Trypanocidal activity of β-lactone-γ-lactam proteasome inhibitors.
Four β-lactone- γ-lactam proteasome inhibitors of natural origin were tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of Trypanosoma brucei. All four compounds displayed activities in the nanomolar range. The most trypanocidal compounds with 50% growth inhibition (GI(50)) values of around 3 nM were the bromine and iodine analogues of salinosporamide A, a potent proteasome inhibitor produced by the marine actinomycete Salinispora tropica. In general, trypanosomes were more susceptible to the compounds than were human HL-60 cells. The data support the potential of β-lactone- γ-lactam proteasome inhibitors for rational anti-trypanosomal drug development.
BioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, UK. dsteverding@hotmail.com
Dietmar
D
Steverding
Xia
X
Wang
Barbara C
BC
Potts
Michael A
MA
Palladino
D001688:Biological Products / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007769:Lactams / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D001688:Biological Products; D004791:Enzyme Inhibitors; D007769:Lactams; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; D014344:Trypanocidal Agents; C475865:marizomib