Li Longbo, Matsuo Bianca, Levitre Guillaume, McClain Edward J, Voight Eric A, Crane Erika A, Molander Gary A
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania 231 South 34th Street Philadelphia Pennsylvania 19104-6323 USA
Drug Discovery Science & Technology, Discovery Research & Development, AbbVie, Inc., 1 North Waukegan Rd North Chicago Illinois 60064-1802 USA.
Chem Sci. 2023 Feb 9;14(10):2713-2720. doi: 10.1039/d3sc00144j. eCollection 2023 Mar 8.
DNA-encoded library (DEL) screens have significantly impacted new lead compound identification efforts within drug discovery. An advantage of DELs compared to traditional screening methods is that an exponentially broader chemical space can be effectively screened using only nmol quantities of billions of DNA-tagged, drug-like molecules. The synthesis of DELs containing diverse, sp-rich spirocycles, an important class of molecules in drug discovery, has not been previously reported. Herein, we demonstrate the synthesis of complex and novel spirocyclic cores an on-DNA, visible light-mediated intermolecular [2 + 2] cycloaddition of olefins with heterocycles, including indoles, azaindoles, benzofurans, and coumarins. The DNA-tagged -methylenecyclobutane substrates were prepared from easily accessible alkyl iodides and styrene derivatives. Broad reactivity with many other DNA-conjugated alkene substrates was observed, including unactivated and activated alkenes, and the process is tolerant of various heterocycles. The cycloaddition was successfully scaled from 10 to 100 nmol without diminished yield, indicative of this reaction's suitability for DNA-encoded library production. Evaluation of DNA compatibility with the developed reaction in a mock-library format showed that the DNA barcode was maintained with high fidelity, with <1% mutated sequences and >99% amplifiable DNA from quantitative polymerase chain reaction (PCR) and next generation sequencing (NGS).
DNA编码文库（DEL）筛选对药物发现中新型先导化合物的鉴定工作产生了重大影响。与传统筛选方法相比，DEL的一个优势在于，仅使用纳摩尔量的数十亿个带有DNA标签的类药物分子，就能有效筛选出指数级更广阔的化学空间。此前尚未报道过包含多样、富含sp的螺环（药物发现中的一类重要分子）的DEL的合成。在此，我们展示了复杂且新颖的螺环核心的合成——通过烯烃与杂环（包括吲哚、氮杂吲哚、苯并呋喃和香豆素）的分子间[2 + 2]环加成反应在DNA上进行可见光介导的反应。带有DNA标签的亚甲基环丁烷底物由易于获取的烷基碘化物和苯乙烯衍生物制备而成。观察到该反应与许多其他DNA共轭烯烃底物具有广泛的反应性，包括未活化和活化的烯烃，并且该过程对各种杂环具有耐受性。环加成反应成功地从10纳摩尔扩大到100纳摩尔，产率没有降低，这表明该反应适用于DNA编码文库的制备。以模拟文库形式评估DNA与所开发反应的兼容性表明，DNA条形码以高保真度得以保留，定量聚合酶链反应（PCR）和下一代测序（NGS）显示突变序列<1%，可扩增DNA>99%。
