(1E,4Z,6E)-5-Hy­droxy-1,7-bis­(2-meth­oxy­phen­yl)-1,4,6-hepta­trien-3-one

In the title compound, C21H20O4, the central hepta­trienone unit is approximately planar, with a maximum atomic deviation of 0.1121 (11) Å; the two benzene rings are twisted with respect to the hepta­trienone mean plane by 2.73 (5) and 29.31 (4)°. The mol­ecule exists in the enol form and the hy­droxy group forms an intra­molecular hydrogen bond with the neighboring carbonyl group. Weak inter­molecular C—H⋯O hydrogen bonding is present in the crystal structure

Selective inhibitors of the PSEN1–gamma-secretase complex

Clinical development of γ-secretases, a family of intramembrane cleaving proteases, as therapeutic targets for a variety of disorders including cancer and Alzheimer’s disease was aborted because of serious mechanism-based side effects in the phase III trials of unselective inhibitors. Selective inhibition of specific γ-secretase complexes, containing either PSEN1 or PSEN2 as the catalytic subunit and APH1A or APH1B as supporting subunits, does provide a feasible therapeutic window in preclinical models of these disorders. We explore here the pharmacophoric features required for PSEN1 versus PSEN2 selective inhibition. We synthesized a series of brain penetrant 2-azabicyclo[2,2,2]octane sulfonamides and identified a compound with low nanomolar potency and high selectivity (>250-fold) toward the PSEN1–APH1B subcomplex versus PSEN2 subcomplexes. We used modeling and site-directed mutagenesis to identify critical amino acids along the entry part of this inhibitor into the catalytic site of PSEN1. Specific targeting one of the different γ-secretase complexes might provide safer drugs in the future

Selective inhibitors of the PSEN1-gamma-secretase complex

Clinical development of Y-secretases, a family of intramembrane cleaving proteases, as therapeutic targets for a variety of disorders including cancer and Alzheimer’s disease was aborted because of serious mechanism-based side effects in the phase III trials of unselective inhibitors. Selective inhibition of specific Y-secretase complexes, containing either PSEN1 or PSEN2 as the catalytic subunit and APH1A or APH1B as supporting subunits, does provide a feasible therapeutic window in preclinical models of these disorders. We explore here the pharmacophoric features required for PSEN1 versus PSEN2 selective inhibition. We synthesized a series of brain penetrant 2-azabicyclo[2,2,2]octane sulfonamides and identified a compound with low nanomolar potency and high selectivity (>250-fold) toward the PSEN1–APH1B subcomplex versus PSEN2 subcomplexes. We used modeling and site-directed mutagenesis to identify critical amino acids along the entry part of this inhibitor into the catalytic site of PSEN1. Specific targeting one of the different Y-secretase complexes might provide safer drugs in the future.The work was supported by an AIO-project (no. HBC.2016.0884). This project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. ERC-834682 CELLPHASE_AD). This work was supported by the Flanders Institute for Biotechnology (VIB vzw), a Methusalem grant from KU Leuven and the Flemish Government, the Fonds voor Wetenschappelijk Onderzoek, KU Leuven, The Queen Elisabeth Medical Foundation for Neurosciences, the Opening the Future campaign of the Leuven Universitair Fonds, the Belgian Alzheimer Research Foundation (SAO-FRA), and the Alzheimer’s Association USA.Peer ReviewedPostprint (published version

Modulation and Characterization of Alzheimer's Disease Associated gamma-Secretase

