Potent Arylsulfonamide Inhibitors of Tumor Necrosis Factor-α Converting Enzyme Able to Reduce Activated Leukocyte Cell Adhesion Molecule Shedding in Cancer Cell Models

被引：33
|
作者：
Nuti, Elisa [2 ]
Casalini, Francesca [2 ]
Avramova, Stanislava I. [2 ]
Santamaria, Salvatore [2 ]
Fabbi, Marina [1 ]
Ferrini, Silvano [1 ]
Marinelli, Luciana [3 ]
La Pietra, Valeria [3 ]
Limongelli, Vittorio [3 ]
Novellino, Ettore [3 ]
Cercignani, Giovanni [4 ]
Orlandini, Elisabetta [2 ]
Nencetti, Susanna [2 ]
Rossello, Armando [2 ]
机构：
[1] Ist Nazl Ric Canc, I-16132 Genoa, Italy
[2] Univ Pisa, Dipartimento Sci Farmaceut, I-56126 Pisa, Italy
[3] Univ Naples Federico 2, Dipartimento Chim Farmaceut & Tossicol, I-80131 Naples, Italy
[4] Univ Pisa, Dipartimento Biol, Unita Biochim, I-56127 Pisa, Italy
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 06期
关键词：
MATRIX-METALLOPROTEINASE INHIBITORS; PROTEIN-LIGAND COMPLEXES; GROWTH-FACTOR RECEPTOR; SELECTIVE INHIBITORS; TACE INHIBITORS; BIOLOGICAL EVALUATION; CARBONIC-ANHYDRASE; FORCE-FIELD; DESIGN; MIGRATION;
D O I：
10.1021/jm901868z
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Activated leukocyte cell adhesion molecule (ALCAM) plays a relevant role in tumor biology and progression. Our previous studies showed that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by nonspecific inhibitors of ADAM-17. For this reason. ADAM-17 may represent a new useful target in anticancer therapy. Herein, we report the synthesis and biological evaluation of new ADAM-17 inhibitors containing an arylsulfonamidic scaffold. Among the new potential inhibitors, two very promising compounds 17 and 18 were discovered, with a nanomolar activity for ADAM-17 isolated enzyme. These compounds proved to be also the most potent in inhibiting soluble ALCAM release in cancer cells, showing a nanomolar activity on A2774 and SKOV3 cell lines.
引用
收藏
页码：2622 / 2635
页数：14
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