Faculty of Chemistry and Chemical Biology , TU Dortmund University , Otto-Hahn-Straße 6 , 44227 Dortmund , Germany.
Max Planck Institute of Molecular Physiology , Otto-Hahn-Straße 11 , 44227 Dortmund , Germany.
J Am Chem Soc. 2019 Jul 3;141(26):10546-10555. doi: 10.1021/jacs.9b05696. Epub 2019 Jun 21.
The translation of well-established molecular biology methods such as genetic coding, selection, and DNA sequencing to combinatorial organic chemistry and compound identification has made extremely large compound collections, termed DNA-encoded libraries, accessible for drug screening. However, the reactivity of the DNA imposes limitations on the choice of chemical methods for encoded library synthesis. For example, strongly acidic reaction conditions must be avoided because they damage the DNA by depurination, i.e. the cleavage of purine bases from the oligomer. Application of micellar catalysis holds much promise for encoded chemistry. Aqueous micellar dispersions enabled compound synthesis under often appealingly mild conditions. Amphiphilic block copolymers covalently functionalized with sulfonic acid moieties in the lipophilic portion assemble in water and locate the Brønsted catalyst in micelles. These acid nanoreactors enabled the reaction of DNA-conjugated aldehydes to diverse substituted tetrahydroquinolines and aminoimidazopyridines by Povarov and Groebke-Blackburn-Bienaymé reactions, respectively, and the cleavage of tBoc protective groups from amines. The polymer micelle design was successfully translated to the Cu/Bipyridine/TEMPO system mediating the oxidation of DNA-coupled alcohols to the corresponding aldehydes. These results suggest a potentially broad applicability of polymer micelles for encoded chemistry.
将成熟的分子生物学方法（如遗传编码、选择和 DNA 测序）转化为组合有机化学和化合物鉴定，使得可以使用称为 DNA 编码文库的极其庞大的化合物库进行药物筛选。然而，DNA 的反应性限制了用于编码文库合成的化学方法的选择。例如，必须避免强烈的酸性反应条件，因为它们会通过脱嘌呤作用（即从寡聚物中切割嘌呤碱基）破坏 DNA。胶束催化在编码化学中具有很大的应用前景。胶束分散体允许在通常吸引人的温和条件下进行化合物合成。亲脂部分共价功能化有磺酸基的两亲嵌段共聚物在水中组装，并将 Brønsted 催化剂定位在胶束中。这些酸纳米反应器分别通过 Povarov 和 Groebke-Blackburn-Bienaymé 反应使 DNA 缀合的醛与各种取代的四氢喹啉和氨基咪唑并吡啶反应，并使伯 Boc 保护基从胺中脱保护。该聚合物胶束设计成功地转化为 Cu/Bipyridine/TEMPO 体系，介导 DNA 偶联的醇氧化为相应的醛。这些结果表明聚合物胶束在编码化学中具有潜在的广泛适用性。
