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Biomedical subjects

S D Wyrick

Publications and source records attributed to S D Wyrick.

At least 55 records · Page 3Linked to original sources
PubMed1988

Phorbol ester binding to oral epithelial cells in the presence of retinoic acid or N-nitrosonornicotine.

Although the specific mechanisms by which phorbol ester tumour promoters exert their various effects are not known, their actions are mediated by cell membrane receptors which contain lipids as major components of the receptor complex. Since cell modulators such as retinoic acid (RA) and nitrosonornicotine (NNN) can alter cell lipids, the binding of a phorbol ester to cells was examined at time intervals when lipid changes mediated by these modulators occur. Epithelial cells prepared from hamster cheek pouches were treated with all-trans RA or NNN for varying periods of time, then specific binding of phorbol esters was investigated. Cells treated with RA for intervals up to 24 h showed decreased binding when compared with untreated cells. Those treated with NNN for up to 168 h showed increased specific binding. The results suggest that alterations in the cell lipids may affect the specific binding of phorbol esters to cells.

Animals↗
PubMed1987

Effects of [(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]alkanoic acids, [(N-alkyl-1-oxo-1H,3H-isoindolin-5-yl)oxy]butanoic acids, and related derivatives on chloride influx in primary astroglial cultures.

It has been shown that agents that inhibit chloride influx and therefore lower intracellular chloride levels in a major cell type in cerebral gray matter, the astrocyte, inhibit astrocytic swelling in vitro and in vivo. In our laboratories, 4-[(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]alkanoic acids and related derivatives have been synthesized and tested for ability to lower intracellular astrocytic chloride levels in an established in vitro cultured rat astrocyte model. In general, derivatives with nitrogen substituents such as relatively small alkyl groups are active at 0.1 mM and/or 0.5 mM levels whereas larger substituents such as cyclopentyl and cyclohexyl are less active. Halogen substitution on the aromatic ring did not enhance activity. Derivatives with acid side chains of four carbons demonstrated superior activity to those of two carbons.

Animals↗
PubMed1986

Membrane actions of male contraceptive gossypol tautomers.

The role of different gossypol tautomers in the interaction of this molecule with membranes has been investigated using the isolated hemiacetal moiety of gossypol and the pH dependency of the keto-enol tautomeric equilibrium. Our results indicate that: the actions of the hemiacetal tautomer cannot explain the effects of gossypol on mitochondrial oxidative phosphorylation, lipid membrane interfacial potentials, and proton conductance of lipid bilayers; the enolate forms of gossypol are the species that bind to the membrane interface and decrease the electrostatic interfacial potential; and the uncharged (keto and/or enol) species in equilibrium with the enolate forms of gossypol give the molecule the ability to carry protons across biological membranes.

Acid-Base Equilibrium↗
PubMed1986

High-performance liquid chromatographic separation of platinum complexes containing the cis-1,2-diaminocyclohexane carrier ligand.

Platinum drugs with the 1,2-diaminocyclohexane (dach) carrier ligand have shown great promise in cancer chemotherapy, but little is known about their metabolism in the body. Since it is possible to radiolabel the dach ligand, it should be possible to quantitate the biotransformation products of these drugs, provided a method were available to separate the biotransformation products. In this paper we describe a two-column high-performance liquid chromatography system which can be used to separate many likely dach-platinum biotransformation products from the parent compounds, and allow their identification. An initial separation on a reverse-phase Partisil ODS-3 column allowed resolution of the uncharged species. The peak fractions from this column were concentrated 10-fold and reinjected onto a cation exchange Partisil 10 SCX column to allow resolution of the positively charged species. This system allowed resolution of two prototype dach-platinum drugs, (cis-1,2-diaminocyclohexane)dichloroplatinum(II) and (cis-1,2-diaminocyclohexane)malonatoplatinum(II), the aquated species likely to form from these drugs, and the complexes formed when these compounds react with glutathione, metallothionein, and amino acids. By using cation exchange chromatography at pH 2.3 as well as pH 4 and by using 14C-labeled amino acids to determine stoichiometry, it was also possible to determine the most likely structures for some of the amino acid complexes. Most importantly, this system allowed clear separation of many of the likely biotransformation products tested from the biologically important aquated species. This system should prove useful for separating and identifying the biotransformation products of dach-platinum drugs in blood and urine, in tissue culture media, and inside the cell.

