Synthesis of thiaheterocyclic benzohydroxamic acids and evaluation of their HDAC6 inhibitory activity

The hydroxamic acid functionality is an important group in different chemistry disciplines, such as coordination chemistry and medicinal chemistry, due to its excellent metal-chelating properties. In this PhD thesis, the interest in the hydroxamic acid moiety is specifically related to effective and selective histone deacetylase 6 (HDAC6) inhibition. HDAC6 is a member of the broader histone deacetylases enzyme family, which regulate the folding of DNA around histones and thus indirectly influence transcription. A major drawback associated with non-selective HDAC inhibitors concerns their toxic side effects. As HDAC6 recently emerged as a relevant drug target, the aim of this PhD thesis is to move away from classical pan-HDAC inhibitors and thus to synthesize new HDAC6 inhibitors with potential applications in medicine. In particular, three novel classes of thiaheterocyclic benzohydroxamic acids were developed as potent HDAC6 inhibitors displaying excellent selectivity on both an enzymatic and a cellular level. The most promising inhibitors identified in this work can be considered as valuable lead structures for elaborate follow-up studies.