Search

Increased plasma cell‐free mitochondrial DNA (cf‐mDNA), a damage‐associated molecular pattern (DAMP) produced by cellular injury, contributes to neutrophil activation/inflammation in trauma patients and arises in cancer and autoimmunity. To further understand relationships between cf‐mDNA released by tissue injury, inflammation, and health benefits of exercise, we examined cf‐mDNA response to prolonged moderate aerobic exercise. Seven healthy moderately trained young men (age = 22.4 ± 1.2) completed a treadmill exercise trial for 90 min at 60% VO 2 max and a resting control trial. Blood was sampled immediately prior to exercise (0 min = baseline), during (+18, +54 min), immediately after (+90 min), and after recovery (R40). Plasma was analyzed for cf‐mDNA, IL‐6, and lactate. A significant difference in cf‐mDNA response was observed between exercise and control trials, with cf‐mDNA levels reduced during exercise at +54 and +90 (with or without plasma volume shift correction). Declines in cf‐mDNA were accompanied by increased lactate and followed by an increase in IL‐6, suggesting a temporal association with muscle stress and inflammatory processes. Our novel finding of cf‐mDNA decline with prolonged moderate treadmill exercise provides evidence for increased clearance from or reduced release of cf‐mDNA into the blood with prolonged exercise. These studies contrast with previous investigations involving exhaustive short‐term treadmill exercise, in which no change in cf‐mDNA levels were reported, and contribute to our understanding of differences between exercise‐ and trauma‐induced inflammation. We propose that transient declines in cf‐mDNA may induce health benefits, by reducing systemic inflammation.

A few 6H-pyrido[4,3-b]carbazoles were prepared for cytotoxicity testing in cultures of human lung cancer cells. Methyl 6-methoxyindoleacetate 13 , prepared by reduction of methyl 4-(2-nitro-5-methoxyphenyl)-3-oxobutyrate 11 , was condensed with 3-acetylpyridine to give the vinyl indole 14 which was quarternized with p-nitrobenzyl bromide. Cyclization of this salt with the aid of sodium methoxide and ethyl nicotinate methiodide gave the 6H-pyrido[4,3-b]carbazole 16 . Brief treatment with tributyl phosphine in boiling DMF gave the ester 17 which, after reduction with LilH4 followed by treatment with methyl isocyanate, gave 5-hydroxymethyl-9-methoxy-11-methyl-6H-pyrido[4,3-b] carbazole N-methylcarbamate 4 9-Methoxyolivacine 19 was oxidized to the aldehyde 22 with seO2. Reduction to the carbinol 24 . proceeded smoothly with NaCNBH3 in acid medium. Treatment with methyl isocyanate gave the carbamate 6 and the acetate 7 was prepared by acetylation of the carbinol 24 .

Indole-2-acetic acid methyl esters: methyl 5-methoxyindole-2-acetate intermediate: 5-methoxy-2-nitrophenylacetic acid intermediate: Methyl (5-methoxy-2-nitrophenylacetyl)acetoacetate intermediate: Methyl 4-(5-methoxy-2-nitrophenyl)-3-oxobutyrate product: Methyl 5-methoxyindole-2-acetate product: methyl (2-nitrophenylacetyl)acetoacetate product: methyl 4-(2-nitrophenyl)-3-oxobutyrate product: methyl indole-2-acetate Keywords: acylation; acylation; annulation, heterocyclic-[M,N]; cleavage, miscellaneous; condensation, carbonyl-active methylene condensations; condensation, miscellaneous; cyclization, reductive cyclization; deacylation; hydrolysis, esters and lactones; hydrolysis, miscellaneous; reduction, NO2 NH2; replacement reactions, hydroxy by halogen; replacement reactions, miscellaneous; tetrahydrofuran; N,N-dimethylformamide, cancer suspect agent; 5-methoxy-2-nitrophenylacetyl chloride, potential explosive; thionyl chloride, toxic, corrosive

Several modifications of the oxazoline ring of WIN 54954, a broad spectrum antipicornavirus compound, have been prepared in order to address the acid lability and metabolic instability of this compound. We have previously shown that the oxadiazole analogue 3 displayed comparable activity against a variety of rhinoviruses and appeared to be stable to acid. A monkey liver microsomal assay was developed to examine the metabolic stability in vitro of both compounds, and it was determined that WIN 54954 displayed 18 metabolic products while 3 was converted to 8 products. Two major products of 3 were determined by LC-MS/MS to be monohydroxylated at each of the terminal methyl groups. Replacement of the methyl on the isoxazole ring with a trifluoromethyl group, while preventing hydroxylation at this position, did not reduce the sensitivity of the molecule to microsomal metabolism at other sites. However, the (trifluoromethyl)oxadiazole 9 not only prevented hydroxylation at this position but also provided protection at the isoxazole end of the molecule, resulting in only two minor products to the extent of 4%. The major product was identified as the monohydroxylated compound 23. The global metabolic protective effect of trifluoromethyl group on the oxadiazole ring was further demonstrated by examining a variety of analogues including heterocyclic replacements of the isoxazole ring. In each case, the trifluoromethyl analogue displayed a protective effect when compared to the corresponding methyl analogue.