Proteasome inhibitors; synthesis and activity of arecoline oxide tripeptide derivatives.
We describe the synthesis and biological activities of a series of methyl 3,4-epoxypiperidine-3-carboxylate tripeptide derivatives that inhibit the chymotryptic and tryptic active sites of the 20S proteasome. Of the series, compound 2 which contains 3-hydroxy-2-methylbenzoyl group at its N-terminal position, displayed the greatest inhibitory potency (IC(50) <1 microM). All derivatives showed favourable pharmacokinetic properties.
Marastoni
Mauro
M
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, I-44100 Ferrara, Italy. mru@dns.unife.it
McDonald
John
J
Baldisserotto
Anna
A
Canella
Alessandro
A
De Risi
Carmela
C
Pollini
Gian Piero
GP
Tomatis
Roberto
R
D001115:Arecoline / Q000031:analogs & derivatives / Q000737:chemistry*; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases; D006801:Humans; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship
D009097:Multienzyme Complexes; D009842:Oligopeptides; D011480:Protease Inhibitors; D001115:Arecoline; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex