Department of Chemistry, CZ-Openscreen, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
International Clinical Research Centre, St. Anne's University Hospital, Pekařská 53, Brno, 656 91, Czech Republic.
Angew Chem Int Ed Engl. 2019 Jan 21;58(4):1062-1066. doi: 10.1002/anie.201810312. Epub 2018 Dec 20.
Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.
报告指出，呋喃[3,2-b]吡啶核心被鉴定为新型支架，可用于研发高效且高选择性的细胞分裂周期蛋白样激酶（CLKs）抑制剂，以及 Hedgehog 信号通路的有效调节剂。最初，通过基于化学选择性金属介导偶联的合成序列，制备了多样化的靶标化合物库，包括通过铜介导的氧化环化来组装呋喃[3,2-b]吡啶支架。对包含 3,5-二取代呋喃[3,2-b]吡啶的亚系列进行优化，得到了高效、细胞活性且高选择性的 CLKs 抑制剂。对激酶非活性的 3,5,7-三取代呋喃[3,2-b]吡啶亚类进行分析，发现它们是 Hedgehog 通路的亚微摩尔调节剂。
