Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule shedding in cancer cell models

Elisa Nuti; Francesca Casalini; Stanislava I Avramova; Salvatore Santamaria; Marina Fabbi; Silvano Ferrini; Luciana Marinelli; Valeria La Pietra; Vittorio Limongelli; Ettore Novellino; Giovanni Cercignani; Elisabetta Orlandini; Susanna Nencetti; Armando Rossello

doi:10.1021/jm901868z

Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule shedding in cancer cell models

J Med Chem. 2010 Mar 25;53(6):2622-35. doi: 10.1021/jm901868z.

Authors

Elisa Nuti¹, Francesca Casalini, Stanislava I Avramova, Salvatore Santamaria, Marina Fabbi, Silvano Ferrini, Luciana Marinelli, Valeria La Pietra, Vittorio Limongelli, Ettore Novellino, Giovanni Cercignani, Elisabetta Orlandini, Susanna Nencetti, Armando Rossello

Affiliation

¹ Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.

PMID: 20180536
DOI: 10.1021/jm901868z

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM Proteins / chemistry
ADAM Proteins / metabolism
ADAM17 Protein
Activated-Leukocyte Cell Adhesion Molecule / metabolism*
Blotting, Western
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Assays
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Enzyme-Linked Immunosorbent Assay
Female
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Kinetics
Models, Chemical
Models, Molecular
Molecular Structure
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Protein Binding
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

2-(4-(but-2-ynyloxy)phenylsulfonamido)-4-(1,3-dioxoisoindolin-2-yl)-N-hydroxybutanamide
Activated-Leukocyte Cell Adhesion Molecule
Enzyme Inhibitors
Hydroxamic Acids
Sulfonamides
benzyl 3-(4-(but-2-ynyloxy)phenylsulfonamido)-4-(hydroxyamino)-4-oxobutylcarbamate
ADAM Proteins
ADAM17 Protein
ADAM17 protein, human