ABSTRACT
NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-(N'-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrol-3-yl}-propionic acid, was designed as FGF receptor 1 inhibitor by computational study and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 10 microM. NP506 inhibited the tyrosine phosphorylation in FGF, VEGF, and PDGF receptors and the activation of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal-kinase (JNK) and AKT after the rhFGF-2 stimulation. The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3-d]pyrimidine scaffold led to the inhibitory effect in two signaling pathways: inhibition of AKT activation in the phosphatidyl inositol 3'-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Cell Proliferation , Cells, Cultured , Drug Design , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Fibroblast Growth Factor 2/metabolism , Humans , Indoles/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , Oxindoles , Phosphorylation , Propionates , Proto-Oncogene Proteins c-akt/metabolism , Pyrroles/pharmacology , Tyrosine/chemistryABSTRACT
NP603, the 6-dimethoxy phenyl indolin-2-one, was designed as FGF receptor 1 inhibitor by computational study. NP603 was synthesized and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 0.4 microM but with similar potency as SU16g. NP603 inhibited the tyrosine phosphorylation in FGF receptor and the activation of extracellular signal-regulated kinase and c-Jun-N-terminal-kinase after the rhFGF-2 stimulation. The increase in activity of NP603 supports the role of Lys514 movement in ligand-receptor binding in modeling study as the movement accommodates the hydrophobic interaction at the receptor pocket leading to the enhancement of binding capacity.
Subject(s)
Enzyme Inhibitors/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemistry , Fibroblast Growth Factor 1/chemistry , Humans , Hydrogen Bonding , Indoles/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , Lysine/chemistry , Models, Chemical , Molecular Conformation , Oxindoles , Propionates , Pyrimidines/pharmacology , Pyrroles/pharmacologyABSTRACT
Manganese was incorporated in the structure of the selected antioxidants to mimic the superoxide dismutase (SOD) and to increase radical scavenging ability. Five manganese complexes (1-5) showed potent SOD activity in vitro with IC(50) of 1.18-1.84 microM and action against lipid peroxidation in vitro with IC(50) of 1.97-8.00 microM greater than their ligands and trolox. The manganese complexes were initially tested in vivo at 50 mg/kg for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mice brain. Only manganese complexes of kojic acid (1) and 7-hydroxyflavone (3) exhibited the significant suppressions on MAP-induced hypermotility and did not significantly decrease the locomotor activity in normal condition. Manganese complex 3 also showed protective effects against learning and memory impairment in transient cerebral ischemic mice. These results supported the brain delivery and the role of manganese in SOD activity as well as in the modulation of brain neurotransmitters in the aberrant condition. Manganese complex 3 from 7-hydroxyflavone was the promising candidate for radical implicated neurodegenerative diseases.
