Novel Sulfonamide Derivatives as Inhibitors of Histone Deacetylase

✍ Scribed by Paul W. Finn; Morwena Bandara; Chris Butcher; Angela Finn; Ruth Hollinshead; Nagma Khan; Norman Law; Sreenivasa Murthy; Rosario Romero; Clare Watkins; Victor Andrianov; Rasma M. Bokaldere; Klara Dikovska; Vija Gailite; Einars Loza; Irina Piskunova; Igor Starchenkov; Maxim Vorona; Ivars Kalvinsh

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: German
• Weight: 374 KB
• Volume: 88
• Category: Article
• ISSN: 0018-019X
• DOI: 10.1002/hlca.200590129

✦ Synopsis

Abstract

Inhibition of the enzyme histone deacetylase (HDAC) is emerging as a novel approach to the treatment of cancer. A series of novel sulfonamide derivatives were synthesized and evaluated for their ability to inhibit human HDAC. Compounds were identified which are potent enzyme inhibitors, with IC~50~ values in the low nanomolar range against enzyme obtained from HeLa cell extracts, and with antiproliferative effects in cell culture. Extensive characterization of the structure–activity relationships of this series identified key requirements for activity. These include the direction of the sulfonamide bond and substitution patterns on the central phenyl ring. The alkyl spacer between the aromatic head group and the sulfonamide functionality also influenced the HDAC inhibitory activity. One of these compounds, m11.1, also designated PXD101, has entered clinical trials for solid tumors and haematological malignancies.