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Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras an efficient entry to DNA-encoded libraries inspired by drug structures

机译:酸和金(i)介导的六胸苷-DNA-杂环嵌合体的合成可有效进入受药物结构启发的DNA编码文库

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摘要

Libraries of DNA-tagged compounds are a validated screening technology for drug discovery. They are synthesized through combinatorial iterations of alternated coding and preparative synthesis steps. Thus, large chemical space can be accessed for target-based screening. However, the need to preserve the functionality of the DNA tag severely restricts the choice of chemical methods for library synthesis. Acidic organocatalysts, transition metals, and oxidants furnish diverse drug-like structures from simple starting materials, but cause loss of genetic information by depurination. A hexathymidine oligonucleotide, called “>hexT” allows the chemist utilizing these classes of catalysts to access a potentially broad variety of structures in the initial step of library synthesis. We exploited its catalyst tolerance to efficiently synthesize diverse substituted β-carbolines, pyrazolines, and pyrazoles from readily available starting materials as >hexT conjugates by acid- and Au(i)-catalysis, respectively. The >hexT conjugates were ligated to coding DNA sequences yielding encoded screening libraries inspired by drug structures.
机译:带DNA标签的化合物的库是用于药物发现的经过验证的筛选技术。它们通过交替编码和准备合成步骤的组合迭代来合成。因此,可以使用较大的化学空间进行基于靶标的筛选。但是,保留DNA标签功能的需求严重限制了文库合成化学方法的选择。酸性有机催化剂,过渡金属和氧化剂可从简单的起始原料中提供多种类似于药物的结构,但会因净化作用而导致遗传信息丢失。六胸苷寡核苷酸,称为“ > hexT ”,使化学家可以利用这些类型的催化剂在库合成的初始步骤中获得可能广泛的结构。我们利用其对催化剂的耐受性,分别通过酸和Au(i)催化有效地从容易获得的起始原料中以> hexT 共轭物的形式有效地合成了各种取代的β-咔啉,吡唑啉和吡唑。将> hexT 结合物连接至编码DNA序列,产生受药物结构启发的编码筛选文库。

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