Wutz D, Gluhacevic D, Chakrabarti A, Schmidtkunz K, Robaa D, Erdmann F, Romier C, Sippl W, Jung M, König B
Institute of Organic Chemistry, University of Regensburg, 93053 Regensburg, Germany.
Org Biomol Chem. 2017 Jun 7;15(22):4882-4896. doi: 10.1039/c7ob00976c.
Histone deacetylases (HDACs) play a crucial role in numerous biological processes and therefore are targeted in anticancer research and in the field of epigenetics. Dithienylethenes (DTEs) and fulgimides were functionalized with hydroxamic acids, which is a known moiety binding to zinc dependent HDACs, to gain photoswitchable HDAC inhibitors. The new DTE based inhibitors showed moderate photochromic properties in polar solvents and the inhibitory activity changes up to a factor of four. The photochromic performance of the prepared fulgimide inhibitors was very good, even in aqueous buffer. They achieved a maximum three-fold difference in inhibitory activity. Docking experiments using the crystal structures of the tested enzymes gave a rationale for the observed moderate differences in the activities of the inhibitors.
组蛋白去乙酰化酶（HDACs）在众多生物过程中发挥着关键作用，因此在抗癌研究和表观遗传学领域成为了研究靶点。二噻吩乙烯（DTEs）和俘精酰亚胺用异羟肟酸进行了功能化修饰，异羟肟酸是一种已知的与锌依赖性HDACs结合的基团，以此获得可光开关的HDAC抑制剂。新型基于DTE的抑制剂在极性溶剂中表现出适度的光致变色特性，其抑制活性变化高达四倍。所制备的俘精酰亚胺抑制剂的光致变色性能非常好，即使在水性缓冲液中也是如此。它们在抑制活性上实现了最大三倍的差异。使用所测试酶的晶体结构进行的对接实验为观察到的抑制剂活性适度差异提供了理论依据。
