De Novo Design, Synthesis and Evaluation of Benzylpiperazine Derivatives as Highly Selective Binders of Mcl-1
文献类型：期刊论文
| 作者 | Ding, Xiao2; Li, Yan3; Lv, Li2; Zhou, Mi3; Han, Li3; Zhang, Zhengxi3; Ba, Qian1; Li, Jingquan1; Wang, Hui1; Liu, Hong2
|
| 刊名 | CHEMMEDCHEM
 |
| 出版日期 | 2013-12 |
| 卷号 | 8期号:12页码:1986-2014 |
| 关键词 | apoptosis bcl-2 family proteins protein-protein interactions selective inhibitors |
| ISSN号 | 1860-7179 |
| DOI | 10.1002/cmdc.201300316 |
| 文献子类 | Article |
| 英文摘要 | Considerable efforts have been made to the development of small-molecule inhibitors of antiapoptotic B-cell lymphoma2 (Bcl-2) family proteins (such as Bcl-2, Bcl-x(L), and Mcl-1) as a new class of anticancer therapies. Unlike general inhibitors of the entire family, selective inhibitors of each member protein can hopefully reduce the adverse side effects in chemotherapy treatments of cancers overexpressing different Bcl-2 family proteins. In this study, we designed four series of benzylpiperazine derivatives as plausible Bcl-2 inhibitors based on the outcomes of a computational algorithm. A total of 81 compounds were synthesized, and their binding affinities to Bcl-2, Bcl-x(L), and Mcl-1 measured. Encouragingly, 22 compounds exhibited binding affinities in the micromolar range (K-i<20M) to at least one target protein. Moreover, some compounds were observed to be highly selective binders to Mcl-1 with no detectable binding to Bcl-2 or Bcl-x(L), among which the most potent one has a K-i value of 0.18M for Mcl-1. Binding modes of four selected compounds to Mcl-1 and Bcl-x(L) were derived through molecular docking and molecular dynamics simulations. It seems that the binding affinity and selectivity of these compounds can be reasonably interpreted with these models. Our study demonstrated the possibility for obtaining selective Mcl-1 inhibitors with relatively simple chemical scaffolds. The active compounds identified by us could be used as lead compounds for developing even more potent selective Mcl-1 inhibitors with potential pharmaceutical applications. |
| WOS关键词 | BCL-2 FAMILY PROTEINS ; SMALL-MOLECULE INHIBITORS ; STRUCTURE-BASED DISCOVERY ; BH3 MIMETIC ABT-737 ; DRUG DISCOVERY ; CANCER-THERAPY ; CELL-DEATH ; X-L ; APOPTOSIS ; POTENT |
| 资助项目 | National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[81025017] ; National Natural Science Foundation of China[81172984] ; National Natural Science Foundation of China[21072213] ; National Natural Science Foundation of China[21002117] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000327504400009 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277359]  |
| 专题 | 药物化学研究室 药物发现与设计中心 |
| 通讯作者 | Ding, Xiao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai 200031, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan Chem, Shanghai 200032, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Ding, Xiao,Li, Yan,Lv, Li,et al. De Novo Design, Synthesis and Evaluation of Benzylpiperazine Derivatives as Highly Selective Binders of Mcl-1[J]. CHEMMEDCHEM,2013,8(12):1986-2014. |
| APA | Ding, Xiao.,Li, Yan.,Lv, Li.,Zhou, Mi.,Han, Li.,...&Wang, Renxiao.(2013).De Novo Design, Synthesis and Evaluation of Benzylpiperazine Derivatives as Highly Selective Binders of Mcl-1.CHEMMEDCHEM,8(12),1986-2014. |
| MLA | Ding, Xiao,et al."De Novo Design, Synthesis and Evaluation of Benzylpiperazine Derivatives as Highly Selective Binders of Mcl-1".CHEMMEDCHEM 8.12(2013):1986-2014. |
入库方式： OAI收割
来源：上海药物研究所
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