ABSTRACT
Flavone (1) was found to protect against ethanol-induced gastric damage in rats; however, it is known that certain compounds in the flavone class, including flavone itself, are inducers of hepatic drug metabolizing enzymes. With the hope of identifying gastroprotective flavones that have minimal effects on drug metabolizing enzymes, we have synthesized and evaluated selected flavone analogs. Gastroprotective potency in the ethanol model was retained by methoxy substitution in the 5-position (4) and by methoxy (12) or methyl (14) substitution in the 7-position. A number of substituted analogs of the potent molecule 5-methoxyflavone (4) were also synthesized, and in many cases, these substitutions provided gastroprotective molecules. In order to assess liver enzyme induction potential, two of the gastroprotective flavones, 7-methoxyflavone (12) and 5-methoxy-4'-fluoroflavone (26), were examined for their effect on liver microsomal cytochrome P450 and 7-ethoxyresorufin O-dealkylase (CYP1A) activity. These two compounds caused minimal changes in the cytochrome P450 concentration and were considerably less potent than beta-naphthoflavone as inducers of CYP1A enzyme activity. Furthermore, following oral administration to rats, 5-methoxy-4'-fluoroflavone (26) was found to protect against indomethacin-induced gastric damage. These results indicate that, through appropriate substitution, flavones can be obtained that are gastroprotective but have minimal effects on drug-metabolizing enzymes.
Subject(s)
Flavonoids/chemical synthesis , Flavonoids/pharmacology , Stomach Diseases/drug therapy , Animals , Cytochrome P-450 CYP1A1 , Cytochrome P-450 Enzyme System/biosynthesis , Cytochrome P-450 Enzyme System/metabolism , Enzyme Induction/drug effects , Ethanol , Indomethacin/pharmacology , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Oxidoreductases/biosynthesis , Oxidoreductases/metabolism , Rats , Rats, Sprague-Dawley , Stomach Diseases/chemically induced , Structure-Activity RelationshipABSTRACT
A high-performance affinity chromatography support based on silica has been developed for the immobilization of proteins containing primary amino groups. A hydrophilic polymer covalently bound to the silica surface minimizes nonspecific protein binding to the support while preserving high binding capacity. The Schiff base reaction involved in the coupling of a ligand to the affinity medium is rapid, allows the use of mild conditions during the coupling process, and results in a very stable linkage. Reaction parameters were studied for protein coupling to the affinity support to determine optimum binding conditions and dynamic capacity as a function of protein size. The stability of the ligand-matrix bond was determined. The performance and reproducibility of the affinity support are demonstrated by its use in the analysis of nitrophenyl sugar derivatives, purification of glycoproteins, and isolation of anti-bovine immunoglobulin G developed in rabbit.
Subject(s)
Chromatography, Affinity/methods , Glutaral , Polyethyleneimine , Silicon Dioxide , Animals , Concanavalin A/isolation & purification , Horseradish Peroxidase/isolation & purification , Humans , Immunoglobulin G/isolation & purification , Molecular WeightABSTRACT
A new urea-bonded chiral stationary phase has been developed in our laboratory. This bonded phase has been shown to resolve N-terminal substituted amino acids and the carboxyl derivatized anti-inflammatory drugs. Typical alpha-value for dinitrobenzoyl phenylglycine was 1.7. Values for derivatized ibuprofen, naproxen, and fenoprofen were 2, 1.84, and 1.6, respectively. Further application of these studies to biologically active compounds such as peptides and drugs is in progress.
Subject(s)
Acids/isolation & purification , Amines/isolation & purification , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Chemical Phenomena , Chemistry , Fenoprofen/analogs & derivatives , Fenoprofen/isolation & purification , Ibuprofen/analogs & derivatives , Ibuprofen/isolation & purification , Naproxen/analogs & derivatives , Naproxen/isolation & purification , Spectrophotometry, Infrared , Stereoisomerism , UreaABSTRACT
A rationale is presented for the development of prostaglandin F2alpha receptor antagonists. The target analogue, 5,6-(dibenzyloxy)-1-oxo-2-propyl-2-indanpropionic acid (3), was shown to have selective activity for antagonism of PGF2alpha when compared to the antagonism of acetylcholine and KCl on the mouse ileum, whereas other 2-indanpropionic acids (1, 2, 4), not substituted with benzyl functions, were considerably less active and nonselective. The results suggest that 3 may serve as a lead compound for further drug development.
Subject(s)
Indans/chemical synthesis , Indenes/chemical synthesis , Propionates/chemical synthesis , Prostaglandins F/antagonists & inhibitors , Acetylcholine/antagonists & inhibitors , Animals , Female , In Vitro Techniques , Indans/pharmacology , Mice , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Potassium Chloride/antagonists & inhibitors , Propionates/pharmacology , Structure-Activity RelationshipABSTRACT
Whereas the 2-propyl- and 2-butyl-5,6-(methylenedioxy)indene calcium antagonists reversed the spasmogenic action of several agonists including PGF2alpha and acetylcholine at 5 X 10(-5) to 10(-4) M on the rat ileum, the corresponding 5,6-dimethoxy analogues exhibited spasmogenic activity at higher concentration (10(-4)-10(-3) M) and exhibited neither spasmogenic nor spasmolytic activity at lower (10(-6)-10(-5) M) concentration. The results are compared to the methyl and 2-ethyl analogues. At 10(-4) M only the butyl analogue was capable of moderate antagonism of acetylcholine and at 10(-3) M all four analogues were capable of moderately antagonizing the actions of acetylcholine.
