Design, synthesis, and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors Shoukou Lee, a Chihiro Shinji, a Kiyoshi Ogura, b Motomu Shimizu, b Satoko Maeda, c Mayumi Sato, b Minoru Yoshida, c Yuichi Hashimoto a and Hiroyuki Miyachi a, * a Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan b Tumor Therapy Project, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan c RIKEN, Hirosawa, Wako, Saitama 351-0198, Japan Received 21 May 2007; revised 7 June 2007; accepted 11 June 2007 Available online 13 June 2007 Abstract—We designed and synthesized hydroxamic acid derivatives bearing a 4-(3-pyridyl)phenyl group as a cap structure, and found that they exhibit potent histone deacetylase (HDAC) inhibitory activity. A representative compound, 17a, showed more potent growth-inhibitory activity against pancreatic cancer cells and greater upregulation of p21 WAF1/CIP1 expression than the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (Zolinza TM ). Ó 2007 Elsevier Ltd. All rights reserved. Epigenetic regulation of specific gene expression is med- iated by several mechanisms, among which one of the most important is post-translational acetylation of the side-chain amino groups of specific histone lysine resi- dues. The acetylation status of histones is modulated by histone acetyltransferases (HAT) and histone deacet- ylases (HDAC). 1,2 HAT is generally considered as a transcriptional activator, and HDAC is considered as a transcriptional inhibitor, because histone acetylation is associated with transcriptionally active chromatin, whereas histone deacetylation is associated with tran- scription repression. Many recent studies have shown that inhibition of HDAC elicits anticancer effects in sev- eral lines of tumor cells by inhibiting cell growth and inducing apoptosis. 3–5 Therefore, compounds that inhi- bit HDAC activity may depress the expression of certain genes, resulting in antiproliferative and antitumor effects. 6 Natural and synthetic HDAC inhibitors have been studied extensively (Fig. 1), and suberoylanilide hydroxamic acid (SAHA; Zolinza TM ) has been approved by the FDA for once-daily oral treatment of advanced cutaneous T-cell lymphoma (CTCL), and further clini- cal studies of Zolinza TM for the treatment of various solid tumors are in progress. Numerous biological studies have indicated that HDACs are heterogeneous, consisting of 18 isozymes, which can be categorized into four classes (class I, class IIa, class IIb, and class III). Class I and class II HDACs are zinc-containing amidehydrolases, and class III HDAC consists of NAD-dependent amidehydrolase. The biological function and distribution of each class of HDACs have been extensively studied from a molec- ular-pharmacological viewpoint, but much remains to be learnt. We have been engaged in structural development studies of the multi-drug template thalidomide for the creation of structurally novel drug leads, 7–12 and have already reported the design and synthesis of potent HDAC inhib- itors with cyclic amide structure (isoindolinone), such as compounds 8 and 9. 13,14 In this paper, we report the design, synthesis, and biological activity of novel HDAC inhibitors with a pyridylphenyl group as a cap structure. Synthetic routes to the present series of cyclic amide derivatives are outlined in Chart 1. 4-Iodobenzoic acid (10) was reduced with BH 3 ÆTHF to afford 4-iodobenzyl alcohol (11). This alcohol was 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.06.038 Keywords: HDAC; HDAC inhibitor; Isoindoklinone; Hydroxamic acid; Pancreatic cancer; p21. * Corresponding author. E-mail: miyachi@iam.u-tokyo.ac.jp Bioorganic & Medicinal Chemistry Letters 17 (2007) 4895–4900