ABSTRACT
Cyclooxygenase (COX) enzymes, or prostaglandin-endoperoxide synthases (PTGS), are heme-containing bis-oxygenases that catalyze the first committed reaction in metabolism of arachidonic acid (AA) to the potent lipid mediators, prostanoids and thromboxanes. Two isozymes of COX enzymes (COX-1 and COX-2) have been identified to date. This review will focus specifically on the neurobiological and neuropathological consequences of AA metabolism via the COX-2 pathway and discuss the potential therapeutic benefit of COX-2 inhibition in the setting of neurological disease. However, given the controversy surrounding the use of COX-2 selective inhibitors with respect to cardiovascular health, it will be important to move beyond COX to identify which down-stream effectors are responsible for the deleterious and/or potentially protective effects of COX-2 activation in the setting of neurological disease. Important advances toward this goal are highlighted herein. Identification of unique effectors in AA metabolism could direct the development of new therapeutics holding significant promise for the prevention and treatment of neurological disorders.
Subject(s)
Central Nervous System/drug effects , Cyclooxygenase 2 Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Arachidonic Acid/metabolism , Cyclooxygenase 2 Inhibitors/adverse effects , Humans , Neuronal Plasticity/drug effects , Oxidative Stress/drug effectsABSTRACT
A series of novel coumarin carboxamides were synthesized, and their tumor cell cytotoxic activity was investigated. These compounds specifically inhibited the growth of cancer cells that have a high level of ErbB-2 expression. Immunoprecipitation analysis of the cell lysates prepared from carboxamide treated cancer cells showed the inhibition of ErbB-2 phosphorylation suggesting the interaction of these compounds with ErbB-2 receptor. The down regulation of the kinase activity was further confirmed by performing in vitro kinase assay with recombinant ErbB-2 incubated with carboxamides. The inhibition of ErbB-2 phosphorylation correlated with down-regulation of ERK1 MAP kinase activation that is involved in proliferative signaling pathway. Furthermore, the cell-killing activity of many of these inhibitors is restricted to tumor cells with no demonstrable cytotoxicity against normal human fibroblasts suggesting that these compounds are tumor-specific.
Subject(s)
Amides/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Coumarins/chemistry , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Receptor, ErbB-2/drug effects , Amides/chemical synthesis , Amides/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Coumarins/chemical synthesis , Female , Fibroblasts/drug effects , Humans , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Structure , Receptor, ErbB-2/metabolismABSTRACT
A new series of styryl acetoxyphenyl sulfides and sulfones possessing (E)- and (Z)-configurations were designed and prepared by stereospecific syntheses. All these compounds were evaluated for their ability to inhibit COX-2 enzyme in vitro. Structure-activity relationship studies on these compounds revealed that only sulfides with (Z)-configuration have potential COX-2 inhibitory activity. This inactivation of the enzyme is believed to be due to the selective covalent modification of COX-2 by the inhibitors.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Prostaglandin-Endoperoxide Synthases/drug effects , Sulfides/chemical synthesis , Sulfides/pharmacology , Sulfones/chemical synthesis , Sulfones/pharmacology , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/chemistry , Magnetic Resonance Spectroscopy , Sheep , Sulfides/chemistry , Sulfones/chemistryABSTRACT
Synthesis of coumarin 3-(N-aryl) sulfonamides was accomplished either by Knoevenagel condensation of anilinosulfonylacetic acids with suitable salicylaldehydes or by the reaction of methyl anilinosulfonylacetates with substituted salicylaldehydes in presence of a catalytic amount of a base. All the compounds tested for antiproliferative activity in different cancer cell lines have shown GI(50) values less than 100 microM.
