518-18-3Relevant articles and documents
Design, synthesis and bioactivity study of evodiamine derivatives as multifunctional agents for the treatment of hepatocellular carcinoma
Fan, Xiaohong,Deng, Jiedan,Shi, Tao,Wen, Huaixiu,Li, Junfang,Liang, Ziyi,Lei, Fang,Liu, Dan,Zhang, Honghua,Liang, Yan,Hao, Xiangyong,Wang, Zhen
, (2021/07/14)
Topoisomerase has been found extremely high level of expression in hepatocellular carcinoma (HCC) and proven to promote the proliferation and survival of HCC. Cancer-associated fibroblasts (CAFs) as a kind of key reactive stromal cell that abundantly present in the microenvironment of HCC, could enhance the metastatic ability and drug resistance of HCC. Therefore, developing new drugs that address the above conundrums would be of the upmost significant in the fight against HCC. Evodiamine, as a multi-target natural product, has been found to exert various biological activities such as anti-cancer and anti-hepatic fibrosis via blocking topoisomerase, NF-κB, TGF-β/HGF, and Smad2/3. Inspired by these facts, 15 evodiamine derivatives were designed and synthesized for HCC treatment by simultaneously targeting Topo I and CAFs. Most of them displayed preferable anti-HCC activities on three HCC cell lines and low cytotoxicity on one normal hepatic cell. In particular, compound 8 showed the best inhibitory effect on HCC cell lines and a good inhibition on Topo I in vitro. Meanwhile, it also induced obvious G2/M arrest and apoptosis, and significantly decreased the migration and invasion capacity of HCC cells. In addition, compound 8 down-regulated the expression of type I collagen in the activated HSC-T6 cells, and induced the apoptosis of activated HSC-T6 cells. In vivo studies demonstrated that compound 8 markedly decreased the volume and weight of tumor (TGI = 40.53%). In vitro and in vivo studies showed that its effects were superior to those of evodiamine. This preliminary attempt may provide a promising strategy for developing anti-HCC lead compounds taking effect through simultaneous inhibition on Topo I and CAFs.
Palladium-Catalyzed Carbonylative Difunctionalization of C=N Bond of Azaarenes or Imines to Quinazolinones
Zhou, Xibing,Ding, Yongzheng,Huang, Hanmin
, p. 1678 - 1682 (2020/05/05)
Supporting information for this article is given via a link at the end of the document. By intercepting the acylpalladium species with C=N bond of azaarenes or imines other than free amines or alcohols, the difunctionalization of C=N bond was established via palladium-catalyzed carbonylation/nucleophilic addition sequence. This method is compatible with a diverse range of azaarenes and imines and allows for the efficient synthesis of a wide range of quinazolinones and derivatives. The synthetic utility has been demonstrated by one-step synthesis of evodiamine and its analogue with inexpensive starting materials.
Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket
Zhang, Tianhua,Lai, Zengwei,Yuan, Suying,Huang, Yi-You,Dong, Guoqiang,Sheng, Chunquan,Ke, Hengming,Luo, Hai-Bin
, p. 9828 - 9837 (2020/10/19)
Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 ? movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.
