Gruenstein, Elisabeth and Sellmer, Andreas and Mahboobi, Siavosh (2019) Enantioselective synthesis and biological investigation of tetrahydro-beta-carboline-based HDAC6 inhibitors with improved solubility. ARCHIV DER PHARMAZIE, 352 (6): e1900026. ISSN 0365-6233, 1521-4184
Full text not available from this repository. (Request a copy)Abstract
Aberrant epigenetic changes in DNA methylation and histone modification by acetylation or deacetylation regulate the pathogenesis of many diseases. Especially selective inhibitors are getting more and more attention. We recently reported on a new class of potent and selective anti-inflammatory and antirheumatic histone deacetylase 6 (HDAC6) inhibitors (e.g., Marbostat-100). The attachment of a morpholinoethoxy part to the head group dramatically enhances the solubility, in particular the solubility in aqueous solutions, of the lead compound Marbostat-100. Here, we present the enantioselective synthesis of small-molecule compounds based on the tetrahydro-beta-carboline core system with improved solubility, and the influence of the stereochemistry on the biological activity. The enantiomers were synthesized in good enantiomeric excess (ee) purity and were potent and selective HDAC6 inhibitors, whereas the S-derivative S-21 is clearly the eutomer. The potency of our selective HDAC6 inhibitors is demonstrated by K-i values in the range of 0.5-2 nM toward HDAC6, and the selectivity was proved in cellular assays by Western blot analysis taking ac-tubulin as surrogate parameter.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HISTONE; IDENTIFICATION; EPIGENETICS; POTENT; enantiomers; HDAC inhibitors; small molecules |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Apr 2020 07:21 |
| Last Modified: | 14 Apr 2020 07:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26907 |
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