Diaminic carbonates, a new class of anti-inflammatory compounds: their biological characterization and mode of action.
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 alpha (huTNFalpha)-induced cytotoxicity in a dose-dependent manner. Structure-function relationship studies indicated precise structural requirements for compounds being active as huTNFalpha inhibitors. ITF1779, one of the most active compounds in inhibiting huTNFalpha-induced cytotoxicity, was selected for further studies. In vitro experiments showed that ITF1779 inhibited not only huTNFalpha-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 factoralpha production.
Porro
G
G
Italfarmaco S.p.A., Centro Ricerche, Milan, Italy.
Bertolini
G
G
Bonardi
M A
MA
Giovanetti
E
E
Lento
P
P
Leoni
F
F
Modena
D
D
Pavich
G
G
Marcucci
F
F
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002082:Butylamines / Q000494:pharmacology*; D002254:Carbonates / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000139:chemically induced / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D002082:Butylamines; D002254:Carbonates; C111785:ITF 1779; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha