Stereodefined and polyunsaturated inhibitors of histone deacetylase based on (2E,4E)-5-arylpenta-2,4-dienoic acid hydroxyamides

Marson, Charles M.; Serradji, Nawal; Rioja, Alphonso S.; Gastaud, Sebastien P.; Alao, John P.; Coombes, R. Charles; Vigushin, David M.

doi:10.1016/j.bmcl.2004.03.012

Cited by 17 publications

(7 citation statements)

References 18 publications

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“…The fractions were also analyzed on a Thermo LCQ Deca Ion Trap mass spectrometer (Thermo Electron, Franklin, MA) in the MS n mode. The remaining fractions were dried under vacuum and each was resuspended in 50 l of dimethyl sulfoxide for determination of histone deacetylase-inhibitory activity as previously described (Vigushin et al, 2001;Marson et al, 2004), with the modifications detailed below.…”

Section: Methodsmentioning

confidence: 99%

Plasma Pharmacokinetics and Metabolism of the Histone Deacetylase Inhibitor Trichostatin a After Intraperitoneal Administration to Mice

Sanderson¹,

Taylor²,

Aboagye³

et al. 2004

Drug Metab Dispos

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ABSTRACT:Trichostatin A is a potent and specific histone deacetylase inhibitor with promising antitumor activity in preclinical models. Plasma pharmacokinetics of trichostatin A were studied following singledose intraperitoneal administration of 80 mg/kg (high dose) or 0.5 mg/kg (low dose) to female BALB/c mice. Plasma trichostatin A concentrations were quantified by high performance liquid chromatography (HPLC)-UV assay (high dose) or by HPLC-multiple reaction monitoring assay (low dose). Trichostatin A was rapidly absorbed from the peritoneum and detectable in plasma within 2 min. C max of 40 g/ml and 8 ng/ml occurred within 5 min, followed by rapid exponential decay in plasma trichostatin A concentration with t 1/2 of 6.3 min and 9.6 min (high and low doses, respectively). Phase I metabolites at the high dose were identified by simultaneous UV and positive ion electrospray mass spectrometry. Trichostatin A underwent extensive metabolism: primary metabolic pathways were Ndemethylation, reduction of the hydroxamic acid to the corresponding trichostatin A amide, and oxidative deamination to trichostatic acid. N-Monomethyl trichostatin A amide was the major plasma metabolite. No didemethylated compounds were identified. Trichostatic acid underwent further biotransformation: reduction and ␤-oxidation of the carboxylic acid, with or without N-demethylation, resulted in formation of dihydro trichostatic acid and dinor dihydro trichostatic acids. HPLC fractions corresponding to trichostatin A and Ndemethylated trichostatin A exhibited histone deacetylase-inhibitory activity; no other fractions were biologically active. We conclude that trichostatin A is rapidly and extensively metabolized in vivo following intraperitoneal administration to mice, and N-demethylation does not compromise histone deacetylase-inhibitory activity.

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Section: Methodsmentioning

confidence: 99%

Plasma Pharmacokinetics and Metabolism of the Histone Deacetylase Inhibitor Trichostatin a After Intraperitoneal Administration to Mice

Sanderson¹,

Taylor²,

Aboagye³

et al. 2004

Drug Metab Dispos

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“…No preliminary modeling was conducted on the HDAC binding site because of poor handling of zinc-hydroxamic acid interactions in all modeling methods. However, given the breadth of HDACi cap group structures reported (22)(23)(24), it was reasonable to expect that the secosteroidal core of triciferol could serve effectively in this capacity when combined with the known affinity of the dienyl hydroxamic acid for HDACs. [ Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1), have revealed that the VDR can accommodate structures with alterations in side chain substitution and length (19)(20)(21), as long as critical hydrogen bonds are maintained at all three hydroxyl groups. HDACis, such as TSA and SAHA, are composed of highly variable ''cap'' structures that bind at the surfaces of HDACs, coupled via a linking chain to hydroxamic acids (22,23) or other groups (24) that chelate active site zinc ions. Triciferol combines the secosteroidal backbone of 1,25D with the dienyl hydroxamic acid of TSA.…”

Section: Resultsmentioning

confidence: 99%

Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist

Tavera-Mendoza¹,

Quach

Dabbas

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Compound A2 was given orally at 5 mg/kg to healthy rats and showed reasonably high plasma levels (C max = 6µg/mL, T max = 15 min). were synthesised and evaluated in vitro [74] ( Table 2). Potency of inhibitors B strongly depended on the substituents on the aromatic ring and the rigidity of the carbon chain fragment.…”

Section: Long-chain (Tsa-and Saha-type) Hydroxamatesmentioning

confidence: 99%

Histone Deacetylase Inhibitors: Latest Developments, Trends and Prospects

Moradei¹,

Maroun²,

Paquin³

et al. 2005

CMCACA

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Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that catalyze the deacetylation and acetylation of lysine residues located in the NH(2) terminal tails of histones and non-histone proteins. Perturbation of this balance is often observed in human cancers and inhibition of HDACs has emerged as a novel therapeutic strategy against cancer. To date, more that 30 groups, academic and industrial, are involved in research related to these target enzymes. Over the past year, dozens of research papers and patent applications describing new HDAC inhibitors belonging to different structural classes have been disclosed. The present review highlights the latest developments in design and synthesis of HDAC inhibitors -- potential anti-cancer drugs.

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Stereodefined and polyunsaturated inhibitors of histone deacetylase based on (2E,4E)-5-arylpenta-2,4-dienoic acid hydroxyamides

Cited by 17 publications

References 18 publications

Plasma Pharmacokinetics and Metabolism of the Histone Deacetylase Inhibitor Trichostatin a After Intraperitoneal Administration to Mice

Plasma Pharmacokinetics and Metabolism of the Histone Deacetylase Inhibitor Trichostatin a After Intraperitoneal Administration to Mice

Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist

Histone Deacetylase Inhibitors: Latest Developments, Trends and Prospects

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