Kekulé-Institut für Organische Chemie und Biochemie , Universität Bonn , Gerhard-Domagk-Str. 1 , D-53121 Bonn , Germany.
Pharmazeutisches Institut , Universität Bonn , An der Immenburg 4 , D-53121 Bonn , Germany.
J Med Chem. 2020 Feb 27;63(4):1684-1698. doi: 10.1021/acs.jmedchem.9b01887. Epub 2020 Feb 13.
Vacuolar type ATPase (V-ATPase) has recently emerged as a promising novel anticancer target based on extensive and studies with archazolids, complex polyketide macrolides, which present the most potent V-ATPase inhibitors known to date. Herein, we report a biomimetic, one-step preparation of archazolid F, the most potent and least abundant archazolid, the design and synthesis of five novel, carefully selected archazolid analogues, and the biological evaluation of these antiproliferative agents, leading to the discovery of a very potent but profoundly simplified archazolid analogue. Furthermore, the first general biological profiling of the archazolids against a broad range of more than 100 therapeutically relevant targets is reported, leading to the discovery of novel and important targets. Finally, first pharmacokinetic data of these natural products are disclosed. All of these data are relevant in the further preclinical development of the archazolids as well as the evaluation of V-ATPases as a novel and powerful class of anticancer targets.
液泡型 ATP 酶 (V-ATPase) 最近成为一种有前途的新型抗癌靶点，这是基于对 archazolids 的广泛研究，archazolids 是一种复杂的多酮大环内酯，是迄今为止已知最有效的 V-ATPase 抑制剂。在此，我们报告了一种仿生的一步制备方法，用于制备最有效和最稀缺的 archazolid F，设计和合成了五种新型、精心选择的 archazolid 类似物，并对这些有抗增殖作用的试剂进行了生物评价，从而发现了一种非常有效但却大大简化的 archazolid 类似物。此外，还首次对 archazolids 针对超过 100 种治疗相关靶标的广泛生物学特性进行了综合分析，发现了新的重要靶标。最后，还首次披露了这些天然产物的药代动力学数据。所有这些数据对于 archazolids 的进一步临床前开发以及将 V-ATPase 作为一种新型强效抗癌靶点的评估都具有重要意义。
