Encoded Library Technologies/NCE Molecular Discovery, GSK, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
Org Lett. 2023 Mar 3;25(8):1241-1245. doi: 10.1021/acs.orglett.2c04043. Epub 2023 Feb 20.
Developing new on-DNA reactions is paramount to the development of new encoded libraries in the pursuit of novel pharmaceutical lead compounds. Lactam-containing molecules have been shown to be effective in a wide range of therapeutic areas and therefore represent a promising target for further investigation by DNA-encoded library screening. In pursuit of this motif, we report a novel method for the introduction of lactam-containing structures onto a DNA headpiece through the Ugi four-center three-component reaction (4C-3CR). This novel method is successful in three different approaches to give unique on-DNA lactam structures: on-DNA aldehyde coupled with isonitriles and amino acids; on-DNA isonitrile coupled with aldehydes and amino acids; and on-DNA isonitrile coupled with amines and acid aldehydes.
开发新的 DNA 反应对于开发新的编码文库以寻找新型药物先导化合物至关重要。含内酰胺的分子已被证明在广泛的治疗领域有效，因此代表了通过 DNA 编码文库筛选进一步研究的有前途的目标。为了追求这一主题，我们报告了一种通过 Ugi 四中心三组分反应 (4C-3CR) 将含内酰胺结构引入 DNA 头部的新方法。这种新方法在三种不同的方法中都成功地得到了独特的 DNA 内酰胺结构：DNA 醛与异腈和氨基酸偶联；DNA 异腈与醛和氨基酸偶联；以及 DNA 异腈与胺和酸醛偶联。
