Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc, 1891 Rutherford Road, Carlsbad, CA 92008, United States.
Bioorg Med Chem Lett. 2011 Jan 1;21(1):588-91. doi: 10.1016/j.bmcl.2010.10.025. Epub 2010 Oct 14.
The synthesis and hybridization properties of an α-L-LNA analog where the 2'-oxygen atom is replaced with an exocyclic methylene group is reported. Contrary to the β-D series where the exocyclic methylene group is extremely well tolerated, this group was very poorly tolerated in the α-L-series and lead to duplex destabilization. Modeling studies showed that the exocyclic methylene group results in a steric clash with the nucleobase 3' to the modified residue. Based on this structural model one can anticipate that replacing the 2'-oxygen atom of α-L-LNA with larger groups is likely to be detrimental to duplex stability. The model also provides insights into what type of 2',4'-bridges are most likely to be tolerated in α-L-LNA modified oligonucleotide duplexes.
报道了一种α-L-LNA 类似物的合成和杂交特性，其中 2'-氧原子被取代为环外亚甲基基团。与β-D 系列相反，其中环外亚甲基基团非常耐受，该基团在α-L 系列中非常不耐受，导致双链体不稳定。建模研究表明，环外亚甲基基团导致与修饰残基 3' 的碱基发生空间位阻。基于这个结构模型，可以预测用更大的基团取代α-L-LNA 的 2'-氧原子可能对双链体稳定性有害。该模型还深入了解了在α-L-LNA 修饰的寡核苷酸双链体中最有可能耐受哪种类型的 2'、4'-桥。
