ABSTRACT
Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion molecule-1 (VCAM-1) expression. Correlations between lipophilicity determined by calculated logP values and inhibitory efficacy were observed among structurally similar compounds of the series. Various substituents were found to be tolerated at several positions of the chalcone backbone as long as the compounds fell into the right range of lipophilicity. The chalcone alpha,beta-unsaturated ketone moiety seemed to be the pharmacophore required for inhibition of VCAM-1 expression. Compound 19 showed significant antiinflammatory effects in a mouse model of allergic inflammation, indicating that this series of compounds might have therapeutic value for human asthma and other inflammatory disorders.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzoates/chemical synthesis , Chalcones/chemical synthesis , Indoles/chemical synthesis , Vascular Cell Adhesion Molecule-1/biosynthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aorta/cytology , Asthma/immunology , Asthma/prevention & control , Benzoates/chemistry , Benzoates/pharmacology , Cells, Cultured , Chalcones/chemistry , Chalcones/pharmacology , Chronic Disease , Depression, Chemical , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelium, Vascular/cytology , Humans , Indoles/chemistry , Indoles/pharmacology , Inflammation/drug therapy , Male , Mice , Mice, Inbred BALB C , Pulmonary Artery/cytology , StereoisomerismABSTRACT
Vascular cell adhesion molecule-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compounds with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compounds have been designed and synthesized starting from probucol (1). Many of these compounds demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivatives (4o, 4p, 4w, and 4x) inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concentration-dependent manner in vitro and showed antiinflammatory effects in an animal model. Compounds 4ad and 4ae are currently in clinical trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, respectively.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antioxidants/chemical synthesis , Phenols/chemical synthesis , Sulfides/chemical synthesis , Vascular Cell Adhesion Molecule-1/biosynthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Cells, Cultured , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Chronic Disease , Cricetinae , Depression, Chemical , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Humans , Inflammation/drug therapy , Interleukin-1/antagonists & inhibitors , Interleukin-1/metabolism , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Male , Mice , Mice, Inbred BALB C , Phenols/chemistry , Phenols/pharmacology , Probucol/chemistry , Structure-Activity Relationship , Sulfides/chemistry , Sulfides/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Novel chalcone derivatives have been discovered as potent inhibitors of TNF-alpha-induced VCAM-1 expression. Thienyl or benzothienyl substitution at the meta-position of ring B helps boost potency while large substitution at the para-position on ring B is detrimental. Various substitutions are tolerated on ring A. A lipophilicity-potency relationship has been observed in several sub-series of compounds.
