- Structural biasing elements for in-cell histone deacetylase paralog selectivity
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We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibit
- Wong, Jason C.,Hong, Roger,Schreiber, Stuart L.
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Read Online
- Dendritic polypeptide-based nanocarriers for the delivery of therapeutic agents
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Dendritic polypeptides useful for the delivery of therapeutic agents into cells are disclosed, together with their methods of preparation. These dendritic polypeptides serve as carriers of drugs, siRNA, aptamers and plasmid DNA in the treatment of various
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Page/Page column 15; 16
(2018/04/25)
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- HISTONE DEACETYLASE INHIBITORS AS THERAPEUTICS FOR NEUROLOGICAL DISEASES
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The invention provides HDAC inhibitors that may be used as therapeutics for the treatment of a neurodegenerative or neuromuscular condition. The invention provides compounds of formula I. The invention also provides pharmaceutical compositions and articles of manufacture that include these compounds, as well as methods of treating and methods of preventing or delaying the onset of a neurodegenerative or neuromuscular condition.
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Page/Page column 39
(2008/06/13)
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- Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors
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Inhibitors of histone deacetylases (HDAC) are emerging as a promising class of anti-cancer agents. A mercaptoamide functionality was designed as a bidentate zinc chelator and incorporated into the hydroxamic acid based SAHA (1) scaffold in order to identify non-hydroxamate compounds as potential inhibitors of histone deacetylases. Two sets of mercaptoamides 2 and 3 with varying spacer length were synthesized and their HDAC inhibitory activity was evaluated. Low micromolar inhibition was observed for mercaptoamides 2e, 3b, and 3d.
- Anandan, Sampath-Kumar,Ward, John S.,Brokx, Richard D.,Bray, Mark R.,Patel, Dinesh V.,Xiao, Xiao-Xi
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p. 1969 - 1972
(2007/10/03)
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- Novel inhibitors of human histone deacetylases: Design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates
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To find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) was designed and synthesized. In this series, compound 7, in which the hydroxamic acid of SAHA is replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. In cancer cell growth inhibition assay, S-isobutyryl derivative 51 showed strong activity, and its potency was comparable to that of SAHA. The cancer cell growth inhibitory activity was verified to be the result of histone hyperacetylation and subsequent induction of p21WAF1/CIP1 by Western blot analysis. Kinetical enzyme assay and molecular modeling suggest the thiol formed by enzymatic hydrolysis within the cell interacts with the zinc ion in the active site of HDACs.
- Suzuki, Takayoshi,Nagano, Yuki,Kouketsu, Akiyasu,Matsuura, Azusa,Maruyama, Sakiko,Kurotaki, Mineko,Nakagawa, Hidehiko,Miyata, Naoki
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p. 1019 - 1032
(2007/10/03)
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- Design and synthesis of non-hydroxamate histone deacetylase inhibitors: Identification of a selective histone acetylating agent
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A series of suberoylanilide hydroxamic acid (SAHA)-based non-hydroxamates was designed, synthesized, and evaluated for their histone deacetylase (HDAC) inhibitory activity. Among these, methyl sulfoxide 15 inhibited HDACs in enzyme assays and caused hyperacetylation of histone H4 while not inducing the accumulation of acetylated α-tubulin in HCT116 cells.
- Suzuki, Takayoshi,Matsuura, Azusa,Kouketsu, Akiyasu,Hisakawa, Shinya,Nakagawa, Hidehiko,Miyata, Naoki
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p. 4332 - 4342
(2007/10/03)
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- Identification of a potent non-hydroxamate histone deacetylase inhibitor by mechanism-based drug design
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In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, we synthesized several suberoylanilide hydroxamic acid (SAHA)-based compounds designed on the basis of the catalytic mechanism of HDACs. Among these compounds, mercaptoacetamide 5b was found to be as potent as SAHA. Kinetic enzyme assays and molecular modeling are also reported. In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, we synthesized several suberoylanilide hydroxamic acid (SAHA)-based compounds designed on the basis of the catalytic mechanism of HDACs. Among these compounds, 5b was found to be as potent as SAHA. Kinetic enzyme assays and molecular modeling suggested that the mercaptoacetamide moiety of 5b interacts with the zinc in the active site of HDACs and removes a water molecule from the reactive site of the deacetylation.
- Suzuki, Takayoshi,Matsuura, Azusa,Kouketsu, Akiyasu,Nakagawa, Hidehiko,Miyata, Naoki
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p. 331 - 335
(2007/10/03)
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- Thiol-based SAHA analogues as potent histone deacetylase inhibitors
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In order to find novel nonhydroxamate histone deacetylase (HDAC) inhibitors, a series of thiol-based compounds modeled after suberoylanilide hydroxamic acid (SAHA) was synthesized, and their inhibitory effect on HDACs was evaluated. Compound 6, in which t
- Suzuki, Takayoshi,Kouketsu, Akiyasu,Matsuura, Azusa,Kohara, Arihiro,Ninomiya, Shin-Ichi,Kohda, Kohfuku,Miyata, Naoki
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p. 3313 - 3317
(2007/10/03)
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- Novel histone deacetylase inhibitors: Design, synthesis, enzyme inhibition, and binding mode study of SAHA-Based non-hydroxamates
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In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) were designed and synthesized as (i) substrate (acetyl lysine) analogues (compounds 3-7), (ii) analogu
- Suzuki, Takayoshi,Nagano, Yuki,Matsuura, Azusa,Kohara, Arihiro,Ninomiya, Shin-Ichi,Kohda, Kohfuku,Miyata, Naoki
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p. 4321 - 4326
(2007/10/03)
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