Design and synthesis of a potent and selective peptidomimetic inhibitor of caspase-3.
In this paper we report the synthesis and characterization of a novel potent and selective inhibitor of caspase-3, a member of the caspase family of cysteine proteases which plays an important role in many human disorders. This molecule represents 3(S)-acetylamino-N-[1-[(((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)carbamoyl)methyl]-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]succinamic acid, a monocyclic conformationally constrained form of the tetrapeptide Ac-DEVD-H, in which a 1,4-benzodiazepine nucleus is introduced internally to the peptidic sequence.
Micale
Nicola
N
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Illinois 60612, USA. nmicale@pharma.unime.it
Vairagoundar
Rajendran
R
Yakovlev
Alexander G
AG
Kozikowski
Alan P
AP
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D006801:Humans; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C495225:3-acetylamino-N-(1-(((2-hydroxy-5-oxo-tetrahydrofuran-3-yl)carbamoyl)methyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)succinamic acid; D001570:Benzodiazepinones; D061945:Caspase Inhibitors; D009842:Oligopeptides; D011994:Recombinant Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015107:4-Butyrolactone