Leonhardt, Michel and Sellmer, Andreas and Kraemer, Oliver H. and Dove, Stefan and Elz, Sigurd and Kraus, Birgit and Beyer, Mandy and Mahboobi, Siavosh (2018) Design and biological evaluation of tetrahydro-beta-carboline derivatives as highly potent histone deacetylase 6 (HDAC6) inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 152. pp. 329-357. ISSN 0223-5234, 1768-3254
Full text not available from this repository. (Request a copy)Abstract
Various diseases are related to epigenetic modifications. Histone deacetylases (HDACs) and histone acetyl transferases (HATS) determine the pattern of histone acetylation, and thus are involved in the regulation of gene expression. First generation histone deacetylase inhibitors (HDACi) are unselective, hinder all different kinds of zinc dependent HDACs and additionally cause several side effects. Subsequently, selective HDACi are gaining more and more interest. Especially, selective histone deacetylase 6 inhibitors (HDAC6i) are supposed to be less toxic. Here we present a successful optimization study of tubastatin A, the synthesis and biological evaluation of new inhibitors based on hydroxamic acids linked to various tetrahydro-beta-carboline derivatives. The potency of our selective HDAC6 inhibitors, exhibiting IC50 values in a range of 1-10 nM towards HDAC6, was evaluated with the help of a recombinant human HDAC6 enzyme assay. Selectivity was proofed in cellular assays by the hyperacetylation of surrogate parameter a-tubulin in the absence of acetylated histone H3 analyzed by Western Blot. We show that all synthesized compounds, with varies modifications of the rigid cap group, were selective and potent HDAC6 inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PICTET-SPENGLER REACTION; ACUTE MYELOID-LEUKEMIA; 1ST GLOBAL APPROVAL; T-REGULATORY CELLS; BENZODIAZEPINE RECEPTOR; PROTEASOMAL DEGRADATION; ORGANIC-MOLECULES; HYBRID MOLECULES; FORCE-FIELD; ACID; Histone deacetylase; HDAC; Histone deacetylase inhibitor; HDACi; Tetrahydro-beta-carboline; Histone deacetylase 6 inhibition assay |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Mar 2020 12:14 |
| Last Modified: | 09 Mar 2020 12:14 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14556 |
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