ABSTRACT
From the authors' previous studies on the Phase I metabolism of rutaecarpine, nine metabolites formed were identified as products of hydroxylation on the aromatic rings in rat liver microsomes. In order to determine the possible metabolic fate of rutaecarpine, the Phase II metabolites of rutaecarpine were characterized in the present study by using liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS). When male Sprague-Dawley rats were treated intravenously with 4 mg kg(-1) rutaecarpine, 16 different Phase I and II metabolites were identified in urine including four sulfate and four glucuronide conjugates. Phase I metabolites of rutaecarpine were identified as four mono-hydroxylated metabolites (M2-5) and four isobaric di-hydroxylated metabolites (M6-9). These metabolites were identical to the in vitro metabolites except one, which was hydroxylated in the aliphatic moiety. In addition, Phase II metabolites were identified as conjugated with sulfate (S1-4) and glucuronide (G1-4). In faeces, 11 different metabolites were identified. The metabolites M8 and glucuronide conjugated (G1-4) were not detected. Structures of all metabolites were confirmed with CID fragmentation spectra of MS(2), MS(3) and retention times by LC/ESI-MS.
Subject(s)
Alkaloids/metabolism , Chromatography, Liquid/methods , Spectrometry, Mass, Electrospray Ionization/methods , Alkaloids/urine , Animals , Bile/chemistry , Glucuronides/chemistry , Glucuronides/metabolism , Indole Alkaloids , Male , Quinazolines , Rats , Rats, Sprague-Dawley , Sulfates/chemistry , Sulfates/metabolismABSTRACT
A series of 1,3- and 2,3-disubstituted 4,5-polymethylenepyrazole derivatives were prepared and their inhibitory activities on cyclooxygenase-2 were evaluated. Among the compounds prepared, 1,3-isomer, 3-cyclohexyl-l-(4-fluorophenyl) 4,5-trimethylenepyra-zole (5be) showed the most potent (IC50 = 0.008 microM) inhibitory activity with little selectivity (13-fold) on cyclooxygenase-2.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/drug effects , Prostaglandin-Endoperoxide Synthases/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/enzymology , Cells, Cultured , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Magnetic Resonance Spectroscopy , Male , Mast Cells/drug effects , Mast Cells/enzymology , Membrane Proteins , Mice , Mice, Inbred BALB C , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
Eight 2-alkylaminosubstituted 5,8-dimethoxy-4-methylquinolines and nine 2-alkylaminosubstituted or 2,6-disubstituted 4-methylquinoline-5,8-diones were synthesized and evaluated in vitro cytotoxicity against four human cancer cell lines (HOP62, SK-OV-3, HCT15 and SF295).
Subject(s)
Antineoplastic Agents/chemical synthesis , Quinolines/chemical synthesis , Antineoplastic Agents/pharmacology , Humans , Quinolines/pharmacology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A series of conformationally controlled 2-PAM derivatives were prepared from 2-acetylpyridine and 2,3-pyrido[b]cycloalkenones in two steps and their reactivities towards parathion poisoned AChE were evaluated. The most planar 2,3-pyrido[b]cyclohexanone oxime methiodide showed an activity comparable to 2-PAM implying E-syn is that the most active conformation of 2-PAM in the biological system.
Subject(s)
Cholinesterase Reactivators/chemistry , Pralidoxime Compounds/chemistry , Acetylcholinesterase/metabolism , Binding Sites , Structure-Activity RelationshipABSTRACT
For the development of new anticonvulsive agents, gamma-vinyl GABA (vigabatrin) and GABA mimetics derivatives were covalently coupled as potential dual acting prodrugs and evaluated for their anticonvulsive activities. Among the prepared compounds, 11 showed the most potent anticonvulsive activity, a shorter onset time and a broader spectrum compared to vigabatrin.
Subject(s)
Anticonvulsants/chemical synthesis , Prodrugs/chemical synthesis , Vigabatrin/chemical synthesis , Animals , Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Bicuculline , Drug Design , Mice , Pentylenetetrazole , Picrotoxin , Prodrugs/chemistry , Prodrugs/metabolism , Prodrugs/therapeutic use , Seizures/chemically induced , Seizures/drug therapy , Vigabatrin/chemistry , Vigabatrin/therapeutic useABSTRACT
A series of disubstituted 4,5-polymethylenepyrazoles were synthesized and evaluated their inhibitory activities against COX-2. Some compounds showed strong (0.3 nM) inhibitory activity on COX-2 and were found somewhat selective (up to 16) on COX-2 over COX-1.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/enzymology , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Male , Mast Cells/drug effects , Mast Cells/enzymology , Mice , Mice, Inbred BALB C , Structure-Activity RelationshipABSTRACT
New HMG-CoA reductase inhibitors, in which 3-substituted 4,5-polymethylenepyrazoles are employed as a hydrophobic anchor connected to tetrahydro-4-hydroxy-2H-pyran-2-one by a two-carbon bridge, were designed and synthesized to exhibit significant inhibitory activity comparable to mevinolin. The most potent enzyme inhibitor (11cc, IC(50)=0.01 muM) is 4-fold more potent than lovastatin.
ABSTRACT
trans-Ethyl 1,2,3,4a,5,6,8a-octahydro-2-benzyl-4-hydroxy-6-methyl-5- isoquinoline-carboxylate was prepared by intramolecular Diels-Alder reaction as a precursor of newly designed aza-analogue of mevinolin.
