Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors
文献类型：期刊论文
| 作者 | Liu Na1; Guo Siqi2,3; Liu Junfang1; Chen Yantao2; Xu Xiaoming1; Zhang Jing1; Kang Yaqing1; Luo Cheng2 ; Chen Shijie2; Chen Hua1
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| 刊名 | CHINESE JOURNAL OF ORGANIC CHEMISTRY
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| 出版日期 | 2020-08-25 |
| 卷号 | 40期号:8页码:2450-2459 |
| 关键词 | DOT1L inhibitor triazolothiadiazole triazolothiadiazine nucleophilic substitution |
| ISSN号 | 0253-2786 |
| DOI | 10.6023/cjoc201910037 |
| 通讯作者 | Chen Shijie(shijiechen@simm.ac.cn) ; Chen Hua(hua-todd@163.com) |
| 英文摘要 | 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 similar to 15k, while under the condition of strong base (NaH), the new dimeric structure analogues 22a similar to 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 mu mol.L-1. Among them, compounds 15k and 22a were the best ones with IC50 values of 25.92 and 10.59 mu mol.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 |
| WOS关键词 | ACCURATE DOCKING ; LEUKEMIA-CELLS ; POTENT ; GLIDE ; DISRUPTOR ; DISCOVERY |
| 资助项目 | Natural Science Interdisciplinary Research Program of Hebei University[DXK201903] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000581125800022 |
| 出版者 | SCIENCE PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292631]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Chen Shijie; Chen Hua |
| 作者单位 | 1.Hebei Univ, Coll Chem & Environm Sci, Key Lab Chem Biol Hebei Prov, Baoding 071002, Hebei, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu Na,Guo Siqi,Liu Junfang,et al. Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors[J]. CHINESE JOURNAL OF ORGANIC CHEMISTRY,2020,40(8):2450-2459. |
| APA | Liu Na.,Guo Siqi.,Liu Junfang.,Chen Yantao.,Xu Xiaoming.,...&Chen Hua.(2020).Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors.CHINESE JOURNAL OF ORGANIC CHEMISTRY,40(8),2450-2459. |
| MLA | Liu Na,et al."Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors".CHINESE JOURNAL OF ORGANIC CHEMISTRY 40.8(2020):2450-2459. |
入库方式： OAI收割
来源：上海药物研究所
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