Novel Peptidyl Aryl Vinyl Sulfones as Highly Potent and Selective Inhibitors of Cathepsins L and B

被引：26

作者：

Mendieta, Laura ^{[1
]}

Pico, Anna ^{[2
]}

Tarrago, Teresa ^{[1
]}

Teixido, Meritxell ^{[1
]}

Castillo, Marcos ^{[2
]}

Rafecas, Llorenc ^{[3
]}

Moyano, Albert ^{[2
]}

Giralt, Ernest ^{[1
,2
]}

机构：

[1] Inst Res Biomed Barcelona, Barcelona 08028, Spain

[2] Univ Barcelona, Dept Quim Organ, E-08028 Barcelona, Spain

[3] ENANTIA SL, Barcelona 08028, Spain

来源：

CHEMMEDCHEM | 2010年 / 5卷 / 09期

关键词：

aryl vinyl sulfones; cathepsins; cysteine proteases; enzymes; medicinal chemistry; CYSTEINE PROTEASE INHIBITORS; CRYSTAL-STRUCTURE; MULTISTAGE TUMORIGENESIS; SPECIFICITY; DESIGN; CANCER; ROLES; IDENTIFICATION; CHEMOTHERAPY; PROTEINS;

D O I：

10.1002/cmdc.201000109

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we present the design, synthesis, and evaluation of a structurally novel library of 20 peptidyl 3-aryl vinyl sulfones as inhibitors of cathepsins L and B. The building blocks, described here for the first time, were synthesized in a highly efficient and enantioselective manner, starting from 3-aryl-substituted allyl alcohols. The corresponding vinyl sulfones were prepared by a new approach, based on a combination of solid-phase peptide synthesis using the Fmoc/tBu strategy, followed by solution-phase coupling to the corresponding (R)-3-amino-3-aryl vinyl sulfones as trifluoroacetate salts. The inhibitory activity of the resulting compounds against cathepsins L and B was evaluated, and the compound exhibiting the best activity was selected for enzymatic characterization. Finally, docking studies were performed in order to identify key structural features of the aryl substituent.

引用

页码：1556 / 1567

页数：12

共 32 条

[1] 1,2-dioxines containing tethered hydroxyl functionality as convenient precursors for pyran syntheses [J].