Sugar amino acid based peptide epoxyketones as potential proteasome inhibitors.
This paper describes the synthesis and biological evaluation of nine epoxomicin-derived sugar amino acid containing peptide epoxyketones. The title compounds are assembled from six sugar amino acid dipeptide isosteres and are synthesized using solution-phase peptide synthesis protocols. Although neither of the compounds displays inhibitory activity towards any of the proteasome active sites, our approach holds promise towards the development of structurally new proteasome inhibitors. It is likely that the central sugar amino acid dipeptide isoster needs to be designed such that it closely resemble dipeptides at position P2 and P3 in proteasome substrates inhibitors, such as the Thr-Ile dipeptide present in the lead compound, epoxomicin.
Risseeuw
Martijn D P
MD
Leiden Institute of Chemistry, Leiden University, The Netherlands.
Florea
Bogdan I
BI
van der Marel
Gijsbert A
GA
Overkleeft
Herman S
HS
Overhand
Mark
M
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D013400:Sugar Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D004791:Enzyme Inhibitors; D007659:Ketones; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D013400:Sugar Acids; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin