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Synthesis and structure activity relationship of 1, 3-benzo-thiazine-2-thiones as selective HDAC8 inhibitors

Human histone deacetylase 8 (HDAC8) is a highly promising target for neuroblastoma and other types of cancer. Several HDAC inhibitors are approved for the treatment of special cancer subtypes or are evaluated in clinical trials. By far the most drugs or drug candidates contain a hydroxamate group th...

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Main Authors: Wolff, Benjamin (Author) , Jänsch, Niklas (Author) , Sugiarto, Wisely Oki (Author) , Frühschulz, Stefan (Author) , Lang, Maraike (Author) , Altintas, Rabia (Author) , Oehme, Ina (Author) , Meyer-Almes, Franz-Josef (Author)
Format: Article (Journal)
Language:English
Published: 7 October 2019
In: European journal of medicinal chemistry
Year: 2019, Volume: 184, Pages: 1-20
ISSN:1768-3254
DOI:10.1016/j.ejmech.2019.111756
Online Access:Verlag, Volltext: https://doi.org/10.1016/j.ejmech.2019.111756
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0223523419309080
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Author Notes:Benjamin Wolff, Niklas Jänsch, Wisely Oki Sugiarto, Stefan Frühschulz, Maraike Lang, Rabia Altintas, Ina Oehme, Franz-Josef Meyer-Almes
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Summary:Human histone deacetylase 8 (HDAC8) is a highly promising target for neuroblastoma and other types of cancer. Several HDAC inhibitors are approved for the treatment of special cancer subtypes or are evaluated in clinical trials. By far the most drugs or drug candidates contain a hydroxamate group that chelates the catalytic zinc ion within HDACs. Most hydroxamate inhibitors are more or less unselective, although there are considerable exceptions demonstrating the general feasibility to develop at least HDAC isoenzyme selective inhibitors. In addition, hydroxamates have recently come under discussion regarding their potential for mutagenicity. Recently, PD-404,182 was discovered as a selective and potent non-hydroxamate inhibitor of HDAC8. However, this active compound turned out to be decomposed in the presence of glutathion (GSH). Here, we describe the synthesis of significantly improved analogs of PD-404,182 that demonstrate both, great selectivity for HDAC8 and also chemical stability in the presence of GSH. The compounds are characterized with respect to structure-activity relationship, binding mode and target engagement in neuroblastoma cells by combining biochemical and biophysical methods with chemoinformatics.
Item Description:Gesehen am 20.02.2020
Physical Description:Online Resource
ISSN:1768-3254
DOI:10.1016/j.ejmech.2019.111756

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