Total Synthesis of Azumamide A and Azumamide E, Evaluation as Histone Deacetylase Inhibitors, and Design of a More Potent Analogue Shijun Wen, † Krystle L. Carey, †,‡ Yoichi Nakao, § Nobuhiro Fusetani, § Graham Packham, ‡ and A. Ganesan* ,† School of Chemistry, UniVersity of Southampton, Southampton SO17 1BJ, United Kingdom, Cancer Sciences DiVision, School of Medicine, UniVersity of Southampton, Southampton SO16 6YD, United Kingdom, and Graduate School of Agricultural and Life Sciences, UniVersity of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan ganesan@soton.ac.uk Received January 8, 2007 ABSTRACT The unprecedented diastereoselective Mannich reaction of a Z-allylsulfoximine was a key step in the total synthesis of the marine natural products azumamide A and E, and an unnatural analogue. Their relative potency as histone deacetylase inhibitors was evaluated and found to correlate with predicted zinc-binding affinity. In eukaryotes, DNA is tightly packaged with histone and non-histone proteins into the higher order structure of chromatin. Protein posttranslational modifications including acetylation, methylation, phosphorylation, and ubiquitinyl- ation constitute a “histone code” 1 that ultimately regulates gene transcription by modulating the unwinding of DNA and recruitment of binding partners. Among the chromatin modifying enzymes, zinc metallohydrolase class I/II histone deacetylases (HDACs) 2 have attracted the most attention as anticancer targets. The two most advanced inhibitors in development are Merck’s synthetic Vorinostat (Figure 1, SAHA, suberoylanilide hydroxamic acid), recently receiving FDA approval, and the natural product FK228 (depsipeptide) in Phase II clinical trials. These exemplify the classic pharmacophore for HDAC inhibitors: a “warhead” binding the active site zinc, linked by a spacer mimicking the substrate’s acetyl-lysine side chain, and a “cap” protruding † School of Chemistry, University of Southampton. ‡ School of Medicine, University of Southampton. § University of Tokyo. (1) (a) Biel, M.; Wascholowski, V.; Giannis, A. Angew. Chem., Int. Ed. 2005, 44, 3186-3216. (b) Nightingale, K. P.; O’Neill, L. P.; Turner, B. M. Curr. Opin. Genet. DeV. 2006, 16, 125-136. (2) (a) Miller, T. A.; Witter, D. J.; Belvedere, S. J. Med. Chem. 2003, 46, 5097-5116. (b) Moradei, O.; Maroun, C. R.; Paquin, I.; Vaisburg, A. Curr. Med. Chem.: Anti-Cancer Agents 2005, 5, 529-560. (c) Bolden, J. E.; Peart, M. J.; Johnstone, R. W. Nat. ReV. Drug DiscoVery 2006, 5, 769- 784. ORGANIC LETTERS 2007 Vol. 9, No. 6 1105-1108 10.1021/ol070046y CCC: $37.00 © 2007 American Chemical Society Published on Web 02/21/2007