1. Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors.
- Author
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De Vreese R, Depetter Y, Verhaeghe T, Desmet T, Benoy V, Haeck W, Van Den Bosch L, and D'hooghe M
- Subjects
- Dose-Response Relationship, Drug, Histone Deacetylase 6, Histone Deacetylase Inhibitors chemical synthesis, Humans, Hydroxamic Acids chemistry, Indoles chemistry, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Histone Deacetylase Inhibitors chemistry, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Hydroxamic Acids pharmacology, Indoles pharmacology
- 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 α-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.
- Published
- 2016
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