Potent arylsulfonamide inhibitors of tumor necrosis factor-α 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

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish
Pages (from-to)2622-2635
Number of pages14
JournalJournal of Medicinal Chemistry
Volume53
Issue number6
DOIs
Publication statusPublished - Mar 25 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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