Antineoplastic Agents↗
PubMed1986

Hypolipidemic activity of 6-substituted 6,7-dihydro-5H-dibenz[c,e]azepine and the effects of 6,7-dihydro-5H-dibenz[c,e]azepine on lipid metabolism of rodents.

A series of 6-substituted derivatives of 6,7-dihydro-5H-dibenz[c,e]azepine was found to be active hypolipidemic agents in rodents at doses of mg/kg per day. The parent drug was found to suppress the enzyme activity of ATP-dependent citrate lyase, sn-glycerol-3-phosphate acyl transferase, and phosphatidate phosphohydrolase. Treatment with 6,7-dihydro-5H-dibenz[c,e]azepine resulted in a reduction of cholesterol, neutral lipid, and triglyceride content in mouse and rat liver. The agent also afforded a reduction in cholesterol, triglycerides and neutral lipids in the chylomicron and very low density lipoprotein (VLDL) fractions. In the high density lipoprotein (HDL) fraction, the triglyceride, neutral lipids, and phospholipids were lowered but the cholesterol content was not. [H3]Cholesterol distribution studies showed that the 3H-content was lowered in the major organs but was elevated in the chyme and stomach, suggesting that the drug accelerated bile secretion of cholesterol or its metabolites.

Animals↗
PubMed1986

Oral epithelial cell lipid synthesis in the presence of retinoic acid or nitrosonornicotine.

The current study examines the effects of N-nitrosonornicotine (NNN) and all trans-retinoic acid (RA) on the synthesis and composition of lipids of oral epithelial cells grown in culture. Cells were exposed to NNN, RA or methylene chloride (the vehicle for the NNN and RA) and the lipids labelled with [14C]-acetate. Lipids were extracted from the cells, separated by paper chromatography, located by autoradiography, and acetate incorporation determined by liquid scintillation spectrometry. Cholesterol labelling was significantly decreased by the RA between 4 and 48 h when compared to the NNN-treated or control cells. After 48 h the incorporation levels in the presence of the two last compounds decreased. Free fatty acid labelling was also significantly less in cells exposed to RA, while labelling of triglycerides and phospholipids was increased. N-nitrosonornicotine seemed to produce a decreased labelling of cholesterol after 96 h continuous exposure. The results of these studies suggest that retinoid rapidly elevates the cell content of lipid formed from the glycerolipid pathway and membrane mechanisms may be modulated by this effect.

Animals↗
PubMed1985

Hypolipidemic activity of indan-1,3-dione derivatives in rodents.

A series of 2-substituted indan-1,3-dione derivatives, including alkyl (C-1-C-5), mono- and disubstituted phenyl, and other 2-aryl derivatives, were tested for hypolipidemic activity of CF1 male mice at 20 mg/kg per day. These derivatives reduced both serum cholesterol and triglycerides after 16 days of administration intraperitoneally. 2-(4-Methoxyphenyl)indan-1,3-dione was one of the more active compounds with 41% reduction of serum cholesterol and 58% reduction of serum triglyceride levels on day 16. This activity was confirmed in the rat after oral administration. 2-(2-Methylphenyl)- and 2-(4-chlorophenyl)indan-1,3-dione were effective in reducing serum triglyceride levels 58% and 53%, respectively, in mice. Serum cholesterol on day 16 was effectively reduced 46% by 2-(2,4-dimethylphenyl)indan-1,3-dione. The indan-1,3-dione derivatives were more effective than clofibrate in lowering lipid levels in mice. A more detailed study on the effects of 2-(4-methoxyphenyl)indan-1,3-dione demonstrated that key enzymes in the de novo synthesis of lipids were inhibited by the drug lowering tissue levels of lipids but raising those in the feces. The alterations in lipid content of rat lipoprotein fractions by the drug appeared favorable.

