摘要/Abstract

依据优势片段结合的药物设计方法，设计了新的连接有氨基脲链的三氮唑并噻二唑类DOT1L（类端粒沉默干扰体1）酶抑制剂.化合物的合成以芳香酸为原料，经五步反应得到了含苄基氯结构的三氮唑并噻二唑中间体13.弱碱性（DIPEA）条件下，化合物13与氨基侧链发生亲核取代反应，得到连氨基脲链的三氮唑并噻二唑类化合物15a~15k；而在强碱性（NaH）条件下，化合物13自身反应得到新的三氮唑并噻二唑连三氮唑并噻二嗪的二聚结构类似物22a~22d.测试了化合物15和22对DOT1L的酶抑制活性，结果显示所测化合物在50 μmol·L^-1时表现出中等或较弱的DOT1L抑制活性，其中化合物15k和二聚类似物22a活性最好，IC₅₀值分别为25.92和10.59μmol·L^-1，但均低于阳性对照物（E）-6-（2-（呋喃-2-基）乙烯基）-3-苯基-[1，2，4]三唑[3，4-b][1，3，4]噻二唑的酶抑制活性.分子对接实验提示，氨基脲侧链体积较大，可能是所合成化合物活性较低的主要原因.
关键词: DOT1L抑制剂, 三氮唑并噻二唑, 三氮唑并噻二嗪, 亲核取代
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.
Key words: DOT1L inhibitor, triazolothiadiazole, triazolothiadiazine, nucleophilic substitution


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