Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule shedding in cancer cell models.
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.
Nuti
Elisa
E
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Casalini
Francesca
F
Avramova
Stanislava I
SI
Santamaria
Salvatore
S
Fabbi
Marina
M
Ferrini
Silvano
S
Marinelli
Luciana
L
La Pietra
Valeria
V
Limongelli
Vittorio
V
Novellino
Ettore
E
Cercignani
Giovanni
G
Orlandini
Elisabetta
E
Nencetti
Susanna
S
Rossello
Armando
A
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C549059:2-(4-(but-2-ynyloxy)phenylsulfonamido)-4-(1,3-dioxoisoindolin-2-yl)-N-hydroxybutanamide; D020410:Activated-Leukocyte Cell Adhesion Molecule; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; C549058:benzyl 3-(4-(but-2-ynyloxy)phenylsulfonamido)-4-(hydroxyamino)-4-oxobutylcarbamate; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human