Proteasome inhibition by peptide-semicarbazones.
Peptide-semicarbazones derived from Z-Trp-Trp-Phe-aldehyde inhibit the chymotryptic activity of the human proteasome at nanomolar concentrations, but are less active in a NFkappaB reporter gene assay. Cyclic semicarbazones, in contrast, combine a strong inhibitory effect on the enzyme with an inhibition of NFkappaB signaling in the nanomolar range. In addition, a practical synthesis for scale-up of such compounds was developed.
Leban
Johann
J
4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany. leban@4sc.com
Blisse
Marcus
M
Krauss
Babett
B
Rath
Sandra
S
Baumgartner
Roland
R
Seifert
Markus H J
MH
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors; D012664:Semicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D010455:Peptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D012664:Semicarbazones; D046988:Proteasome Endopeptidase Complex