LTQ FT MS Accurate Mass and SRM Data Dependent Exclusion MSn Measurements for Structure Determination of FK228 and Its Metabolites

Tozuka, Zenzaburo; Strupat, Wolfgang Metelmann; Shiraga, Toshifumi; Ishimura, Rika; Hashimoto, Tomoko; Kawamura, Akio; Kagayama, Akira

doi:10.5702/massspec.53.89

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…The second thiol serves an equally important role in packaging the depsipeptides for cellular uptake. With FK228, there is mass spectrometric evidence that the cysteine thiol can form glutathione conjugates or add intramolecularly in a Michael reaction to the Dhb residue. Our observations with 15 demonstrate that the cysteine can be dispensed with, provided the zinc-binding thiol is protected in a prodrug manner.…”

Section: Resultsmentioning

confidence: 99%

The First Biologically Active Synthetic Analogues of FK228, the Depsipeptide Histone Deacetylase Inhibitor

Yurek‐George

Cecil

et al. 2007

J. Med. Chem.

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The FK228 and spiruchostatin bicyclic depsipeptide natural products are among the most potent histone deacetylase (HDAC) inhibitors known. Although FK228 is in advanced clinical trials, the complexity of the natural products has precluded mechanistic studies and the discovery of structure-activity relationships. By total synthesis, we have prepared the first depsipeptide analogues. Our results prove that the dehydrobutyrine residue in FK228 is not essential, and other residues can be substituted without loss of HDAC inhibitory activity. Conformational restriction by the macrocyclic scaffold is important, as a linear peptide was inactive. The intramolecular disulfide formed with a cysteine side chain can be removed provided the zinc-binding thiol is protected to ensure good cellular availability. Like the natural products, the analogues are selective against class I isoforms, with nanomolar inhibition of class I HDAC1 and significantly less potency against class II HDAC6.Eukaryotic DNA is packaged together with histone and nonhistone proteins into the higher order structure of chromatin. Chromatin proteins feature extensive posttranslational modification 1 including methylation, acetylation, phosphorylation, ubiquitinylation, sumoylation, and poly-ADPribosylation. These dynamic alterations are believed to constitute a 'histone code' 2 that mediates protein-DNA and protein-protein interactions in chromatin and thereby ultimately regulates gene transcription. Consequently, the modulation of the chromatin histone code offers opportunities for targeting diverse disease states at a higher level of intervention than individual signal transduction pathways. Among the enzymes involved in chromatin remodeling, zinc-dependent histone deacetylases (HDACs a ) are currently at the most advanced stage in drug discovery, with one FDA approval and numerous other compounds in clinical development. These metalloenzymes catalyze the hydrolysis of acetyllysine residues back to lysine. Since the latter, unlike acetyllysine, is protonated at physiological pH, this switch has a dramatic effect on chromatin structure and recruitment of binding partners. Furthermore, reversible lysine acetylation is now recognized 3 as a general posttranslational modification with important functional consequences in nuclear and cytoplasmic proteins unrelated to chromatin, thus increasing the therapeutic importance of this event.HDAC inhibitor design has concentrated 4 on the class I and class II zinc-dependent enzymes, comprising HDACs 1-11 in the human genome. These hydrolases share a highly conserved catalytic domain containing an active site zinc ion, and the majority of inhibitors fall into five broad structural classes (Figure 1): short chain aliphatic carboxylic acids, hydroxamic acids, benzamides, cyclic peptides, and the depsipeptides. HDAC inhibitors are typically substrate mimics of the linear acetyllysine side chain with a zinc-binding group replacing the scissile acetamide and a 'cap' at the other end extending beyond the enzyme substrate-bi...

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Section: Resultsmentioning

confidence: 99%

The First Biologically Active Synthetic Analogues of FK228, the Depsipeptide Histone Deacetylase Inhibitor

Yurek‐George

Cecil

et al. 2007

J. Med. Chem.

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“…We have developed FK506 NF-AT transcription inhibitor [2], FK228 PPAR inhibitor [3], NF-kB Decoy oligo nucleotide (ON) [4,5] and AO85 Exon Skipping ON [6,7] that control transcription. FK506 and NF-κB decoy ON inhibits expression of inflammatory cytokines, such as TNF and IL-1 which trigger inflammation cascades to dermatitis.…”

Section: How To Search the Small Molecule Ligands Of The Nuclear Receptors To Control Transcription Of Pharmaceutical Active Properties Umentioning

confidence: 99%

Multi omics by LC-MS/MS to search small molecule ligands of nuclear receptors to control transcription of pharmaceutical active proteins for drug discovery

Tozuka¹,

Kunisawa²

2018

Trends in Res

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“…In order to avoid unpredictable toxicity caused by toxic active metabolites, the US Food and Drug Administration (FDA) issued the Guidance for Safety Testing of Drug Metabolites (MIST) 1 in 2008. 8 The structural analysis of in vitro NC metabolites in human liver microsomes was conducted using the high resolution and high mass accuracy Fourier Transform Ion Cyclotron Resonance mas Spectrometry (FTICRMS), 9 and the data dependent exclusion MSn measurement by Linear Trap Quadropole (LTQ) 10 to find seven new in vitro NC metabolites in human liver microsomes and six new in vivo NC metabolites in human plasma. Total drug-related exposure is possible to be measured by LC/RI and LC-RI-MS, but it is impossible to be measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Quantitative and Qualitative Liquid Chromatography–Radioisotope–Mass Spectrometry Analysis for Safety Testing of Tolbutamide Metabolites Without Standard Samples

Tozuka

Aoyama

Nozawa

et al. 2011

Journal of Pharmaceutical Sciences

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LTQ FT MS Accurate Mass and SRM Data Dependent Exclusion MSn Measurements for Structure Determination of FK228 and Its Metabolites

Cited by 4 publications

References 19 publications

The First Biologically Active Synthetic Analogues of FK228, the Depsipeptide Histone Deacetylase Inhibitor

The First Biologically Active Synthetic Analogues of FK228, the Depsipeptide Histone Deacetylase Inhibitor

Multi omics by LC-MS/MS to search small molecule ligands of nuclear receptors to control transcription of pharmaceutical active proteins for drug discovery

Comprehensive Quantitative and Qualitative Liquid Chromatography–Radioisotope–Mass Spectrometry Analysis for Safety Testing of Tolbutamide Metabolites Without Standard Samples

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