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

The antimalarial activity and pharmacology of a series of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors (HDACIs) was evaluated. In in vitro growth inhibition assays approximately 50 analogs were evaluated against four drug resistant strains of Plasmodium falciparum. The range of 50% inhibitory concentrations (IC 50 s) was 0.0005 to >1 M. Five analogs exhibited IC 50 s of <3 nM, and three of these exhibited selectivity indices of >600. The most potent compound, WR301801 (YC-2-88) was shown to cause hyperacetylation of P. falciparum histones, which is a marker for HDAC inhibition in eukaryotic cells. The compound also inhibited malarial and mammalian HDAC activity in functional assays at low nanomolar concentrations. WR301801 did not exhibit cures in P. berghei-infected mice at oral doses as high as 640 mg/kg/day for 3 days or in P. falciparum-infected Aotus lemurinus lemurinus monkeys at oral doses of 32 mg/kg/day for 3 days, despite high relative bioavailability. The failure of monotherapy in mice may be due to a short half-life, since the compound was rapidly hydrolyzed to an inactive acid metabolite by loss of its hydroxamate group in vitro (half-life of 11 min in mouse microsomes) and in vivo (half-life in mice of 3.5 h after a single oral dose of 50 mg/kg). However, WR301801 exhibited cures in P. berghei-infected mice when combined at doses of 52 mg/kg/day orally with subcurative doses of chloroquine. Next-generation HDACIs with greater metabolic stability than WR301801 may be useful as antimalarials if combined appropriately with conventional antimalarial drugs.Considerable research activity has focused on understanding the "histone code," and in particular on the design of hydroxamate-based histone deacetylase inhibitors (HDACIs) as novel therapeutics for the treatment of a wide range of disorders, including cancer and neurodegenerative diseases (26). HDACIs owe their action to their ability to reactivate silenced genes by modulating the condensation status of DNA. The posttranslational acetylation status of chromatin is determined by the competing activities of two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) which control the acetylation of lysine residues on histone tails. In general, HATs function to acetylate lysine groups in nuclear histones, resulting in neutralization of the charges on the histones and a more open, transcriptionally active chromatin structure, while the HDACs function to deacetylate and suppress transcription. A shift in the balance of acetylation on chromatin may result in changes in the regulation of patterns of gene expression (16,24,37,39). Since many cancers are associated with aberrant transcriptional activity, and HDACs can affect transcription factors and gene regulation, these enzymes have been identified as attractive targets for cancer therapy. Indeed, chemical inhibitors of HDACs have been shown to inhibit tumor cell growth and induce differentiation and cell death (28). Several such inhibitory agents,...

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“…WR301801 exhibited an IC 50 of 10 nM in the mammalian HDAC inhibition assay (Fig. 2), confirming the results of earlier studies (9,23).…”

Section: Resultssupporting

confidence: 89%

“…We have not yet considered the issue of the mechanism of action, toxicity, and selectivity in detail. Earlier studies have shown that WR301801 is a nM inhibitor of mammalian HDAC (9,23). This was confirmed in a functional assay here (Fig.…”

Section: Discussionsupporting

confidence: 88%

Antimalarial Activity of Phenylthiazolyl-Bearing Hydroxamate-Based Histone Deacetylase Inhibitors

Dow

Chen

Andrews

et al. 2008

Antimicrob Agents Chemother

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“…223 1,5-Triazole derivatives have shown activity against numerous cancer cell lines, 205,215,[224][225][226][227] and against the parasites Trypanosoma cruzi 70,228 and Plasmodium falciparum. 205 They have also been employed in the search for new antimicrobiotics 229 and antifungal agents. 230 Institute's panel screen (NCI-60 panel) compared to vorinostat and dasatinib.…”

Section: Target-oriented Medicinal Chemistrymentioning

confidence: 99%

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

et al. 2016

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The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry and the construction of 2 electronic devices. This review discusses the mechanism, scope and applications of the RuAAC reaction, covering the literature during the last 10 years. CONTENTS

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“…256 SAHA, clinically approved to treat persistent or refractory T-cell lymphoma, inhibits growth of P. falciparum D6 and W2 strains with IC 50 values of 247 and 161 nM, respectively. 256 One of SAHA's derivatives (188, Figure 105) was found to be about 14-and 5-fold more active than its parent compound, with IC 50 values of 17 and 32 nM for P. falciparum D6 and W2, respectively. Similarly, Marfurt et al have disclosed that 2-aminosubericbased HDAC inhibitors present potent in vitro activity against sensitive (3D7) and drug-resistant (K1) P. falciparum strains.…”

Section: Antitumoralsmentioning

confidence: 99%

“Recycling” Classical Drugs for Malaria

et al. 2014

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

Cited by 120 publications

References 52 publications

Antimalarial Activity of Phenylthiazolyl-Bearing Hydroxamate-Based Histone Deacetylase Inhibitors

Antimalarial Activity of Phenylthiazolyl-Bearing Hydroxamate-Based Histone Deacetylase Inhibitors

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“Recycling” Classical Drugs for Malaria

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