Metabolic activation of 2-substituted derivatives of myristic acid to form potent inhibitors of myristoyl CoA:protein N-myristoyltransferase

Biochemistry ◽  
1990 ◽  
Vol 29 (46) ◽  
pp. 10566-10573 ◽  
Author(s):  
Lisa A. Paige ◽  
Guo Qiang Zheng ◽  
Shawn A. DeFrees ◽  
John M. Cassady ◽  
Robert L. Geahlen
Keyword(s):  
Myristic Acid ◽  
Metabolic Activation ◽  
Derivatives Of

Derivate des Benzo[1.3]dioxols, 431 Über Benzo [1.3] dioxolcarbonsäuren / Derivatives of 1,3-Benzodioxoles, 43 1,3-Benzodioxolecarboxylic Acids

1978 ◽  
Vol 33 (7-8) ◽  
pp. 465-471
Author(s):  
Franz Daliacker ◽  
Volker Mues ◽  
In-O Kim
Keyword(s):  
Carboxylic Acid ◽  
Methyl Ester ◽  
Benzoic Acid ◽  
Myristic Acid ◽  
Good Yield ◽  
Acid Ester ◽  
Acid Methyl Ester ◽  
Acid Methyl ◽  
Derivatives Of

Abstract We describe the possibilities of formation and preparation of the “natural” 1,3-benzodioxolecarboxylic acids 1, 2, 4, 6 b, and 7, already mentioned in literature. Myristic acid (3e) was prepared in good yield from 3-methoxy-4,5-dihydroxy-benzoic acid ester (3c) , which could be easily made from 3-methoxy-2,3-carbonyldioxy-benzoic acid methylester (3b). Myristicic acid methylester (3d) could be subjected to methylation and hydrolysis leading to 3e without any difficulties. 4.6-dimethoxy-1,3-benzodioxole-5-carboxylic acid (5b) was prepared in good yields by oxidation of 4,6-dimethoxy-1,3-benzodioxole-5-aldehyde (5a). 5.7-dimethoxy-1,3-benzodioxole-carboxylic acid (13f), one of the “unnatural” 1,3-benzodioxolecarboxylic acids, derivatives of o-ipiperonylic acid (8), was prepared from 5-amino-7-methoxy-1,3- benzodioxole-4carboxylic acid methyl ester (13b) by diazotisation, elimination of nitrogen, methylation, and hydrolysis. A comparison of our measured pkA-values showed the strongest acidity belonging to 5,6-dimethoxy-1,3-benzodioxole-4-carbocylic acid (11).

DIFFERENTIAL SURVIVAL AS AN INDICATOR OF POTENTIAL MUTAGENICITY USING REPAIR DEFICIENT STRAINS OF SACCHAROMYCES CEREVISIAE AND SCHIZOSACCHAROMYCES POMBE

1982 ◽  
Vol 24 (6) ◽  
pp. 771-775 ◽  
Author(s):  
Earle R. Nestmann ◽  
Eric R. Stephen ◽  
David J. Kowbel ◽  
A. Nasim
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Schizosaccharomyces Pombe ◽  
Metabolic Activation ◽  
Test System ◽  
Yeast Cells ◽  
Wild Type ◽  
Differential Survival ◽  
Exogenous Enzymes ◽  
Direct Acting ◽  
Derivatives Of

A method is presented to screen chemicals for potential mutagenicity on the basis of their ability to cause more killing in cells of repair-deficient yeast than in wild type cells. Two species were chosen in the event that one might be more sensitive to certain chemicals. The strains used were RAD+ and rad6 derivatives of Saccharomyces cerevisiae and RAD+ and rad3 derivatives of Schizosaccharomyces pombe. This report describes the test system and results for 12 known, direct-acting mutagens (i.e., not requiring mammalian metabolic activation). These compounds showed more lethality in one or both of the repair-deficient strains, indicating that they induce damage to DNA which is subject to repair in wild type cells. Advantages of this system include the use of eukaryotic yeast cells which can be manipulated as easily as bacteria, and that exogenous enzymes (S9) can be added for metabolic activation. Growing yeast cells can activate certain promutagens, and preliminary experiments showed positive responses for diethylnitrosamine and 2-acetylaminofluorene without the addition of S9.

2 Final Report on the Safety Assessment of Benzophenones-1, 3, 4, 5, 9, and 11

1983 ◽  
Vol 2 (5) ◽  
pp. 35-77 ◽  
Keyword(s):  
Safety Assessment ◽  
Skin Irritation ◽  
Metabolic Activation ◽  
Final Report ◽  
Oral Ingestion ◽  
Rabbit Skin ◽  
Animal Data ◽  
Irritation Test ◽  
Skin Irritation Test ◽  
Derivatives Of

