Stereoselective Synthesis of Photoreactive Peptidomimetic ?-Secretase Inhibitors.

Division of Molecular Pharmacology & Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
The Journal of Organic Chemistry (Impact Factor: 4.72). 11/2004; 69(21):7344-7. DOI: 10.1021/jo0486948
Source: PubMed


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.

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    • "Compounds JC-8, Compound 3, Compound E, GSI-34, and L-685,458 are all synthesized in our laboratory (Chun et al., 2004; Placanica et al., 2009; Shelton et al., 2009a; Yang et al., 2009) and dissolved in DMSO. "
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    ABSTRACT: γ-Secretase is composed of four proteins that are obligatory for protease activity: presenilin, nicastrin, Aph1, and Pen-2. Despite the progress toward understanding the function of these individual subunits, there is no information available pertaining to the modulation of γ-secretase in response to environmental changes in cells. Here, we show that hypoxia upregulates γ-secretase activity through a direct interaction with Hif-1α, revealing an unconventional function for Hif-1α as an enzyme subunit, which is distinct from its canonical role as a transcription factor. Moreover, hypoxia-induced cell invasion and metastasis are alleviated by either γ-secretase inhibitors or a dominant-negative Notch coactivator, indicating that γ-secretase/Notch signaling plays an essential role in controlling these cellular processes. The present study reveals a mechanism in which γ-secretase can achieve temporal control through conditional interactions with regulatory proteins, such as Hif-1α, under select physiological and pathological conditions.
    Cell Reports 08/2014; 8(4). DOI:10.1016/j.celrep.2014.07.028 · 8.36 Impact Factor
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    • "Along with the finding of high γ-secretase activity in synaptic membranes, the plasma membrane marker N-cadherin also correlated well with activity in the iodixanol gradient. Labelling of active γ-secretase in an approach similar to ours has demonstrated the existence of γ-secretase on the cell surface in cell culture [35], and Chyung et al [9] showed that around 6% of the total γ-secretase is present at the cell surface. "
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    ABSTRACT: A key player in the development of Alzheimer's disease (AD) is the gamma-secretase complex consisting of at least four components: presenilin, nicastrin, Aph-1 and Pen-2. gamma-Secretase is crucial for the generation of the neurotoxic amyloid beta-peptide (Abeta) but also takes part in the processing of many other substrates. In cell lines, active gamma-secretase has been found to localize primarily to the Golgi apparatus, endosomes and plasma membranes. However, no thorough studies have been performed to show the subcellular localization of the active gamma-secretase in the affected organ of AD, namely the brain. We show by subcellular fractionation of rat brain that high gamma-secretase activity, as assessed by production of Abeta40, is present in an endosome- and plasma membrane-enriched fraction of an iodixanol gradient. We also prepared crude synaptic vesicles as well as synaptic membranes and both fractions showed high Abeta40 production and contained high amounts of the gamma-secretase components. Further purification of the synaptic vesicles verified the presence of the gamma-secretase components in these compartments. The localization of an active gamma-secretase in synapses and endosomes was confirmed in rat brain sections and neuronal cultures by using a biotinylated gamma-secretase inhibitor together with confocal microscopy. The information about the subcellular localization of gamma-secretase in brain is important for the understanding of the molecular mechanisms of AD. Furthermore, the identified fractions can be used as sources for highly active gamma-secretase.
    PLoS ONE 01/2010; 5(1):e8948. DOI:10.1371/journal.pone.0008948 · 3.23 Impact Factor
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    ABSTRACT: Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (Abeta peptides) in the form of senile plaques as well as neurofibrillary tangles (NFTs) in the brain. In the amyloidogenic pathway, the amyloid-beta precursor protein (APP) is cleaved by beta-secretase first, followed by gamma-secretase cleavage producing therefore Abeta. This review summarizes the recent findings in the AD field and focuses on the different gamma-secretase inhibitors that have been developed as a therapeutic approach toward AD.
    Current pharmaceutical design 02/2006; 12(33):4313-35. DOI:10.2174/138161206778792994 · 3.45 Impact Factor
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