Development of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins
文献类型：期刊论文
| 作者 | YANG CHENGWEN1; CHEN SHA1; ZHOU MI1; LI YAN1; LI YANGFENG1; ZHANG ZHENGXI1; LIU ZHEN1; BA QIAN1; LI JINGQUAN1; WANG HUI1 |
| 刊名 | ChemMedChem
 |
| 出版日期 | 2014 |
| 卷号 | 9期号:7页码:1436-1452 |
| 其他题名 | Development of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins |
| 通讯作者 | YAN XIAOMEI ; 马大为 ; 王任小 |
| 英文摘要 | Antiapoptotic Bcl-2 family proteins, such as Bcl-x(L), Bcl-2, and Mcl-1, are often overexpressed in tumor cells, which contributes to tumor cell resistance to chemotherapies and radio-therapies. Inhibitors of these proteins thus have potential applications in cancer treatment. We discovered, through structure-based virtual screening, a lead compound with micromolar binding affinity to Mcl-1 (inhibition constant (K-i)=3 mu m). It contains a phenyltetrazole and a hydrazinecarbothioamide moiety, and it represents a structural scaffold not observed among known Bcl-2 inhibitors. This work presents the structural optimization of this lead compound. By following the scaf-fold-hopping strategy, we have designed and synthesized a total of 82 compounds in three sets. All of the compounds were evaluated in a fluorescence-polarization binding assay to measure their binding affinities to Bcl-x(L), Bcl-2, and Mcl-1. Some of the compounds with a 3-phenylthiophene-2-sulfonamide core moiety showed sub-micromolar binding affinities to Mcl-1 (K-i=0.3-0.4 mm) or Bcl-2 (K-i approximate to 1 mu m). They also showed obvious cytotoxicity on tumor cells (IC50 < 10 mu m). Two-dimensional heteronuclear single quantum coherence NMR spectra of three selected compounds, that is, YCW-E5, YCW-E10, and YCW-E11, indicated that they bind to the BH3-binding groove on Bcl-x(L) in a similar mode to ABT-737. Several apoptotic assays conducted on HL-60 cells demonstrated that these compounds are able to induce cell apoptosis through the mitochondrial pathway. We propose that the compounds with the 3-phenylthiophene-2-sulfonamide core moiety are worth further optimization as effective apoptosis inducers with an interesting selectivity towards Mcl-1 and Bcl-2. |
| 学科主题 | 生命有机化学 |
| 收录类别 | SCI |
| 原文出处 | http://dx.doi.org/10.1002/cmdc.201400058 |
| 语种 | 英语 |
| 源URL | [http://ir.sioc.ac.cn/handle/331003/38951]  |
| 专题 | 上海有机化学研究所_生命有机化学国家重点实验室 |
| 作者单位 | 1.中科院上海有机化学研究所 2.厦门大学 3.中科院上海生命科学研究院 |
| 推荐引用方式 GB/T 7714 | YANG CHENGWEN,CHEN SHA,ZHOU MI,et al. Development of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins[J]. ChemMedChem,2014,9(7):1436-1452. |
| APA | YANG CHENGWEN.,CHEN SHA.,ZHOU MI.,LI YAN.,LI YANGFENG.,...&王任小.(2014).Development of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins.ChemMedChem,9(7),1436-1452. |
| MLA | YANG CHENGWEN,et al."Development of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins".ChemMedChem 9.7(2014):1436-1452. |
入库方式： OAI收割
来源：上海有机化学研究所
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