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Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors

(2016) ORGANIC & BIOMOLECULAR CHEMISTRY. 14(8). p.2537-2549
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Abstract
The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit alpha-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.
Keywords
DEACETYLASE 6 INHIBITORS, HISTONE DEACETYLASE, HYDROXAMIC ACIDS, FORCE-FIELD, TUBASTATIN, FAMILY, MUTAGENICITY, DISCOVERY, IMMUNITY, DESIGN

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Citation

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Chicago
De Vreese, Rob, Yves Depetter, Tom Verhaeghe, Tom Desmet, Veronick Benoy, Wanda Haeck, Ludo Van Den Bosch, and Matthias D’hooghe. 2016. “Synthesis and SAR Assessment of Novel Tubathian Analogs in the Pursuit of Potent and Selective HDAC6 Inhibitors.” Organic & Biomolecular Chemistry 14 (8): 2537–2549.
APA
De Vreese, R., Depetter, Y., Verhaeghe, T., Desmet, T., Benoy, V., Haeck, W., Van Den Bosch, L., et al. (2016). Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors. ORGANIC & BIOMOLECULAR CHEMISTRY, 14(8), 2537–2549.
Vancouver
1.
De Vreese R, Depetter Y, Verhaeghe T, Desmet T, Benoy V, Haeck W, et al. Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors. ORGANIC & BIOMOLECULAR CHEMISTRY. 2016;14(8):2537–49.
MLA
De Vreese, Rob, Yves Depetter, Tom Verhaeghe, et al. “Synthesis and SAR Assessment of Novel Tubathian Analogs in the Pursuit of Potent and Selective HDAC6 Inhibitors.” ORGANIC & BIOMOLECULAR CHEMISTRY 14.8 (2016): 2537–2549. Print.
@article{8500771,
  abstract     = {The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit alpha-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.},
  author       = {De Vreese, Rob and Depetter, Yves and Verhaeghe, Tom and Desmet, Tom and Benoy, Veronick and Haeck, Wanda and Van Den Bosch, Ludo and D'hooghe, Matthias},
  issn         = {1477-0520},
  journal      = {ORGANIC \& BIOMOLECULAR CHEMISTRY},
  language     = {eng},
  number       = {8},
  pages        = {2537--2549},
  title        = {Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors},
  url          = {http://dx.doi.org/10.1039/c5ob02625c},
  volume       = {14},
  year         = {2016},
}

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