Proteasome inhibition by a totally synthetic beta-lactam related to salinosporamide A and omuralide.
A new and effective proteasome inhibitor, beta-lactam 3, has been accessed enantioselectively by multistep synthesis from the readily prepared intermediates 7 and 8 which were joined by a [2 + 2]-cycloaddition reaction to form the spiro beta-lactam 9 stereoselectively. The intermediate 9 was converted to 3 in seven steps and 30% overall yield. The beta-lactam 3 is stable for many days in water at pH 7, in contrast to the natural beta-lactones salinosporamide A (1) and omuralide (2). In common with 1 and 2, the beta-lactam 3 effectively inhibits the mammalian proteasome.
Hogan
Philip C
PC
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Corey
E J
EJ
D004355:Drug Stability; D006207:Half-Life; D007700:Kinetics; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; D047090:beta-Lactams / Q000138:chemical synthesis / Q000494:pharmacology*
D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; D047090:beta-Lactams; C117645:omuralide; C475865:marizomib