Generation and Assessment of Fusions Between HDACi and TKi
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Keywords:
Hydroxamic acid
Hydroxamic acid
HDAC11
Histone deacetylase 2
Histone deacetylase 5
Histone acetyltransferase
Histone deacetylase inhibitor
HDAC10
SAP30
Histone H4
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Histone deacetylases (HDACs) alter the acetylation status of chromatin and thereby effect gene expression. The inappropriate recruitment of HDACs may be one mechanism by which oncogenes can alter gene expression in favor of excessive cell proliferation, making inhibition of HDACs a potential target for the development of small-molecule anticancer agents. As a consequence there are several HDAC inhibitors currently undergoing clinical trials for the treatment of solid and non-solid tumors. This review examines recent synthetic methods used to prepare the diverse family of HDAC inhibitors, and includes syntheses of several of the current clinical candidates. The review is divided into the structural classes of known HDAC inhibitors, including non-peptidic hydroxamic acids, non-hydroxamate analogs and cyclic peptides.
Hydroxamic acid
HDAC11
Histone deacetylase 5
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Hydroxamic acid is a potent moiety not only in the field of cancer therapy but also as a mutagenic agent. Among the various derivatives of hydroxamic acid, SAHA (Suberoylanilide Hydroxamic Acid) is considered as a potent anticancer agent. Scientists from the different corner synthesized different hydroxamic acid moieties with some straight chain oxazole, thiadiazole, biphenyl moieties in the terminal position. Acetylation and deacetylation of histones of the core proteins of nucleosomes in chromatin play an important role in the regulation of gene expression. The level of acetylation of histones is established and maintained by two classes of enzymes, histone acetyltransferase and histone deacetylases, which have been identified as transcriptional coactivators and transcriptional corepressors, respectively. There is increasing evidence that aberrant histone acetylation has been linked to various malignant diseases. Great efforts are currently underway for the design of more potent and less toxic candidates for the treatment of cancer. In recent years, hydroxamic acid derivatives have attracted increasing attention for their potential as highly efficacious in combating various etiological factors associated with cancer. Our main intention to draw an attention is that this single functional moiety has not only fit in the receptor but also create a diversified activity.
Hydroxamic acid
Moiety
Histone acetyltransferase
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Histone deacetylases (HDACs) alter the acetylation status of the amino terminal region of histone proteins, which are complexed with DNA in the nucleosome. This acetylation status determines DNA accessibility and, in turn, influences gene expression. The inappropriate recruitment of HDACs may be one mechanism by which oncogenes can alter gene expression in favour of excessive proliferation and this makes inhibition of HDACs a potential target for the development of small molecule anticancer agents. There are several HDAC inhibitors currently in cancer clinical trials and approximately twenty research organisations with ongoing programmes in this field. This review examines the HDAC patent literature from 1997 to mid-2002 with some discussion of primary literature and older citations when appropriate. The review is divided into the structural classes of known HDAC inhibitors that include the non-peptidic hydroxamic acids, cyclic peptides, benzamides, butyric acid analogues and electrophilic ketones.
Hydroxamic acid
HDAC11
Histone deacetylase 5
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Propidium iodide
Histone deacetylase inhibitor
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Vorinostat
Hydroxamic acid
Histone deacetylase 5
Panobinostat
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Hydroxamic acid
Moiety
Histone deacetylase inhibitor
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Hydroxamic acid
Histone acetyltransferase
HDAC1
HDAC11
Histone deacetylase inhibitor
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Antiproliferative and Differentiating Activities of a Novel Series of Histone Deacetylase Inhibitors
Histone deacetylases are promising molecular targets for the development of antitumor agents. A novel series of histone deacetylase inhibitors of the hydroxamic acid type were synthesized for structure-activity studies. Thirteen tricyclic dibenzo-diazepine, -oxazepine, and -thiazepine analogues were studied and shown to induce variable degrees of histone H3/H4 and tubulin acetylation in a cellular model of myeloid leukemia sensitive to all-trans retinoic acid (ATRA). Multiparametric correlations between acetylation of the three substrates, tumor cell growth inhibition, and ATRA-dependent cytodifferentiation were performed, providing information on the chemical functionalities governing these activities. For two analogues, antitumor activity in the animal was demonstrated.
Hydroxamic acid
Vorinostat
K562 cells
Histone deacetylase 2
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