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that causes the most common form of dementia, affecting approximately 5% of the population over the age of 65 years in Europe. Short-term memory impairment, disorientation, aphasia, and a general cognitive decline are common symptoms early in disease development. According to the World Health Organization, an estimated 37 million people worldwide currently have dementia; AD affects about 18 million of them. In spite of tremendous research efforts, there is no causal therapy for AD. Histopathological hallmarks of AD are the extracellular plaques consisting of the amyloid β-peptide (Aβ) and neurofibrillary tangles which are found in the brains of the AD patients. Aβ is heterogeneously produced by the sequential cleavages of amyloid precursor protein (APP) by the two aspartic proteases: β- and γ-secretase. Intramembrane cleavage by γ-secretase occurs with little sequence specificity, resulting in Aβ fragments of different length, predominantly Aβ40, Aβ42, and some Aβ38. Aβ42 being the most aggregatory, and is believed to trigger the amyloid cascade, a pathological series of neurotoxic events, which eventually leads to neurodegeneration and finally AD. γ-Secretase has been an attractive target in many ways for AD therapeutics since it catalyzes the final step in the release of Aβ. The present work describes the design, synthesis and biological evaluation of γ-secretase modulators, affinity probes and photoaffinity labels. Epidemiological studies have indicated a close association between prolonged use of nonsteroidal anti-inflammaroy drugs (NSAIDs), and reduced risk for AD. Therefore, cyclooxygenase (COX) inhibitors such as flurbiprofen, sulindac sulfoxide and meclofenamic acid were converted into amides and esters and anticipated that the modification of acid functionality would reduce the COX inhibitory activity while increasing the γ-secretase modulatory activity. However, the conversion of the acid moiety of COX inhibitors into their amides or esters resulted either in inverse modulation or inhibition. Further efforts were then focussed on carprofen, a COX-2 inhibitor which is approved for the use in dogs and cows. N-substitution of carprofen resulted in potent modulators of γ-secretase, and the compounds displayed little or no effect on γ-secretase cleavage at the ε-site. Knowing about the relevance of N-substitution of carprofen and the necessity of the free acid functionality for γ-secretase modulation, a series of N-substituted carbazolyloxy acetic acids was synthesized. As anticipated, they turned out to be effective modulators of γ-secretase and displayed little or no effect on γ-secretase cleavage at the ε-site. An analogous derivative of the LXR agonist TO-901317 was synthesized, but the hexafluorocarbinol moiety was replaced by an oxyacetic acid in order to transform it into a modulator of γ-secretase. As expected, the introduction of the acid moiety changed the mode of action from an inverse modulation to normal modulation of γ-secretase. A series of NSAIDs derived affinity labels was synthesized in order to identify and characterize the binding site by immunoprecipitation assay. Flurbiprofen derived photoaffinity label captured active γ-secretase complex in a dose dependant manner, but others either failed to provide a binding partner or resulted in unspecific binding. Flurbiprofen and DAPT derived photoaffnity labels were synthesized in order to investigate the binding site via covalent bond formation with the active site on the γ-secretase complex. The photaffnity labelling experiment carried out with a flurbiprofen derived photoaffnity probe revealed that it binds to the C-terminal fragment of presenilin (PS). Whereas, DAPT derived photoaffinity label displayed very weak binding to PS, the active site of γ-secretase

Hybrid ortho/allosteric ligands for the adenosine A(1) receptor

Many G protein-coupled receptors (GPCRs), including the adenosine A(1) receptor (A(1)AR), have been shown to be allosterically modulated by small molecule ligands. So far, in the absence of structural information, the exact location of the allosteric site on the A(1)AR is not known. We synthesized a series of bivalent ligands (4) with an increasing linker length between the orthosteric and allosteric pharmacophores and used these as tools to search for the allosteric site on the A(1)AR. The compounds were tested in both equilibrium radioligand displacement and functional assays in the absence and presence of a reference allosteric enhancer, (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone, PD81,723 (1). Bivalent ligand N(6)-[2-amino-3-(3,4-dichlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl-9-nonyloxy-4-phenyl]-adenosine 4h (LUF6258) with a 9 carbon atom spacer did not show significant changes in affinity or potency in the presence of 1, indicating that this ligand bridged both sites on the receptor. Furthermore, 4h displayed an increase in efficacy, but not potency, compared to the parent, monovalent agonist 2. From molecular modeling studies, we speculate that the allosteric site of the A(1)AR is located in the proximity of the orthosteric site, possibly within the boundaries of the second extracellular loop of the receptor

Two new ceramides from the fruit pulp of <i>Acanthopanax senticosus</i> (Rupr. et Maxim) Harms

<div><p>Two new ceramides, (3<i>S</i>,4<i>S</i>,5<i>R</i>)-3-octadecanoylamino-4-hydroxy-5-dodecane-2,3,4,5-tetrahydrofuran (<b>1</b>) and (3<i>S</i>,4<i>S</i>,5<i>R</i>)-3-[(2<i>R</i>)-2-hydroxyhexacosanoylamino]-4-hydroxy-5-[(4<i>E</i>)-dodecane-4-ene]-2,3,4,5-tetrahydrofuran (<b>2</b>), together with eight known compounds, eleutheroside A (<b>3</b>), eleutheroside B (<b>4</b>), eleutheroside E (<b>5</b>), 7-hydroxy-6-methoxy-coumarin (<b>6</b>), 6,7-dimethoxycoumarin (<b>7</b>), 5α,8α-epidioxyergosta-6,22-dien-3-ol (<b>8</b>), stigmasterol (<b>9</b>) and rutin (<b>10</b>), were isolated from the fruit pulp of <i>Acanthopanax senticosus</i> (Rupr. et Maxim) Harms. Their structures were elucidated by means of physicochemical properties and spectroscopic methods (1D, 2D NMR and MS).</p></div