Heterocyclic Ketones as Inhibitors of Histone Deacetylase Anil Vasudevan, a, * Zhiqin Ji, b RobinR.Frey, b CarolK.Wada, b Douglas Steinman, b H.RobinHeyman, b YanGuo, b Michael L. Curtin, b JunGuo, b Junling Li, b Lori Pease, b KeithB.Glaser, b Patrick A. Marcotte, b Jennifer J. Bouska, b StevenK.Davidsen b and Michael R. Michaelides b a Medicinal Chemistry Technologies, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA b Cancer Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA Received 29 July 2003; revised 4 September 2003; accepted 4 September 2003 Abstract—Several heterocyclic ketones were investigated as potential inhibitors of histone deacetylase. Nanomolar inhibitors such as 22 and 25 wereobtained,theanti-proliferativeactivityofwhichwereshowntobemediatedbyHDACinhibition. # 2003PublishedbyElsevierLtd. A balance between Histone Deacetylase (HDAC) and Histone Acetyl Transferase (HAT) determines the extent of acetylation of chromatin proteins. HDAC- mediated hypoacetylation increases positive charges at histone lysine residues and condenses the chromatin structure, generally leading to transcriptional repres- sion. Recent studies indicate that HDACs are not only involved in the regulation of chromatin structure and gene expression, but also the regulation of cell cycle progression and tumorigenesis (Fig.1). 1 Severalclassesofcompoundsthatinhibittheactivityof partiallypurifiedHDACs,causegrowtharrestofawide range of transformed cells in culture and inhibit the growth of human xenografts in tumor growth studies have been identified. 2 Some of these inhibitors have been shown to act selectively, altering the transcription of less than 2% of expressed genes 3a and several are undergoing clinical evaluation. 3b Because HDAC is a zinc metalloenzyme, the majority of inhibitors have a metal chelating element attached to an aromatic group via a hydrophobic linker. The HDAC inhibitors tri- chostatin A (TSA) (lit. IC 50 3.4 nM) 4 and suberoyl ani- lide hydroxamic acid (SAHA) (lit. IC 50 10 nM) 5 both contain a hydroxamic acid moiety as the zinc-binding group. 6 TheX-raycrystalstructuresofTSAandSAHA boundtoanHDAChomologuehavebeenreportedand confirm that the metal-binding group interacts with the active site zinc, with the linker spanning the tube-like portion of the binding pocket and positioning the aro- matic groups so as to make contact with the pocket entrance. 7 Previous publications have delineated efforts aimed at optimizing hydroxamic acid containing compounds such as 1 identified via screening of the Abbott com- pound collection. 8 Recently, non-hydroxamate HDAC inhibitors containing electrophilic ketones such as tri- fluoromethylketonesand a-ketoamides,exemplifiedby 2 and 3 have been reported. 9 As a continuation of our quest for non-hydroxamate HDAC inhibitors, a range of electrophilic ketones were synthesized and evaluated in this study, some of which are shown in Table 1.The synthesis of these compounds was accomplished by one 0960-894X/$ - see front matter # 2003 Published by Elsevier Ltd. doi:10.1016/j.bmcl.2003.09.007 Bioorganic & Medicinal Chemistry Letters 13 (2003) 3909–3913 Figure 1. HDAC inhibitors. *Corresponding author. Tel.: +1-847-938-6594; fax: +1-847-935- 0310; e-mail: anil.vasudevan@abbott.com