Institute of Microbial Pharmaceuticals, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, PR China.
Bioorg Chem. 2020 Jan;94:103420. doi: 10.1016/j.bioorg.2019.103420. Epub 2019 Nov 4.
A concise total synthesis of an exceedingly potent anti-inflammatory agent violacin A as well as the preparation of thirty analogues of this lead from commercially available orcinol are described. Highlights of our synthetic efforts involve Friedel-Crafts acylation, the regioselective etherification and esterification of phenolic hydroxyl groups, and Baker-Venkatamaran rearrangement to form basic skeleton of violacin A. The deprotection reaction with Pd-catalytic was involved to avoid the elimination of the hemiacetal hydroxyl at C2. In addition, all synthetic compounds were screened for anti-inflammatory activity against nitric oxide (NO) production using lipopolysaccharide (LPS)-induced Raw264.7 cells. A range of violacin A derivatives 11b, 11d, 11f, 12e, 12g, 13g, 17d-g exhibited stronger anti-inflammatory effect than that of violacin A. Notably, halogeno-benzyloxy substituent at C-7 were favourable for anti-inflammatory activities of violacin A derivatives. Additionally, Western blot results indicated halogeno-benzyloxy derivatives inhibited pro-inflammatory cytokines releases correlated with the suppression of NF-κB signaling pathway.
本文描述了一种强效抗炎剂 violacin A 的简洁全合成，以及 30 种该先导化合物的类似物的制备。我们的合成工作重点包括 Friedel-Crafts 酰化、酚羟基的区域选择性醚化和酯化，以及 Baker-Venkatamaran 重排以形成 violacin A 的基本骨架。涉及 Pd 催化的脱保护反应以避免 C2 位的半缩醛羟基消除。此外，所有合成化合物均采用脂多糖 (LPS) 诱导的 Raw264.7 细胞筛选对一氧化氮 (NO) 产生的抗炎活性。一系列 violacin A 衍生物 11b、11d、11f、12e、12g、13g、17d-g 表现出比 violacin A 更强的抗炎作用。值得注意的是，C-7 位的卤代苄氧基取代基有利于 violacin A 衍生物的抗炎活性。此外，Western blot 结果表明，卤代苄氧基衍生物通过抑制 NF-κB 信号通路抑制与促炎细胞因子释放相关。
