示碱基三重基序，从而导致一个、两个、三个或四个碳将α碳连接到侧链胺，合成了一组bPNAs。与这些bPNA的DNA杂交的热变性显示，最佳的侧链连接是四个碳，对应于赖氨酸衍生物。因此，通过Fmoc-赖氨酸的ε-胺与腺嘌呤、胞苷、尿苷和三聚氰胺的乙醛衍生物的双还原烷基化制备每个侧链显示两个碱基的单体。有了这些结构单元，制备DKP bPNA以显示天然和合成（三聚氰胺）碱的组合。初步的熔化研究表明，结合签名的胞苷和三聚氰胺展示bPNAs富含T的DNA的非规范结构，虽然这种行为的全面表征正在进行中。所描述的方便且潜在可扩展的方法使得能够快速获得低（<1 kD）分子量和先前建立的细胞渗透性的DNA结合支架。我们期望这种直接有效的核酸结合剂的方法将使非经典核酸杂交的研究成为可能。
We report a synthesis of bifacial peptide nucleic acids (bPNAs) with novel diketopiperazine (DKP) backbones that display unnatural melamine (M) bases, as well as native bases. To examine the structure–function scope of DKP bPNAs, we synthesized a set of bPNAs by using diaminopropionic acid, diaminobutyric acid, ornithine, and lysine derivatives to display the base-tripling motifs, which result in one, two, three, or four carbons linking the alpha carbon to the side-chain amine. Thermal denaturation of DNA hybrids with these bPNAs revealed that the optimal side-chain linkage was four carbons, corresponding to the lysine derivative. Accordingly, monomers displaying two bases per side-chain were prepared through double reductive alkylation of the ε-amine of Fmoc-lysine with acetaldehyde derivatives of adenine, cytidine, uridine, and melamine. With these building blocks in hand, DKP bPNAs were prepared to display a combination of native and synthetic (melamine) bases. Preliminary melting studies indicate binding signatures of cytidine- and melamine-displaying bPNAs to T-rich DNAs of noncanonical structure, though full characterization of this behavior is ongoing. The convenient and potentially scalable method described enables rapid access to DNA-binding scaffolds of low (<1 kD) molecular weight and previously established cell permeability. We expect that this straightforward and efficient approach to nucleic acid binders will enable studies on noncanonical nucleic acid hybridization.
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