Schwarz Oliver, Jakupovic Sven, Ambrosi Horst-Dieter, Haustedt Lars Ole, Mang Christian, Müller-Kuhrt Lutz
Analyticon Discovery GmbH, Hermannswerder Haus 17, 14473 Potsdam, Germany.
J Comb Chem. 2007 Nov-Dec;9(6):1104-13. doi: 10.1021/cc700098t. Epub 2007 Sep 13.
Recently, we developed a concept known as biology-oriented synthesis (BIOS), which targets the design and synthesis of small- to medium-sized compound libraries on the basis of genuine natural product templates to provide screening compounds with high biological relevance. We herein describe the parallel solution phase synthesis of two BIOS-based libraries starting from alpha-santonin (1). Modification of the sesquiterpene lactone 1 by introduction of a thiazole moiety followed by a Lewis-acid-mediated lactone opening yielded a first library of natural product analogues. An acid-mediated dienone-phenol rearrangement of 1 and a subsequent etherification/amidation sequence led to a second natural product-based library. After application of a fingerprint-based virtual screening on these compounds, the biological screening of 23 selected library members against 5-lipoxygenase resulted in the discovery of four potent novel inhibitors of this enzyme.
最近，我们提出了一种名为生物导向合成（BIOS）的概念，该概念旨在基于真正的天然产物模板设计和合成中小型化合物库，以提供具有高度生物学相关性的筛选化合物。在此，我们描述了从α-山道年（1）开始的两个基于BIOS的库的平行溶液相合成。通过引入噻唑部分对倍半萜内酯1进行修饰，随后进行路易斯酸介导的内酯开环反应，得到了第一个天然产物类似物库。1的酸介导的二烯酮-苯酚重排以及随后的醚化/酰胺化序列产生了第二个基于天然产物的库。在对这些化合物进行基于指纹的虚拟筛选后，对23个选定的库成员针对5-脂氧合酶进行生物筛选，结果发现了该酶的四种有效的新型抑制剂。
