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  

Design,Synthesis,and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors

作　　者：刘娜 郭思岐 刘俊芳 陈彦韬 徐晓明 张静 康亚青 罗成 陈示洁 陈华 Liu Na;Guo Siqi;Liu Junfang;Chen Yantao;Xu Xiaoming;Zhang Jing;Kang Yaqing;Luo Cheng;Chen Shijie;Chen Hua(Key Laboratory of Chemical Biology of Hebei Province,College of Chemistry and Environmental Science,Hebei University,Baoding,Hebei 071002;State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Science,Shanghai 201203;School of Pharmacy,Nanchang University,Nanchang 330006)

机构地区：[1]河北大学化学与环境科学学院,河北省化学生物学重点实验室,河北保定071002 [2]中国科学院上海药物研究所新药研究国家重点实验室,上海201203 [3]南昌大学药学院,南昌330006

出　　处：《有机化学》2020年第8期2450-2459,共10页Chinese Journal of Organic Chemistry

基　　金：河北大学自然科学多学科交叉研究计划(No.DXK201903)资助项目。

摘　　要：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50μmol·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.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 50μmol·L^-1.Among them,compounds 15k and 22a were the best ones with IC50 values of 25.92 and 10.59μmol·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.

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 

分 类 号：TQ460.1[化学工程—制药化工]