Fakultät für Chemie und Chemische Biologie , Technische Universität Dortmund , Otto-Hahn-Straße 4a , 44227 Dortmund , Germany.
Abteilung Chemische Biologie , Max Planck Institut für Molekulare Physiologie , Otto-Hahn-Straße 11 , 44227 Dortmund , Germany.
J Am Chem Soc. 2019 Apr 3;141(13):5381-5391. doi: 10.1021/jacs.9b00040. Epub 2019 Mar 19.
Halogen bonding (XB) has recently emerged as a promising noncovalent activation mode that can be employed in catalysis. However, methodologies utilizing XB remain rare, and the hydrogen-bonding (HB) catalysis congeners are more widespread in comparison. Herein, we demonstrate a remarkable case whereby employment of XB catalysis in strain-release glycosylation generates O, N-glycosides in excellent anomeric selectivity exceeding HB activation. Deeper investigation unraveled XB catalyst dependencies on multiple stages of the mechanism and a hitherto unknown XB-glycosyl acceptor activation. We present a proof of concept to interrogate sp-rich glycosidic chemical space for novel biological activity, by integrating XB-catalyzed construction of a glycosidic compound collection, and evaluating these analogues via cell-based phenotypic screens. We show that XB-catalyzed strain-release glycosylation defines a new class of glycosides that inhibit the hedgehog signaling pathway through a nonsmoothened mode of action, opening new opportunities to combat acquired cancer resistance.
卤键（XB）作为一种新兴的非共价活化模式，在催化中具有广阔的应用前景。然而，利用 XB 的方法仍然很少，相比之下，氢键（HB）催化类似物更为普遍。在此，我们展示了一个显著的例子，即在应变释放糖基化中采用 XB 催化可以生成 O、N-糖苷，具有优异的端基选择性，超过 HB 活化。进一步的研究揭示了 XB 催化剂对反应机制多个阶段的依赖性，以及一种迄今为止未知的 XB-糖基受体活化。我们提出了一个概念验证，通过整合 XB 催化的糖苷化合物库的构建，并通过基于细胞的表型筛选来评估这些类似物，来探究富含 sp 的糖苷化学空间中的新型生物学活性。我们表明，应变释放糖基化的 XB 催化定义了一类新的糖苷，它们通过非 Smoothened 作用模式抑制 hedgehog 信号通路，为对抗获得性癌症耐药性开辟了新的机会。
