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  • 1
    Language: English
    In: Journal of medicinal chemistry, 11 August 2011, Vol.54(15), pp.5576-82
    Description: Histone deacetylases (HDACs) are a group of enzymes that modulate gene expression and cell state by deacetylation of both histone and non-histone proteins. A variety of HDAC inhibitors (HDACi) have already undergone clinical testing in cancer. Real-time in vivo imaging of HDACs and their inhibition would be invaluable; however, the development of appropriate imaging agents has remained a major challenge. Here, we describe the development and evaluation of (18)F-suberoylanilide hydroxamic acid ((18)F-SAHA 1a), a close analogue of the most clinically relevant HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). We demonstrate that 1a has near identical biochemical activity profiles to that of SAHA and report findings from pharmacokinetic studies. Using a murine ovarian cancer model, we likewise show that HDAC inhibitor target binding efficacy can be quantitated within 24 h of administration. 1a thus represents the first (18)F-positron emission tomography (PET) HDAC imaging agent, which also exhibits low nanomolar potency and is pharmacologically analogous to a clinically relevant HDAC inhibitor.
    Keywords: Fluorine Radioisotopes ; Histone Deacetylase Inhibitors ; Hydroxamic Acids
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 2
    In: Nature, 2009, Vol.459(7243), p.55
    Description: Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron- specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2- overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.
    Keywords: Dendritic Spines ; Histone Deacetylase ; Learning ; Synapses ; Chromatin ; Synaptic Density ; Neural Networks ; Animal Models ; Plasticity (Synaptic) ; Neurodegeneration ; Acetylation ; Promoters ; Memory ; Hdac2 Protein ; Cognitive Ability ; Behavioral and Cognitive Neuroscience ; Biochemical & Neurophysiological Correlates, Lesions and Stimuli;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Bioorganic & Medicinal Chemistry, 15 December 2017, Vol.25(24), pp.6486-6491
    Description: Several derivatives of Santacruzamate-A, a natural product that is structurally related to SAHA, were synthesized to explore the potential of carbamates and oxalylamides as novel biasing element for targeting the catalytic site of zinc-dependent histone deacetylases (HDACs). An additional class of Santacruzamate-A derivatives was synthesized to investigate the influence of the cap group and the linker element on HDAC inhibitory activity. All compounds were evaluated in dose response for their in vitro cytotoxic activity in MTT assay in HCT116 cells. HDAC inhibitory activity was evaluated in vitro by western blot analysis for histone hyperacetylation assay and biochemically for representative human HDACs isoforms. Two novel compounds were identified to exhibit potent time dependent anti proliferative activity. However, unlike hydroxamic acid analogues, the tested Santacruzamate-A derivatives showed no noticeable HDAC inhibitory activity. The ethylcarbamate moiety as unusual zinc-binding group displayed no ability to coordinate the zinc ion and thus, presumably, was not able to reproduce known inhibitor-substrate zinc-binding group interactions with the HDAC catalytic site. This study confirmed that the accommodation of the zinc-binding group is deeply critical of the positioning of the linker and the projection of the cap group toward the different surface pockets of the enzyme.
    Keywords: Hdac ; Antiproliferation ; Tumor Progression ; Zinc-Binding Group ; Histone Acetylation ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 4
    Language: English
    In: Cell, 21 May 2015, Vol.161(5), pp.999-1011
    Description: Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient ( ) and leptin receptor-deficient ( mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity. Celastrol, a natural compound found in the roots of the thunder god vine, increases leptin sensitivity to suppress food intake and dramatically reduce body weight of obese mice.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 5
    Language: English
    In: Angewandte Chemie International Edition, 09 July 2012, Vol.51(28), pp.6813-6813
    Keywords: Dyes/Pigments ; Fluorescent Probes ; Imaging Agents ; Radiopharmaceuticals ; Synthetic Methods
    ISSN: 1433-7851
    E-ISSN: 1521-3773
    Source: John Wiley & Sons, Inc.
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  • 6
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.1949-1949
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 7
    Language: English
    In: Cell, May 21, 2015, Vol.161(5), p.999(13)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2015.05.011 Byline: Junli Liu, Jaemin Lee, Mario Andres Salazar Hernandez, Ralph Mazitschek, Umut Ozcan Abstract: Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity. Author Affiliation: (1) Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA (2) Massachusetts General Hospital, Center for Systems Biology, Boston, MA 02114, USA (3) The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA Article History: Received 26 November 2014; Revised 5 January 2015; Accepted 16 April 2015 Article Note: (miscellaneous) Published: May 21, 2015
    Keywords: Leptin – Analysis ; Obesity – Drug Therapy ; Obesity – Analysis
    ISSN: 0092-8674
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: Angewandte Chemie International Edition, 07 May 2012, Vol.51(19), pp.4603-4606
    Description: : BODIPY‐based imaging probes can be tracelessly transformed into hybrid PET/fluorescence imaging reagents by direct F/F exchange without the need for redesign. This approach has the potential to accelerate not only the development of imaging agents, but perhaps also the screening of therapeutic molecules.
    Keywords: Dyes/Pigments ; Fluorescent Probes ; Imaging Agents ; Radiopharmaceuticals ; Synthetic Methods
    ISSN: 1433-7851
    E-ISSN: 1521-3773
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  • 9
    Language: English
    In: Angewandte Chemie International Edition, 07/09/2012, Vol.51(28), pp.6813-6813
    Keywords: Chemistry;
    ISSN: Angewandte Chemie International Edition
    E-ISSN: 14337851
    E-ISSN: 15213773
    Source: Wiley (via CrossRef)
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  • 10
    Language: English
    In: Angewandte Chemie International Edition, 06 April 2010, Vol.49(16), pp.2869-2872
    Description: : A series of activatable (“turn‐on”) tetrazine‐conjugated fluorescent probes was developed, which react rapidly in an inverse‐electron‐demand [4+2] cycloaddition with strained dienophiles such as ‐cyclooctene, thereby strongly increasing the fluorescence intensity (see picture). The novel turn‐on probes were applied for intracellular live‐cell imaging of a microtubuli‐binding ‐cyclooctene modified taxol.
    Keywords: Bioorthogonal Reactions ; Cycloaddition ; Fluorogenic Tags ; Imaging ; Tetrazine
    ISSN: 1433-7851
    E-ISSN: 1521-3773
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