Author:

Keywords:

Science & Technology, Physical Sciences, Chemistry, Organic, Chemistry, DEACETYLASE 6 INHIBITORS, HISTONE DEACETYLASE, HYDROXAMIC ACIDS, FORCE-FIELD, TUBASTATIN, FAMILY, MUTAGENICITY, DISCOVERY, IMMUNITY, DESIGN, Dose-Response Relationship, Drug, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Indoles, Models, Molecular, Molecular Structure, Structure-Activity Relationship, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, Organic Chemistry, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

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.