Synthesis, antiproliferative and apoptotic activities of N-(6(4)-indazolyl)-benzenesulfonamide derivatives as potential anticancer agents

• DOI: 10.1016/j.ejmech.2012.09.013
• Publication Date: 2012-09-17T13:45:40Z
• Authors: Najat Abbassi; Hakima Chicha; El Mostapha Rakib; Abdellah Hannioui; Mdaghri Alaoui; Abdelouahed Hajjaji; Detlef Geffken; Cinzia Aiello; Rosaria Gangemi; Camillo Rosano; Maurizio Viale
• Keywords: Sulfonamides; Indazoles; G1 Phase; Antineoplastic Agents; Apoptosis; Flow Cytometry; Microtubules; Resting Phase, Cell Cycle; 01 natural sciences; 0104 chemical sciences; 3. Good health; G2 Phase Cell Cycle Checkpoints; Molecular Docking Simulation; Polyploidy; Inhibitory Concentration 50; Kinetics; Mice; Structure-Activity Relationship; Tubulin; Cell Line, Tumor; Animals; Humans; Cell Proliferation

Recently, it has been reported that compounds bearing a sulfonamide moiety possess many types of biological activities, including anticancer activity. The present work reports the synthesis and antiproliferative evaluation of some N-(6(4)-indazolyl)benzenesulfonamides and 7-ethoxy-N-(6(4)-indazolyl)benzenesulfonamides. All compounds were evaluated for their in vitro antiproliferative activity against three tumor cell lines: A2780 (human ovarian carcinoma) A549 (human lung adenocarcinoma) and P388 (murine leukemia). The results indicated that sulfonamides 2c, 3c, 6d, 8, 13, 3b and 16 were endowed with a pharmacologically interesting antiproliferative activity with compounds 2c and 3c showing the lower IC(50) (from 0.50 ± 0.09 to 1.83 ± 0.52 μM and from 0.58 ± 0.17 to 5.83 ± 1.83 μM, respectively). Moreover, these indazoles were able to trigger apoptosis through the upregulation of the typical apoptosis markers p53 and bax. As regard to the hypothetic targets of these compounds, a preliminary docking analysis showed that all compounds seemed to interact with β-tubulin, in particular compound 3b that showed the lower Ki. The cytofluorimetric analysis of the cell cycle phases indicates that all compounds, when administered at their IC(75), caused a block in the G2/M phase of the cell cycle with the generation of subpopulations of cells with a number of chromosome >4n. When the IC(50)s were applied we observed a prevalent block in the G0/G1 phase except for compounds 16 and 8 where a partial G2/M block was present with a concomitant decrease of cells in the G0/G1 and S phases of the cell cycle. Altogether these results suggest a possible, but not exclusive, interaction with microtubules.