摘要/Abstract

以DOT1L（Disruptor of telomeric silencing 1-like）抑制剂（8）为母体结构，对其核心骨架三氮唑并噻二唑两端的取代基进行结构修饰，设计合成了两个系列的三氮唑并噻二唑类结构衍生物，并测试了化合物在浓度为50 μmol/L时的DOT1L酶抑制活性.结果表明，所测化合物均表现出一定的酶抑制活性，其中N，N-二甲基-4-（6-甲基-[1，2，4]三唑并[3，4-b][1，3，4]噻二唑-3-基）苯胺（14b）和（R）-{1-{{3-[4-（二甲基氨基）苯基]-[1，2，4]三唑并[3，4-b][1，3，4]噻二唑-6-基叔丁基}甲基}哌啶-3-基}氨基甲酸叔丁酯（16a）具有显著的DOT1L抑制活性，IC₅₀值分别为7.37和7.84 μmol/L，与阳性对照化合物8的酶抑制活性相当.构效分析表明，当苯基连三氮唑并噻二唑部分占据S-腺苷-L-甲硫氨酸（SAM）结合位点时，R¹为4-N，N-二甲基、分子尾部R²基团为疏水基团，适宜于分子与酶的结合，且其体积对活性影响较小.
关键词: DOT1L抑制剂, 三氮唑并噻二唑, 结构改造, 疏水基团, 构效关系
A series of novel derivatives containing triazolo-thiadiazole moiety have been synthesized by structural modifications on a lead disruptor of telomeric silencing 1-like (DOT1L) inhibitor 8. All the compounds have been evaluated for their DOT1L inhibitory activities at the concentration of 50 μmol/L. The results showed that the tested compounds showed certain DOT1L inhibitory activities. Among them, N,N-dimethyl-4-(6-methyl-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazol-3-yl)aniline (14b) and (R)-tert-butyl (1-((3-(4-(dimethylamino)phenyl)-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazol-6-yl)methyl)-piperidin-3-yl)carba- mate (16a) were the best ones with IC₅₀ values of 7.37 and 7.84 μmol/L, respectively, near that of the positive control 8. The structure-activity analysis showed that when the triazolo-thiadiazole moiety occupied the binding-site of S-adenosylmethionine (SAM) in DOT1L and R¹ group was 4-N,N-dimethyl, the hydrophobic substituents as the tailed R² groups would be accommodated into the DOT1L binding site, and the sizes of the substituents seemed no effects on their DOT1L inhibitory activities of the compounds.
Key words: DOT1L inhibitor, ttriazolo-thiadiazole, structural modification, hydrophobic substituent, structure-activity analysis


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