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Antiproliferative and differentiating activities of a novel series of histone deacetylase inhibitors.

ABSTRACT: 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.

SUBMITTER: Binaschi M

PROVIDER: S-EPMC4007903 | biostudies-other | 2010 Nov

REPOSITORIES: biostudies-other

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Antiproliferative and differentiating activities of a novel series of histone deacetylase inhibitors.

Binaschi Monica M Boldetti Andrea A Gianni Maurizio M Maggi Carlo Alberto CA Gensini Martina M Bigioni Mario M Parlani Massimo M Giolitti Alessandro A Fratelli Maddalena M Valli Claudia C Terao Mineko M Garattini Enrico E

ACS medicinal chemistry letters 20100720 8

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 ...[more]

PMID: 24900225

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Thailandepsins: bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities.

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| S-EPMC3204160 | biostudies-literature

Antiproliferative and Apoptotic Activities of Sequence-Specific Histone Acetyltransferase Inhibitors

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2017-06-28 | GSE100466 | GEO

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2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity.

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| S-EPMC4689404 | biostudies-literature

Design, synthesis and evaluation of antiproliferative activity of melanoma-targeted histone deacetylase inhibitors.

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Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics.

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| S-EPMC5490397 | biostudies-other

Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities.

Project description:Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36-2.91 M and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.

| S-EPMC7036849 | biostudies-literature

Antimalarial and antileishmanial activities of histone deacetylase inhibitors with triazole-linked cap group.

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Project description:Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors are in various phases of clinical trials as anti-cancer drugs. The majority of HDAC inhibitors non-selectively influence the activities of eleven human HDAC isoforms, which are divided into distinct classes. This tutorial review focuses on the recent progress toward the identification of class-selective and isoform-selective HDAC inhibitors. The emerging trends suggest that subtle differences in the active sites of the HDAC isoforms can be exploited to dictate selectivity.

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Virtual screening and experimental validation of novel histone deacetylase inhibitors.

Project description:Histone deacetylases (HDACs) are promising therapeutic targets for the treatment of cancer, diabetes and other human diseases. HDAC inhibitors, as a new class of potential therapeutic agents, have attracted a great deal of interest for both research and clinical applications. Increasing efforts have been focused on the discovery of HDAC inhibitors and some HDAC inhibitors have been approved for use in cancer therapy. However, most HDAC inhibitors, including the clinically approved agents, do not selectively inhibit the deacetylase activity of class I and II HDAC isforms, and many suffer from metabolic instability. This study aims to identify new HDAC inhibitors by using a high-throughput virtual screening approach.An integration of in silico virtual screening and in vitro experimental validation was used to identify novel HDAC inhibitors from a chemical database.A virtual screening workflow for HDAC inhibitors were created by integrating ligand- and receptor- based virtual screening methods. Using the virtual screening workflow, 22 hit compounds were selected and further tested via in vitro assays. Enzyme inhibition assays showed that three of the 22 compounds had HDAC inhibitory properties. Among these three compounds, ZINC12555961 significantly inhibited HDAC activity. Further in vitro experiments indicated that ZINC12555961 can selectively inhibit proliferation and promote apoptosis of cancer cells.In summary, our study presents three new and potent HDAC inhibitors and one of these HDAC inhibitors shows anti-proliferative and apoptosis-inducing activity against various cancer cell lines. These results suggest that the developed virtual screening workflow can provide a useful source of information for the screening and validation of new HDAC inhibitors. The new-found HDAC inhibitors are worthy to further and more comprehensive investigations.

| S-EPMC4955146 | biostudies-literature

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