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学科主题: 生命有机化学
题名: Development of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins
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
作者: YANG CHENGWEN1; CHEN SHA1; ZHOU MI1; LI YAN1; LI YANGFENG1; ZHANG ZHENGXI1; LIU ZHEN1; BA QIAN1; LI JINGQUAN1; WANG HUI1; YAN XIAOMEI1; Ma DW(马大为)1; Wang RX(王任小)1
通讯作者: YAN XIAOMEI ; 马大为 ; 王任小
刊名: ChemMedChem
发表日期: 2014
DOI: 10.1002/cmdc.201400058
卷: 9, 期:7, 页:1436-1452
收录类别: SCI
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.
语种: 英语
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内容类型: 期刊论文
URI标识: http://ir.sioc.ac.cn/handle/331003/38951
Appears in Collections:生命有机化学国家重点实验室_期刊论文

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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

Recommended Citation:
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.
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