- Radiosynthesis of 6-([18F]fluoroacetamido)-1-hexanoic-anilide ([18F]FAHA) for PET imaging of histone deacetylase (HDAC)
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Radiosynthesis of a novel substrate for histone deacetylase (HDAC), 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA, [18F]-3) is reported. For precursor synthesis, compound 1 (6-amino-1-hexanoicanilide) was prepared
- Mukhopadhyay, Uday,Tong, William P.,Gelovani, Juri G.,Alauddin, Mian M.
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- Design, synthesis and biological evaluation of novel o-aminobenzamide derivatives as potential anti-gastric cancer agents in vitro and in vivo
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Although gastric cancer has become a major public health problem, oral agents applied in clinics for gastric cancer therapy are scarce. Therefore, to explore new oral chemical entities with high efficiency and low toxicity, 41 o-aminobenzamide derivatives based on the scaffolds of MS-275 and SAHA were designed, synthesized, and evaluated for their anti-gastric cancer abilities in vitro and in vivo. Structure-activity relationships were discussed, leading to the identification of compounds F8 (IC50 = 0.28 μM against HGC-27 cell) and T9 (IC50 = 1.84 μM against HGC-27 cell) with improved cytotoxicity, anti-gastric cancer proliferation potency, induction of cell apoptosis and cell cycle arrest ability, inhibition of cell migration and invasion. What is worth mentioning is that compound F8 was more efficient and less toxic than the positive drug capecitabine in vivo on the HGC-27-xenograft model. Meanwhile, compound F8 exhibited suitable pharmacokinetic properties and less acute toxicity (LD50 > 1000 mg/kg). Besides, western blotting analysis, IHC analysis, differentially expressed proteins analysis and ABPP experiment indicated that compound F8 could modulate molecular pathways involved in apoptosis and cell cycle progression. Consequently, compound F8 is a strong candidate for the development of human gastric cancer therapy.
- Deng, Xuemei,Feng, Hanzhong,Feng, Yiyue,He, Yongxing,Jiang, Weifan,Li, Junfang,Li, Zhao,Liu, Dan,Lu, Yingmei,Shi, Tao,Wang, Zhen,Zhang, Honghua,Zhang, Jian
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- Design, synthesis and preliminary bioactivity evaluations of 8-hydroxyquinoline derivatives as matrix metalloproteinase (MMP) inhibitors
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Matrix metalloproteinases (MMPs) play important roles in many diseases including cancer. With moderate metal-binding affinity, 8-hydroxyquinoline has gained much interest in current drug design and development. Specially, it has been reported that 8-hydroxyquinoline derivatives serve as MMP-2 inhibitors with micromolar IC50 values. In the current study, a series of 8-hydroxyquinoline derivatives were designed and synthesized as new MMP-2 and MMP-9 inhibitors. The most active compounds 5e and 5h not only displayed good inhibitory activities against MMP-2/9 with IC50 at submicromolar level, but also possessed potent anti-proliferative, anti-invasive and anti-angiogenesis activity in A549 cell line. Western blot also revealed that 5e and 5h down-regulate the expression of MMP-2 and MMP-9 in A549 cell line. Moreover, flow cytometry analysis indicated that compound 5e could promote apoptosis of A549 cells in vitro. Molecular docking analysis also revealed favorable binding modes of 5e in the active sites of MMP-2 and MMP-9.
- Chen, Chen,Yang, Xinying,Fang, Hao,Hou
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- Versatile probes for the selective detection of vicinal-dithiol-containing proteins: Design, synthesis, and application in living cells
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Endogenous vicinal-dithiol-containing proteins (VDPs) that have two thiol groups close to each other in space play a significant importance in maintaining the cellular redox microenvironment. Approaches to identify VDPs mainly rely on monitoring the different concentration of monothiol and total thiol groups or on indirect labeling of vicinal thiols by using p-aminophenylarsenoxide (PAO). Our previous work has reported the direct labeling of VDPs with a highly selective receptor PAO analogue, which could realize fluorescence detection of VDPs directly in living cells. Herein, we developed a conjugated approach to expand detectable tags to nitrobenzoxadiazole (NBD), fluorescein, naphthalimide, and biotin for the synthesis of a series of probes. Different linkers have also been introduced toward conjugation of VTA2 with these functional tags. These synthesized flexible probes with various features will offer new tools for the potential identification and visualization of vicinal dithiols existing in different regions of VDPs in living cells. These probes are convenient tools for proteomics studies of various disease-related VDPs and for the discovery of new drug targets. Copyright
- Huang, Chusen,Yin, Qin,Meng, Jiangjiang,Zhu, Weiping,Yang, Yi,Qian, Xuhong,Xu, Yufang
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p. 7739 - 7747
(2013/07/19)
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- Highly selective fluorescent probe for vicinal-dithiol-containing proteins and in situ imaging in living cells
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It pays to be direct: In a rapid and specific approach to the detection of vicinal-dithiol-containing proteins (VDPs), the use of a fluorescent probe (see picture) enabled the direct readout of fluorescence. This approach based on fluorescence polarization, electrophoresis, and the direct imaging of VDPs permits the noninvasive study of VDPs both in vitro and in living cells and offers insight into their potential roles in cell function. Copyright
- Huang, Chusen,Yin, Qin,Zhu, Weiping,Yang, Yi,Wang, Xin,Qian, Xuhong,Xu, Yufang
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p. 7551 - 7556
(2011/10/05)
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- SULFAMIDE AND SULFAMATE DERIVATIVES AS HISTONE DEACETYLASE INHIBITORS
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This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the invention provides for compounds of formula (I), and racemic and scalemic mixtures, diastereomers and enantiomers thereof: or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, prodrug or complex thereof, wherein Y, L, Z, W, M, Ra, Rb and Rc are as defined in the specification.
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Page/Page column 75
(2010/11/29)
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- Mercaptoamides as histone deacetylase inhibitors
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Mercaptoamide compounds, represented by Formulas (IA), (IB), (IIA), and (IIB): or a pharmaceutically acceptable salt thereof, inhibit histone deacetylase enzyme and are useful for the treatment and/or prevention of various infections, cancerous diseases, and conditions.
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Page/Page column 37
(2010/10/20)
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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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- 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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