ABSTRACT
Recently, pyrazole derivatives as high affinity and selective A2A adenosine receptor antagonists have been reported. But, so far, there are no reports about the inhibitory effects of multi-substituted pyrazole derivatives on apoptosis of vascular endothelial cells (VECs). In this study, we synthesized six pyrazole derivatives and characterized the structures of the compounds by IR, (1)H NMR, mass spectroscopy, and element analysis. The biology assay showed that a novel pyrazole derivative, ethyl 3-(o-chlorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (MPD) at low concentration (25muM) increased VECs viability and inhibited VECs apoptosis induced by deprivation of serum and FGF-2. During this process, the levels of integrin beta4, reactive oxygen species (ROS), and p53 were depressed obviously. The data suggested that MPD was a potential inhibitor of apoptosis associated with the signal pathway mediated by integrin beta4, ROS, and p53 in VECs.
Subject(s)
Apoptosis/drug effects , Endothelial Cells/drug effects , Integrin beta4/drug effects , Pyrazoles/pharmacology , Reactive Oxygen Species/antagonists & inhibitors , Tumor Suppressor Protein p53/drug effects , Apoptosis/physiology , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cells, Cultured , DNA/drug effects , DNA/metabolism , DNA Fragmentation/drug effects , Dose-Response Relationship, Drug , Endothelial Cells/metabolism , Humans , Integrin beta4/metabolism , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Stereoisomerism , Structure-Activity Relationship , Tumor Suppressor Protein p53/metabolismABSTRACT
We synthesized a series of novel small molecules, 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine derivatives, by tandem reduction-oxirane opening of 2-nitroaroxymethyloxiranes in moderate or excellent yields. We investigated the effects of all of the compounds on HUVEC apoptosis and A549 cell growth. The results showed that 6,8-dichloro-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine was the most effective small molecule in promoting HUVEC apoptosis and inhibiting A549 cell proliferation, but 6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine could remarkably inhibit HUVEC apoptosis and might induce the formation of microvessel.
