Sulfamides as novel histone deacetylase inhibitors Amal Wahhab a, * , David Smil a , Alain Ajamian a , Martin Allan a , Yves Chantigny a , Eric Therrien a , Natalie Nguyen a , Sukhdev Manku a , Silvana Leit a , Jubrail Rahil b , Andrea J. Petschner b , Ai-Hua Lu b , Alina Nicolescu b , Sylvain Lefebvre c , Samuel Montcalm c , Marielle Fournel c , Theresa P. Yan c , Zuomei Li c , Jeffrey M. Besterman c , Robert Déziel a a Department of Medicinal Chemistry, MethylGene Inc., 7220 rue Frederick-Banting, Montreal, Que., Canada H4S 2A1 b Department of Lead Discovery, MethylGene Inc., 7220 rue Frederick-Banting, Montreal, Que., Canada H4S 2A1 c Department of Molecular Biology, MethylGene Inc., 7220 rue Frederick-Banting, Montreal, Que., Canada H4S 2A1 article info Article history: Received 4 November 2008 Revised 20 November 2008 Accepted 21 November 2008 Available online 27 November 2008 Keywords: Sulfamide HDAC inhibitors HDAC1 HDAC6 abstract The sulfamide moiety has been utilized to design novel HDAC inhibitors. The potency and selectivity of these inhibitors were influenced both by the nature of the scaffold, and the capping group. Linear long- chain-based analogs were primarily HDAC6-selective, while analogs based on the lysine scaffold resulted in potent HDAC1 and HDAC6 inhibitors. Ó 2008 Elsevier Ltd. All rights reserved. Histone deacetylases (HDACs) are a family of 18 enzymes that play an important role in the regulation of gene expression, cell growth, and proliferation by regulating the deacetylation of e-N- acetyl groups on the L-lysine residues at the N-terminal tails of core histones, tubulin, and other proteins. 1a These enzymes are divided into two categories: zinc-dependent (HDAC1-11) and NAD + - dependent enzymes (known as sirtuins, Sirt1-7, or HDAC class III). The zinc-dependent enzymes are divided into class I (HDAC1, 2, 3, and 8), class IIa (HDAC4, 5, 7, and 9), class IIb (HDAC6 and 10), and class IV (HDAC11), which exhibits properties of both class I and class II HDACs. 1b,c The majority of the known HDAC inhibitors (HDACis) are hydroxamic acids. 2a,2b SAHA (Zolinza Ò , Vorinostat) was approved in 2006 to treat cutaneous T-cell lymphoma (CTCL), 3a and a num- ber of other HDACis are in different stages of clinical develop- ment. 3b–d The quest for HDACis resulted in a number of diverse structures, 4a,b such as aliphatic acids, 4c hydroxamic acids, 2a,b,4d,e o-aminoanilides, 4f cyclic peptides, 4g electrophilic ketones, 4h and thiols 4i–k (Fig. 1). These structures all share a common pharmaco- phore composed of a zinc-binding group (ZBG), a linker (scaffold), and a surface recognition domain (cap). 5 The crystal structures of both the histone deacetylase-like protein (HDLP) complexed with SAHA and TSA 6a , and that of HDAC8 6b,c suggest that the carbonyl and hydroxyl groups of the hydroxamic acid chelate the zinc ion in the active site in a bidentate fashion. SAHA 3a is reported to be a pan-HDACi while MGCD0103, an o- aminobenzanilide currently in Phase I/II cancer clinical trials, is an isotype-selective inhibitor. 4f The nature of the ZBG seems to confer both the activity and selectivity of these inhibitors. Search for ZBGs that could serve as a suitable pharmacophore in the design of novel HDACis is the sub- ject of our current research. In this letter, we detail the identifica- tion of a new class of HDACis bearing the sulfamide moiety as the ZBG. Sulfamides are well-documented inhibitors of carbonic anhy- drase, among other zinc-dependent enzymes. 7a–c To test our hypothesis that the sulfamide moiety could act as an efficient ZBG for HDACis, we fixed the ‘cap region’ using biphenyla- mide and varied both the sulfamide parent structure and the length of the linker. Sulfamides 4a–c were prepared according to Scheme 1 starting from the Boc-protected amino acids utilizing standard coupling conditions. The one-step procedure for the synthesis of sulfamide 4a from amine 3a utilizing sulfuric diamide 8 resulted in low yields and required high temperatures. We therefore opted for the two- step procedure, making the benzyl carbamates 9a,b 4b and 4c, fol- lowed by hydrogenation to furnish sulfamides 5a and 5b. The reac- tion of 3b with ClSO 2 NCO and t-BuOH gave the t-butyl carbamate intermediate which was methylated with MeI to produce 6. Depro- tection with TFA furnished the mono-methylated sulfamide 7a. 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.11.081 * Corresponding author. Tel.: +1 514 337 3333; fax: +1 514 337 0550. E-mail address: wahhaba@methylgene.com (A. Wahhab). Bioorganic & Medicinal Chemistry Letters 19 (2009) 336–340 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl