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.
Elisa Nuti  1 ,  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
Affiliations
  • 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.