连氨基脲链的三氮唑并噻二唑类DOT1L抑制剂的设计, 合成及活性

Based on the drug design method of combination of privileged fragments, a series of novel triazolothiadiazole derivatives linked with amino side chain containing urea group were designed as potential DOT1L (disruptor of telomeric silencing 1-like) inhibitors. The intermediate 13 with benzyl chloride on triazolothiadiazole structure was synthesized from aromatic acid through five steps. Under the condition of weak base (DIPEA), the nucleophilic substitution reaction between 13 and amino chain with urea group resulted in triazolothiadiazole derivatives linked with amino side chain containing urea group 15a~15k, while under the condition of strong base (NaH), the new dimeric structure analogues 22a~22d bearing with triazolothiadiazole-triazolothiadiazine were obtained by intermolecular reaction of two molecules of 13. The inhibitory activities of compounds 15 and 22 against DOT1L were tested. The results showed that the tested compounds exhibited moderate or weak DOT1L inhibitory activities at 50 μmol•L^-1. Among them, compounds 15k and 22a were the best ones with IC₅₀ values of 25.92 and 10.59 μmol•L^-1, respectively, lower than that of the positive control (E)-6-(2-(furan-2-yl)vinyl)-3-phenyl-[1,2, 4]triazolo[3,4-b] [1,3,4]thiadiazole (10). The results of docking experiments suggested that the bulky amino-urea side chain might be the main reason for the loss of the activities of the compounds, which sterically hindered the molecular from binding to the DOT1L enzyme.