Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors |
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| Institution: | 1. Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged H-6720, Hungary;2. MTA-SZTE Stereochemistry Research Group, Dóm tér 8, Szeged H-6720, Hungary;1. Biomolecular & Analytical Mass Spectrometry, Chemistry Department, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium;2. Department of Biophysical Chemistry, Lund University, PO Box 124, SE-22100 Lund, Sweden;3. Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle, Germany;4. Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Strasse 3, D-06120 Halle, Germany |
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| Abstract: | A series of SAHA-like molecules were prepared introducing different lactam-carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound 28 (ST8078AA1) that showed IC50 values between 2 and 10 nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC50 = 0.5 μM against H460 cells, ranking 28 as one of the most potent HDAC inhibitors described so far. |
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| Keywords: | HDAC Anticancer Pan-inhibitor Hydroxamic acid Heterocycles |
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