Benzophenones-1 to 12 are substituted derivatives of 2-hydroxybenzophe-none. They are used as photostabilizers in cosmetics and have a photoprotective effect on the skin. When ingested and absorbed, Benzophenones were primarily conjugated and excreted in the urine. Benzophenones were practically nontoxic when chronically administered orally to rats, and Benzophenones-3 and 4 were nontoxic when applied to the skin of rabbits at doses of > 5 g/kg. Subchronic oral ingestion of Benzophenone-3 at 1 % was nontoxic to rats; however, another study showed Benzophenone-3 at 0.5% was toxic. Benzophenone-1 elicited toxic effects in rats at 0.6 g/kg. Benzophenones were nonirritating or mildly irritating to rabbit skin at concentrations of up to 100% and practically nonirritating to the eyes of rabbits. A subchronic skin irritation test indicated that Benzophenone-4 was capable of causing minimal irritation in rabbits at a concentration of 10%. Benzophenone-3 was reported to be nonsensitizing and nonphototoxic in guinea pigs and rabbits. Benzophenones-1, 3, 4, 5, and 9 were nonmutagenic both with and without metabolic activation in the Ames test. Skin irritation and sensitization in humans indicated that Benzophenones were mildly irritating and sensitizing at concentrations greater than those used in cosmetics. On the basis of the available animal data and clinical human experience, it is concluded that Benzophenone-1, 3, 4, 5, 9, and 11 are safe for topical application to humans in the present practices of use and concentration in cosmetics.

Genotoxicity of influents and effluents of the wastewater treatment plant

1996 ◽  
Vol 34 (7-8) ◽  
pp. 9-14 ◽  
Author(s):  
M. Filipic ◽  
M. J. Toman
Keyword(s):  
Wastewater Treatment ◽  
Wastewater Treatment Plant ◽  
Parent Strain ◽  
Municipal Wastewater ◽  
Treatment Plant ◽  
Domestic Wastewater ◽  
Metabolic Activation ◽  
Mutagenic Potential ◽  
Treatment Procedures ◽  
Derivatives Of

Wastewaters are treated through different processes of wastewater treatment procedures. Nevertheless they often contain mutagens especially when the proportion of industrial wastewater in comparison to municipal wastewater is high. In this study we evaluated mutagenic potential of influents and effluents from a wastewater treatment plant that is processing both industrial and domestic wastewater. The mutagenicity of XAD-2 extracts of influent and effluent was evaluated by means of Ames test using S. typhimurium strains TA100 and TA98 in the presence and in the absence of metabolic activation. Extracts that were mutagenic to strain TA98 without metabolic activation were suspected to contain nitropolyaromatic hydrocarbons (nitro-PAHs). To confirm this hypothesis they were tested with nitroreductase (TA98NR) and O-acetiltransferase (TA98/1,8DNP6) deficient derivatives of strain TA98, that are resistant to nitropolyaromatic hydrocarbons. The nitroreductase deficient strain TA98NR was less sensitive to the mutagenic extracts of influent than the parent strain TA98. The O-acetiltransferase deficient strain TA98/1,8DNP6 was resistant to the mutagenic extracts of influent. The mutagenic extracts of the effluent were nearly equally mutagenic to the parent strain TA98 and both deficient strains TA98NR and TA98/1,8DNP6. On the basis of the responses of nitroreductase deficient strains on the influent and effluent it was concluded that the influent contained nitro-PAHs. These were not removed or inactivated during the biological treatment of the wastewater, but activated to the final nucleophylic form able to induce mutations strain TA98 and in its nitroreductase deficient derivatives TA98NR and TA98/1,8DNP6.

Effects of tertiary and quaternary derivatives of aminomethylenedioxyindenes on some experimental arrhythmias

1982 ◽  
Vol 60 (12) ◽  
pp. 1636-1642 ◽  
Author(s):  
Joseph J. Lynch ◽  
Ralf G. Rahwan ◽  
Richard J. Brumbaugh ◽  
Donald T. Witiak
Keyword(s):  
Cardiac Tissue ◽  
Metabolic Activation ◽  
Antiarrhythmic Activity ◽  
Cardiac Cells ◽  
Electrophysiological Properties ◽  
Calcium Dependent ◽  
Derivatives Of ◽  
Antiarrhythmic Effects

The 2-n-propyl- and 2-n-butyl-3-dimethylamino-5, 6-methylenedioxyindene hydrochlorides are intracellular calcium antagonists with coronary dilating and antiarrhythmic effects against ouabain- and calcium-induced arrhythmias. In the present study, pretreatment with these tertiary methylenedioxyindenes afforded significant protection against the calcium-dependent arrhythmias induced by chloroform in mice. On the other hand, their antiarrhythmic activity against aconitine- and metha-choline-induced arrhythmias in rats (in which calcium does not play a primary etiological role) was suggestive but not impressive. The quaternary derivative, 2-n-butyl-5, 6-methylenedioxy-3-trimethylammonium iodide, which was synthesized with the expectation of being devoid of antiarrhythmic activity owing to its exclusion from the intracellular compartment, unexpectedly demonstrated greater antiarrhythmic potency than the tertiary analogues against calcium-induced arrhythmias in rats and chloroform-induced arrhythmias in mice. Like the tertiary methylenedioxyindenes, the protective activity of the quaternary analogue against arrhythmias induced by aconitine or by methacholine in rats was suggestive but not impressive. Because of the relative inactivity of the quaternary methylenedioxyindene in vitro, it is proposed that its in vivo activity may be due either to metabolic activation or to concentration in cardiac tissue in sufficient quantity to allow diffusion into cardiac cells down a concentration gradient or to alter membrane electrophysiological properties to the extent of exerting antiarrhythmic activity.

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