Animals↗
PubMed1985

Comparison of the hypolipidemic activity of cyclic vs. acyclic imides.

Two series of nitrogen-substituted cyclic and acyclic imides were examined for hypolipidemic activity in mice after dosing for 16 days at a dose of 20 mg/kg per day. The hypolipidemic activity of the unsubstituted, N-butyl, N-3-oxobutyl, and N-2-carboxyethyl derivatives of diacetimide and succinimide were compared as well as the unsubstituted and N-substituted dibenzimide and diphenimide. It was shown that an imide functionality incorporated into a ring was not necessary for hypocholesterolemic activity. Good hypocholesterolemic activity was observed in both series of acyclic and cyclic imides. However, a cyclic imido structure was a necessary requirement for good hypotriglyceridemic activity. A decrease in hypotriglyceridemic activity was noted when comparing the cyclic imides to their respective acyclic congeners.

Animals↗
PubMed1984

Structure-activity studies on antihyperlipidemic N-benzoylsulfamates, N-benzylsulfamates, and benzylsulfonamides.

A series of aryl substituted N-benzoyl- and N-benzylsulfamic acid sodium salts and benzylsulfonamide sodium salts have been prepared and examined for antihyperlipidemic activity in male CF1 mice at a dose level of 20 mg/kg/d ip for 16 d. These substances were also subjected to toxicological evaluation and chemical stability studies. In general, both series of sulfamates and sulfonamides significantly lowered serum cholesterol and triglyceride levels in mice. The compounds were nonmutagenic, showed no acute toxicity or impaired liver or kidney function in male mice, and were chemically stable both as the monohydrates and in aqueous solution over a pH range of 3.5-7.4. While both series of sulfamates and sulfonamides lowered serum cholesterol and triglyceride levels, the sulfamates were relatively more potent with regard to decreasing cholesterol levels, while the sulfonamides were more effective in lowering serum triglyceride levels in mice.

Animals↗
PubMed1984

Antihyperlipidemic activity of o-chlorobenzylsulfonamide in rodents.

o-Chlorobenzylsulfonamide was observed to be a potent hypolipidemic agent in rodents, reducing serum cholesterol levels 71% and triglyceride levels 49% at 60 mg/kg/d. The agent was effective both in normal and hyperlipidemic mice and was active both orally and intraperitoneally. o-Chlorobenzylsulfonamide significantly inhibited phosphatidate phosphohydrolase activity and marginally inhibited sn-glycerol-3-phosphate acyl transferase activity both in vitro and in vivo. The lowering of serum cholesterol levels appeared to be correlated with the accelerated excretion of cholesterol via the bile into the feces, with a marginal reduction of cholesterol absorption from the intestine. Reduced concentrations of lipids, e.g., cholesterol, triglycerides, and neutral lipids, were observed in the liver, small intestine, and blood lipoprotein fractions of rats.

Absorption↗
PubMed1984

Hypolipidemic activity of phthalimide derivatives V: Reduced and hydrolytic products of simple cyclic imides.

A series of cyclic imides and related compounds have previously been shown to possess hypolipidemic activity at the low dose level of 20 mg/kg/d. Hydrolytic and reduced products of the cyclic imides were synthesized and examined to discern if possible metabolic products were the active chemical species of these hypolipidemic agents. Phthalimide proved to be the most active cyclic imide tested. Unfortunately, the new products did not, in general, improve hypolipidemic activity in rodents. The exceptions were piperidine which demonstrated improved hypotriglyceridemic activity, and 3,4,5,6-dibenzohomopiperidin-2-one, which demonstrated improved hypocholesterolemic activity compared to phthalimide.

Animals↗
PubMed1984

Biological activity of the hypolipidemic agent, N2-n-butylindazolone.

