Abstract
This study describes the effect of novel 6-Arylbenzimidazo[1,2-c]quinazoline derivatives as tumor necrosis factor alpha (TNF-alpha) production inhibitors. The newly synthesized compounds were tested for their in vitro ability to inhibit the lipolysaccharide (LPS) induced TNF-alpha secretion in the human promyelocytic cell line HL-60. The compound 6-Phenyl-benzimidazo[1,2-c]quinazoline, coded as Gl, resulted as the most potent inhibitor and with no significant cytotoxic activity. Thus, 6-Arylbenzimidazo[1,2-c]quinazoline derivatives may have a potential as anti-inflammatory agents.
Highlights
Described as a protein factor capable of killing tumor cells in vitro, tumor necrosis factor alpha (TNF-α) has been demonstrated to participate in several biological processes; it is a potent pro-inflammatory agent and has been implicated in a variety of acute and chronic inflammatory diseases (Beutler and Cerami, 1989)
In order to establish an in vitro biological assay to determine the potential of new compounds to inhibit TNF-α production we used the human promyelocytic leukemia cell line, HL-60
HL-60 cells were first stimulated with LPS alone (10 μg/mL) but no secretory answer was observed after 6 h (Fig. 2B)
Summary
Described as a protein factor capable of killing tumor cells in vitro, tumor necrosis factor alpha (TNF-α) has been demonstrated to participate in several biological processes; it is a potent pro-inflammatory agent and has been implicated in a variety of acute and chronic inflammatory diseases (Beutler and Cerami, 1989). The successful introduction of TNF-α neutralizing agents, Infliximab, Etanercept and Adalimumab for clinical applications, such as for the treatment of many inflammatory diseases including Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis and psoriasis (Le and Abbenante, 2005), has ushered in a new era in the treatment of these chronic inflammatory conditions. The success of these novel agents and their impressively demonstrated clinical benefits has stimulated the search for new anti-cytokine small molecules (Wagner and Laufer, 2006).
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