Novel Sulfonamide Derivatives as Inhibitors of Histone Deacetylase

Abstract

Dedicated to Professor Rolf Huisgen on the occasion of his 85th birthday 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.

A novel platinum complex of the histone deacetylase inhibitor belinostat: Rational design, development and in vitro cytotoxicity

“…This reported synthesis was inspired by a previously published synthesis of belinostat [16] where 2-(4-amino-benzyl)-malonic acid dimethyl ester was reacted with 1 instead of aniline. The sulfonyl chloride compound, 1, was reacted with 2- respectively.…”

“…[15] Though the arylsulfonamide group in belinostat is meta substituted we selected the para analogue (p-Bel, Figure 2) for our study on the basis that it has comparable HDAC inhibitory and anti-proliferative activity as compared to belinostat but its synthesis is more facile. [16] We sought to derivatise p-Bel with a dicarboxylate linker so as to facilitate its binding to and hydrolysis from a cis-diammine Pt(II) moiety. We utilised molecular modelling to identify which p-Bel to develop with a view to facilitating complexation to Pt while minimising any negative impact on HDAC inhibitory activity.…”

Synthesis of Sulfonamides and Evaluation of Their Histone Deacetylase (HDAC) Activity

“…2, 172.0, 137.1, 135.7, 135.3, 129.5, 129.2, 128.5, 128.4, 128.3, 128.1, 126.7, 67.3, 61.0, 57.0, 52.7, 48.3, 39.4 H 5.76, N 6.38; found: C 59.18, H 5.87, N 6.27. (6) 3, 172.1, 140.6, 135.3, 128.5, 128.4, 128.3, 128.1, 126.1, 67.3, 61.9, 61.4, 56.0, 48.6, 35.2, 31.7, 31 6, 135.3, 128.5, 128.4, 128.3, 128.1, 126.1, 67.3, 61.9, 61.4, 56.0, 48.6, 35.2, 31.7, 31 3067, 3034, 2954, 2881, 1743, 1638, 1455, 1330, 1148, 1017, 849 cm -1 ; 1 H-NMR (CDCl 3 ) δ 7.52-7.30 (m, 5H), 7.24-7.14 (m, 1H), 7.00-6.83 (m, 2H), 5.29-5.11 (m, 2H), 4.75-4.60 (m, 1H), 4.52-4.42 (m, 1H), 3.53-3.28 (m, 4H), 3.04 (t, J = 6.5 Hz, 2H), 2.36-2.24 (m, 1H), 2.12-1.90 (m, 3H); 13 C-NMR (CDCl 3 ) δ 172. 5, 140.5, 135.3, 128.6, 128.4, 128.3, 127.0, 125.6, 124.0, 67.3, 61.3, 48.7, 44.7, 31.3, 30.6, 25 Anal.…”

“…More recently, the Angibaud group [5] reported the preparation of a series of pyrimidyl-5-hydroxamic acids having significant HDAC activity in human tumor cell lines. The Kalvinsh group [6] demonstrated that a series of novel sulfonamide derivatives were synthesized and evaluated for their ability to inhibit human HDAC. The Delorme group [7] developed of potential antitumor agents as a new set of sulfonamide derivatives.…”

5-Membered cyclic hydroxamic acids as HDAC inhibitors

“…Visualization of TLC plates was made with short wave (254 nm) UV light. Flash column chromatography was carried out using silica gel 0.035-0.070 mm (Merck (8h), 3-formyl-indole-1-carboxylic acid tert-butyl ester 21 (8a), 3-formyl-N-phenyl-benzenesulfonamide 22 (8i), were synthesized according to literature procedures.…”