Stereoselective synthesis of photoreactive peptidomimetic gamma-secretase inhibitors.
The first asymmetric synthesis of novel, potent photoreactive gamma-secretase inhibitors 2 and 3 has been accomplished. Two stereoselective methods for the preparation of lactone 9 are described. Protected benzophenone intermediate 19 is prepared via an aldol-elimination reaction followed by a PtO(2)-catalyzed asymmetric hydrogenation. Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing gamma-secretase activity in the plasma membrane of intact cells.
Chun
Jiong
J
Molecular Pharmacology & Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Yin
Ye Ingrid
YI
Yang
Guangli
G
Tarassishin
Leonid
L
Li
Yue-Ming
YM
D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry / Q000201:enzymology; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D010450:Endopeptidases / Q000737:chemistry / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000737:chemistry*; D010777:Photochemistry; D013237:Stereoisomerism
D002219:Carbamates; D004151:Dipeptides; D004791:Enzyme Inhibitors; C410009:L 685458; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human