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Development of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins
Alternative TitleDevelopment of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins
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
2014
Source PublicationChemMedChem
Volume9Issue:7Pages:1436-1452
AbstractAntiapoptotic 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.
Subject Area生命有机化学
DOI10.1002/cmdc.201400058
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Indexed BySCI
Language英语
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Document Type期刊论文
Identifierhttp://ir.sioc.ac.cn/handle/331003/38951
Collection生命有机化学国家重点实验室
Corresponding AuthorYAN XIAOMEI; Ma DW(马大为); Wang RX(王任小)
Affiliation1.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
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.
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