Total Synthesis of Trapoxin A, a Fungal HDAC Inhibitor from <i>Helicoma ambiens</i>

Servatius, Phil; Kazmaier, Uli

doi:10.1021/acs.joc.8b01569

Cited by 16 publications

(15 citation statements)

References 62 publications

(61 reference statements)

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“…Schreiber 15 and Kazmaier 16 developed the only syntheses for trapoxin A and analogues. Despite its promising activity, very few synthetic derivatives of trapoxin A have been reported due to difficulties in modifying its structure.…”

Section: Resultsmentioning

confidence: 99%

Trapoxin A Analogue as a Selective Nanomolar Inhibitor of HDAC11

Peng

Seto

et al. 2023

ACS Chem. Biol.

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Histone deacetylases (HDACs) are enzymes that regulate many important biological pathways. There is a need for the development of isoform-selective HDAC inhibitors for further biological applications. Here, we report the development of trapoxin A analogues as potent and selective inhibitors of HDAC11, an enzyme that can efficiently remove long-chain fatty acyl groups from proteins. In particular, we show that one of the trapoxin A analogues, TD034, has nanomolar potency in enzymatic assays. We show that in cells, TD034 is active at low micromolar concentrations and inhibits the defatty acylation of SHMT2, a known HDAC11 substrate. The high potency and selectivity of TD034 would permit further development of HDAC11 inhibitors for biological and therapeutic applications.

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Section: Resultsmentioning

confidence: 99%

Trapoxin A Analogue as a Selective Nanomolar Inhibitor of HDAC11

Peng

Seto

et al. 2023

ACS Chem. Biol.

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“…Recently, we also became interested in the synthesis of the cyclic HDAC inhibitors. We developed syntheses for chlamydocin [34], Cyl-1 [35], and trapoxin [36] using either Claisen rearrangements [37,38] or Pd-catalyzed allylic alkylations [39,40] as key steps for the synthesis of the unusual Aoe, which was then incorporated into the different tetrapeptides.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and late stage modifications of Cyl derivatives

Servatius¹,

Kazmaier²

2022

Beilstein J. Org. Chem.

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A peptide Claisen rearrangement is used as key step to generate a tetrapeptide with a C-terminal double unsaturated side chain. Activation and cyclization give direct access to cyclopeptides related to naturally occurring histone deacetylase (HDAC) inhibitors Cyl-1 and Cyl-2. Late stage modifications on the unsaturated amino acid side chain allow the introduction of functionalities which might coordinate to metal ions in the active center of metalloproteins, such as histone deacetylases.

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“…This brought our focus also on the HDACs as interesting targets for the development of new cytostatics. We developed syntheses for chlamydocin [36], Cyl-1 [37] and trapoxin [38] using either Claisen rearrangements [39,40] or Pd-catalyzed allylic alkylations [41,42] as key steps for the synthesis of the unusual Aoe, which was then incorporated into the different tetrapeptides.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and late stage modifications of Cyl-derivatives

Servatius¹,

Kazmaier²

2021

Preprint

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A peptide Claisen rearrangement is used as key step to generate a tetrapeptide with a C-terminal double unsaturated side chain. Activation and cyclization give direct access to cyclopeptides related to naturally occurring histone deacetylases (HDAC) inhibitors Cyl-1 and Cyl-2. Late stage modifications on the unsaturated amino acid side chain allow the introduction of functionalities which might coordinate to metal ions in the active center of metalloproteins, such as histone deacetylases.

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Total Synthesis of Trapoxin A, a Fungal HDAC Inhibitor from Helicoma ambiens

Cited by 16 publications

References 62 publications

Trapoxin A Analogue as a Selective Nanomolar Inhibitor of HDAC11

Trapoxin A Analogue as a Selective Nanomolar Inhibitor of HDAC11

Synthesis and late stage modifications of Cyl derivatives

Synthesis and late stage modifications of Cyl-derivatives

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