Small molecules continue to have extraordinary utility as both therapeutics and tools to empower biological studies. Indeed, no other class of molecules has so significantly influenced the quality of human health and the elucidation of molecular mechanisms of homeostatic and pathogenic states. Histone deacetylase (HDAC) inhibitors are of particular interest in both of these domains, as evidenced by increased reports of their synthesis as well as the FDA approval of several molecules of their class. Histone deacetylases are a class of enzymes, comprising 18 isoforms, that regulate the acetylation state of DNA, a key effector of transcription. Our current interest in Niemann-Pick Type C (NPC), a rare neurodegenerative disease caused by aberrations in the mechanisms underlying lysosomal storage, led us to undertake the synthesis of novel HDAC inhibitors. It has been shown that pan-HDAC inhibitors such as vorinostat can have therapeutic potential in NPC, perhaps through inducing overexpression of the implicated protein NPC-1. While these therapeutic effects have been increasingly examined, the fundamental biological question of which HDAC isoform is implicated in the disease has yet to be resolved. Furthermore, a drawback of HDAC inhibitors is their off-target effects. Therefore, the development of selective HDAC inhibitors would not only enable the elucidation of NPC’s fundamental mechanisms, but also guide downstream therapeutic development. Through computational modeling, we proposed a series of HDAC inhibitors that could potentially selectively inhibit HDAC 1, 2, and 3, or a combination thereof. The syntheses rely on key transition-metal cross couplings such as the venerable Suzuki, Stille, Sonogashira, and Heck reactions. The molecules are synthesized convergently through use of two comparably elaborated components that are joined by a late stage amide bond formation. Biological investigations of the resulting compounds are underway.<br/>

Investigation and synthesis of isoform-selective histone deacetylase inhibitors

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.