Previously, a series of N-substituted indazolone derivatives proved to be effective hypolipidemic agents in rodents. The most effective agent, N2-n-butylindazolone, at 20 mg/kg/d was shown to suppress the levels of cytoplasm acetyl coenzyme A required for cholesterol and fatty acid synthesis as well as sn-glycerol-3-phosphate acyl transferase and phosphatidate phosphohydrolase activities. Lipid content of the liver, small intestine, and serum lipoprotein fractions was lowered, whereas lipid content was increased in fecal excretions by drug treatment for 14 d. The absorption of orally administered cholesterol from the intestine was severely reduced after drug administration. The mode of action of N2-n-butylindazolone appears to be similar to cyclic imides possessing hypolipidemic activity.

Animals↗
PubMed1984

Hypolipidemic activity of phthalimide derivatives. 7. Structure-activity studies of indazolone analogues.

The apparent benefit of limiting serum cholesterol and triglyceride levels either by dietary restriction or drug therapy has prompted work in our laboratories toward development of a suitable antihyperlipidemic agent. We have demonstrated the antihyperlipidemic activity of a series of phthalimide derivatives in rodents to be significantly greater than that of clofibrate at a dose of 20 mg/(kg day), intraperitoneally. Here we report the synthesis and biological evaluation of a series of indazolone derivatives, which are heterocycles that are structurally related to the phthalimides . In general, structure-activity relationships within the phthalimide series may be extended to the indazolones . While indazolone itself is only moderately active, N1-carbethoxy substitution produced a more active compound. Substitution of the N2 position with an n-butyl group afforded the most active compound, as also seen in the phthalimide series. Aromatic substitution with electron-releasing and -withdrawing groups lessened the antihyperlipidemic activity.

Animals↗
PubMed1978

Effects of molecular modification on hypocholesteremic activity of 1,3-bis(substituted phenoxy)-2-propanones and related derivatives.

A series of 1,3-bis(substituted phenoxy)-2-propanones, long-chain ketones, and related derivatives has been synthesized, and it has been found that certain analogues produce significant lowering of serum cholesterol levels in Sprague-Dawley rats. These compounds possess no estrogenic properties and are nontoxic at 10 mg/kg/day. Physical studies on these compounds include an attempt to correlate hypocholesteremic activity with the lipophilic, electronic, and steric properties of the compounds. The 1-octanol-H2O partition coefficient was measured for certain derivatives and the pi constant for the substituents was calculated. Hammett's sigma constants for aromatic substituents were obtained from the literature. The only correlation found to exist is between hypocholesteremic activity and steric size and position of the aromatic substituents in the propanones.

Animals↗
PubMed1977

Hypolipidemic activity of in vitro inhibitors of hepatic and intestinal sn-glycerol-3-phosphate acyltransferase and phosphatidate phosphohydrolase.

A number of agents including a series of 1,3-bis (substituted phenoxy)-2-propanones were screened in vitro for their ability to inhibit hepatic and intestinal microsomal sn-glycerol-3-phosphate acyltransferase and phosphatidate phosphohydrolase. Effective inhibitors reduced in vivo hepatic and intestinal glycerolipid production and with one exception also lowered serum triglyceride levels, suggesting that agents which inhibit potential rate-limiting steps of glycerolipid biosynthesis may be effective hypolipidemic agents. Two compounds, 1-methyl-4-piperidyl bis (p-chlorophenoxy) acetate (Sah 42-348) and 1,3-bis (p-methylphenoxy)-2-propanone were the best inhibitors of glycerolipid biosynthesis and lipid-lowering agents. The lipid-altering effects of both drugs were compared to chlorophenoxyisobutyrate during high fructose intake in rats. Each agent reduced fructose induced glycerolipid biosynthesis and serum triglyceride levels to similar degrees.

Acetone↗
PubMed1976

Cycloalkanones. 8. Hypocholesterolemic activity of long-chain ketones related to pentadecanone.

Aliphatic analogs of 2,8-dibenzylcyclooctanone which includes C15-C18 ketones have been investigated for hypocholesterolemic activity in rats. The position of the carbonyl group in the chain for maximum activity appears to be the 2 position. 2-Hexadecanone reduced serum cholesterol levels significantly without altering serum triglyceride levels. This drug was not estrogenic at effective doses which is in contrast to the cyclooctanones which possess this activity.

Animals↗