Histone Deacetylase Inhibitors: Role in Gene Expression and Development of New Anticancer Drug Candidates

Histone deactylase (HDAC) suppresses gene expression by removing acetyl groups from lysine residues in chromatin. Inhibitors play an important role by restoring the ability of the gene to be expressed, which is crucial if the gene is a tumor suppressor gene. HDACs consist of four classes, spanning 18 isozymes. Current HDAC inhibitors approved and in development are considered pan-inhibitors, blocking a wide array of HDAC isozymes, increasing the risk of adverse effects. b-thujaplicin is derived from the heartwood of trees in the cupressaceae family and from it is derived the troplone scaffold. The tropolone scaffold involves several advantages over other classes of HDAC inhibitors, such as various positions in which diverse functional groups can attach and thus can direct specificity to certain HDAC isozymes. Herein we describe our efforts to develop compounds at the a-position of the tropolone scaffold as well as preliminary biologic data