Linear TMC-95-Based Proteasome Inhibitors
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- 作者：Nicolas Basse ; Sandrine Piguel ; David Papapostolou ; Alexandra Ferrier-Berthelot ; Nicolas Richy ; Maurice Pagano ; Pierre Sarthou ; Joë ; lle Sobczak-Thé ; pot ; Michè ; le Reboud-Ravaux ; Joë
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：June 14, 2007
- 年：2007
- 卷：50
- 期：12
- 页码：2842 - 2850
- 全文大小：167K
- 年卷期：v.50,no.12(June 14, 2007)
- ISSN：1520-4804
文摘
We have designed and evaluated 45 linear analogues of the natural constrained cyclopeptide TMC-95A.These synthetically less demanding molecules are based on the tripeptide sequence Y-N-W of TMC-95A.Structural variations in the amino acid side chains and termini greatly influenced both the efficiency andselectivity of action on a given type of active site. Inhibition constants were submicromolar (Ki 
300 nM)despite the absence of the entropically favorable constrained conformation that is characteristic of TMC-95A and its cyclic analogues. These linear compounds were readily prepared and reasonably stable in culturemedium and could be optimized to inhibit one, two, or all three proteasome catalytic sites. Cytotoxicityassays performed on a series of human tumor cell lines identified the most potent inhibitors in cells.
300 nM)despite the absence of the entropically favorable constrained conformation that is characteristic of TMC-95A and its cyclic analogues. These linear compounds were readily prepared and reasonably stable in culturemedium and could be optimized to inhibit one, two, or all three proteasome catalytic sites. Cytotoxicityassays performed on a series of human tumor cell lines identified the most potent inhibitors in cells.