A Series of Potent and Selective, Triazolylphenyl-Based Histone Deacetylases Inhibitors with Activity against Pancreatic Cancer Cells and Plasmodium falciparum

Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 07/2008; 51(12):3437-48. DOI: 10.1021/jm701606b
Source: PubMed


The discovery of the rules governing the inhibition of the various HDAC isoforms is likely to be key to identifying improved therapeutics that act as epigenetic modulators of gene transcription. Herein we present results on the modification of the CAP region of a set of triazolylphenyl-based HDACIs, and show that the nature of substitution on the phenyl ring plays a role in their selectivity for HDAC1 versus HDAC6, with low to moderate selectivity (2-51-fold) being achieved. In light of the valuable selectivity and potency that were identified for the triazolylphenyl ligand 6b in the inhibition of HDAC6 (IC50 = 1.9 nM), this compound represents a valuable research tool and a candidate for further chemical modifications. Lastly, these new HDACIs were studied for both their anticancer and antimalarial activity, which serve to validate the superior activity of the HDACI 10c.

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    • "A sufficiently large set of compounds with their HDAC8 inhibitory activity data is essential in pharmacophore model generation . In literature, a variety of assay procedures are used to determine the HDAC8 inhibition of chemical compounds [34] [35] [36] [37] [38]. More than 500 compounds along with their experimental activity data were identified from various scientific resources. "
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    ABSTRACT: Zinc-dependent histone deacetylase 8 removes the epsilon-acetyl groups present in the N-terminal lysine residues of histone proteins, thereby restricting various transcription factors from being expressed. Inhibition of this enzyme has been reported to be a novel strategy in cancer treatment. To identify novel and diverse leads for use in potent histone deacetylase 8 inhibitor design, a pharmacophore model showing high correlation between experimental and estimated activities was generated using the best conformations of training set compounds from molecular docking experiments. The best pharmacophore model was validated using four different strategies and then used in database screening for novel virtual leads. Hit compounds were selected and subjected to molecular docking using GOLD. The top-scored compound was further optimized for improved binding. The optimization step led to a new set of compounds with both improved binding at the active site and estimated activities. The identified virtual leads could be used for designing potent histone deacetylase 8 inhibitors as anti-cancer therapeutics.
    Journal of molecular graphics & modelling 11/2010; 29(3):382-95. DOI:10.1016/j.jmgm.2010.07.007 · 1.72 Impact Factor
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    • "Other HDAC inhibitors, including SAHA, trichostatin and hydroxamate derivatives, have also been shown to exhibit antimalarial effects [11] [12] [13]. Thus, the inhibition of plasmodial HDACs could be a possible approach for the development of novel and selective antimalarial drugs [4] [13]. RNA interference (RNAi) has emerged as a powerful method for studying gene function in both unicellular and multicellular organisms and has been applied to the study of functions of many genes associated with human disease, in particular those associated with oncogenesis and infectious diseases [14]. "
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    ABSTRACT: Acetylation and deacetylation of histones play important roles in transcription regulation, cell cycle progression and development events. The steady state status of histone acetylation is controlled by a dynamic equilibrium between competing histone acetylase and deacetylase (HDAC). We have used long PfHDAC-1 double-stranded (ds)RNA to interfere with its cognate mRNA expression and determined the effect on malaria parasite growth and development. Chloroquine- and pyrimethamine-resistant Plasmodium falciparum K1 strain was exposed to 1-25 microg of dsRNA/ml of culture for 48 h and growth was determined by [3H]-hypoxanthine incorporation and microscopic examination. Parasite culture treated with 10 microg/ml pfHDAC-1 dsRNA exhibited 47% growth inhibition when compared with either untreated control or culture treated with an unrelated dsRNA. PfHDAC-1 dsRNA specifically blocked maturation of trophozoite to schizont stages and decreased PfHDAC-1 transcript 44% in treated trophozoites. These results indicate the potential of HDAC-1 as a target for development of novel antimalarials.
    Biochemical and Biophysical Research Communications 05/2009; 381(2):144-7. DOI:10.1016/j.bbrc.2009.01.165 · 2.30 Impact Factor
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    • "The potential antiparasitic activity of HDACi's has been reported before by others (13, 32–34), but obtaining drugs selective of Apicomplexan parasites is the major challenge. We observed that FR235222 inhibits parasite proliferation without affecting dramatically normal human host cells; parasites are ∼10 times more sensitive to FR235222 than HFF cells in our in vitro conditions, thus revealing a certain specificity of action of FR235222 toward parasites (Fig. 1 A and Fig. S7). "
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    ABSTRACT: Plasmodium and Toxoplasma are parasites of major medical importance that belong to the Apicomplexa phylum of protozoa. These parasites transform into various stages during their life cycle and express a specific set of proteins at each stage. Although little is yet known of how gene expression is controlled in Apicomplexa, histone modifications, particularly acetylation, are emerging as key regulators of parasite differentiation and stage conversion. We investigated the anti-Apicomplexa effect of FR235222, a histone deacetylase inhibitor (HDACi). We show that FR235222 is active against a variety of Apicomplexa genera, including Plasmodium and Toxoplasma, and is more potent than other HDACi's such as trichostatin A and the clinically relevant compound pyrimethamine. We identify T. gondii HDAC3 (TgHDAC3) as the target of FR235222 in Toxoplasma tachyzoites and demonstrate the crucial role of the conserved and Apicomplexa HDAC-specific residue TgHDAC3 T99 in the inhibitory activity of the drug. We also show that FR235222 induces differentiation of the tachyzoite (replicative) into the bradyzoite (nonreplicative) stage. Additionally, via its anti-TgHDAC3 activity, FR235222 influences the expression of approximately 370 genes, a third of which are stage-specifically expressed. These results identify FR235222 as a potent HDACi of Apicomplexa, and establish HDAC3 as a central regulator of gene expression and stage conversion in Toxoplasma and, likely, other Apicomplexa.
    Journal of Experimental Medicine 05/2009; 206(4):953-66. DOI:10.1084/jem.20082826 · 12.52 Impact Factor
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