Yang Qingjing, Wang Zihao, Hor Catherine Hong Huan, Xiao Haitao, Bian Zhaoxiang, Wang Jun Joelle
Department of Chemistry, Hong Kong Baptist University, Hong Kong.
Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China.
Sci Adv. 2022 Jun 3;8(22):eabm9603. doi: 10.1126/sciadv.abm9603.
Flavanols are privileged heterocyclic compounds in medicinal chemistry. It is notable to develop an efficient and straightforward protocol for accessing chiral flavanols with precise control of the stereocenters. Here, a highly efficient kinetic resolution of chromenes was reported via Cu-catalyzed asymmetric hydroboration. This previously unidentified approach features a one-step synthesis of chiral flavan-3-ols containing two vicinal stereogenic centers via a highly efficient kinetic resolution ( factor up to 1060, >99% ee for most products). In addition, the anti-inflammation effects of these diversified flavan-3-ols were studied by the in vitro experiments and RNA sequencing analysis. These flavan-3-ols showed inhibitory effects on the secretion of pro-inflammation cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as inhibiting the inflammation responses through down-regulating the gene transcriptions closely related to PI3K-Akt signaling pathway and TNF signaling pathway. The results suggested that these newly synthesized flavan-3-ols have the potential to be lead compounds for anti-inflammatory drugs.
黄烷醇是药物化学中重要的杂环化合物。开发一种高效且直接的方法来精确控制立体中心从而获得手性黄烷醇是值得关注的。在此，报道了一种通过铜催化的不对称硼氢化反应实现的高效色烯动力学拆分方法。这种前所未有的方法通过高效动力学拆分（因子高达1060，大多数产物的对映体过量值>99%）一步合成了含有两个相邻立体中心的手性黄烷-3-醇。此外，通过体外实验和RNA测序分析研究了这些多样化的黄烷-3-醇的抗炎作用。这些黄烷-3-醇对促炎细胞因子如白细胞介素-1β（IL-1β）、IL-6和肿瘤坏死因子-α（TNF-α）的分泌具有抑制作用，并且通过下调与PI3K-Akt信号通路和TNF信号通路密切相关的基因转录来抑制炎症反应。结果表明，这些新合成的黄烷-3-醇有潜力成为抗炎药物的先导化合物。
