RT Journal Article
SR Electronic
T1 Diaminic Carbonates, a New Class of Anti-inflammatory Compounds: Their Biological Characterization and Mode of Action
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 193
OP 200
VO 285
IS 1
A1 Giuliana Porro
A1 Giorgio Bertolini
A1 M. Antonietta Bonardi
A1 Elena Giovanetti
A1 Paola Lento
A1 Flavio Leoni
A1 Daniela Modena
A1 Gianfranco Pavich
A1 Fabrizio Marcucci
YR 1998
UL http://jpet.aspetjournals.org/content/285/1/193.abstract
AB Taking advantage of a standard assay on mouse LM cells (murine fibroblast-like cells), we found that several diaminic carbonates, a new class of organic compounds synthesized in our laboratories, were able to inhibit human tumor necrosis factor α (huTNFα)-induced cytotoxicity in a dose-dependent manner. Structure-function relationship studies indicated precise structural requirements for compounds being active as huTNFα inhibitors. ITF1779, one of the most active compounds in inhibiting huTNFα-induced cytotoxicity, was selected for further studies. In vitro experiments showed that ITF1779 inhibited not only huTNFα-induced cytotoxicity on LM cells but also another response of the same cells, interleukin-1-induced interleukin-6 production. Receptor-binding studies performed under nonequilibrium conditions and morphologic evidence of vacuole formation in cells treated with high concentrations of ITF1779 showed that the effects were strikingly similar to those of chloroquine, a lysosomotropic agent. Consistent with a mechanism of action of diaminic carbonates closely matching that of chloroquine are some structural similarities between the two classes of compounds, in particular their both being diprotic weak bases. Moreover, ITF1779 was shown to be active in vivo because it afforded protection against lipopolysaccharide-induced shock in mice, a systemic inflammatory response crucially dependent on tumor necrosis factorα production. The American Society for Pharmacology and Experimental Therapeutics