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DFMO, a trypanostatic drug, presents a satisfactory intestinal absorption but its elimination from the blood is rapid so that high doses are necessary to obtain a therapeutic effect. In this study, we propose a strategy to enhance the bioavailability of DFMO by using lipidomimetic derivatives. Three lipidomimetic DFMO derivatives called ODFMO, S-DFMO and Chol-DFMO were designed to reach easily the plasma and to be cleaved preferentially by plasma esterases progressively liberating free DFMO. Chol-DFMO only could be cleaved partially whereas the other compounds appeared to be stable in a reconstituted intestinal medium and mouse plasma. Nevertheless, the use of DFMO derivatives in T. b. bruceiexperimental chemotherapy appeared as an interesting approach. Thus, ODFMO was trypanocidal in vitrowhereas DFMO, the active principle, was only trypanostatic. Nevertheless, this compound did not release DFMO in mouse blood as expected and acted therefore not as a prodrug. Oral treatment using low doses of compound O-DFMO was able to cure 40 % mice while the active principle (eflornithine) administered at 50 fold higher molarity failed to cure any mice. This indicates that compound ODFMO acts by a specific mechanism which remains to be investigated. S-DFMO was less active and Chol-DFMO had no in vitroactivity but released small amounts of DFMO in mice, however, too slight to obtain a therapeutic effect.

Influence of numerous parameters (solvent, base, coupling reagent) in the coupling of conjugated carboxylic acid with methyl ester amino acids hydrochloride, allowing the synthesis of various substituted amino acid derivatives, has been investigated. Usefulness of this method is illustrated in the synthesis of trans-clovamide. This natural polyphenol compound, whose synthesis is correlated with resistance to plant disease, presents important antioxidant activities.

The phospholipid analogue with two short fatty chains, 1-dodecyl-2-[1-14C] octanamido-sn-2-deoxy-gly cero-3-phosphocholine ([14C] phospholipid analogue), with a non-hydrolyzable bond at position 2 of the glycerol, is an inhibitor of phospholipase A2. It was obtained after chemical synthesis and 0.5 μmol was solubilized in Na+taurocholate with an equimolar amount of 1-octadecanoyl 2-[3H]eicosatetraenoyl-sn- glycero-3-phosphocholine which is the current substrate of phospholipases A2. Both molecules were introduced into the duodenum of rats in order to follow their captations by intestinal mucosa cells for 30, 60 or 90 min. The [14C] phospholipid analogue was poorly split by phospholipases A2(pancreatic juice and intracellular enzymes). It disappeared from the intestinal contents (87% of the dose gone in 90 min) as rapidly as the tritiated lecithin (81%) but this was later split by the phospholipases at a higher rate.

The [14C] phospholipid analogue l-dodecyl-2-[l-14C] octanamido-sn-2-deoxy glycero-3-phosphocholine was synthetized. With 2 short fatty chains linked by alkyl and amido bonds to positions 1 and 2 of the glycerophosphate backbone, it was an inhibitor of phospholipase A2 in ionophore A23187-stimulated macrophages. Its uptake by rat peritoneal macrophages and its resistance towards phospholipases A2 were determined at nanomolar or micromolar concentrations in the culture medium. A control substrate for phospholipases A2 activity was established with the lecithin 1-octadecanoyl 2-[3H] eicosatetraenoyl-sn-glycero-3-phosphocholine ([3H] 20:4-GPC), a source of [3H] arachidonic acid after cleavage at position 2.Non-stimulated-or ionophore A23187-stimulated macrophages incorporated extensively the [I4C] phospholipid analogue added at 30-4000 nM. At 4000 nM which induced 50% inhibition of the phospholipase, 40% of the dose was found associated with the [I4C] phospholipids of 2 ×106 stimulated macrophages after 120 min incubation, while only low amounts of [I4C] non-phosphorous lipids were detected. It is concluded that the [14C] phospholipid analogue was readily taken up by the macrophages with limited hydrolysis.

Rat peritoneal macrophages were cultured with a specific and potent phospholipase A2 activator A 23187, with 1-stearoyl-2-[3H]arachidonoyl-sn-GPC as source of [3H] arachidonic acid, and with a dialkyl-GPC, at 2, 10 or 20 μmlM. Four dialkyl-GPCs were prepared by chemical synthesis. Position 2 of rac-glycerol was alkylated with an alkane chain of 8 carbons and position 1 was alkylated with various alkane chains (8,10, 12, or 16 carbons).[3HI arachidonic acid was split, then recovered with cell nonesterified fatty acids and nonphosphorous glycerolipids after endocellular phospholipase A2 activity. It was also recovered with fatty acids and eicosanoids isolated from culture medium.Inhibition of fatty acid release and eicosanoid synthesis depended on mixed chain dialkyl-GPC structures. The highest inhibitory effect on arachidonic acid release was reached with 1-decyl-2octyl-GPC and was practically as high in culture medium (IC50 at 5 μmlM) as in cells (IC50 at 4 μmlM). 1,2-di-octyl-GPC and 1-dodecyl-2-octyl-GPC had weaker inhibitory effects (but higher in culture medium than in cells). The asymmetrical 1-hexadecyl-2-octyl-GPC poorly affected enzyme activity.

Determination of biogenic amines in invertebrates, by means of high-performance liquid chromatography (HPLC), is of considerable physiological significance. In insects, octopamine is released into the hemolymph in response to stress, and exhibits some myogenic properties in both insects and nematodes. The first part of the present paper deals with the synthesis of N-acetyloctopamine from octopamine and with its characterization. The second part deals, for the first time, with the detection of these biogenic amines in insects and nematodes using the chromatographic system with electrochemical detection. N-acetyloctopamine was detected in a chromatographic system enabling determination in biological samples. The interest of the used method is in the simultaneous detection of various biogenic amines. Improvements can certainly be made for detection of more specific to invertebrates compounds such as tyramine, octopamine and N-acetylated derivatives.

At concentrations 1–20gmMin culture medium of rat peritoneal macrophages which were stimulated with ionophore A23187, the phospholipid analogues 1-decyl-2-octyl-glycero- phosphocholine and 1-dodecyl-2-octanamido-2-deoxy glycerophosphocholine were found more potent inhibitors than 1-octyl-2-octylthio-2-deoxy glycerophosphocholine to lower the phospholipase A2activities. The inhibitory effect was measured by [3H] eicosatetraenoic acid ([3H]20:4) release in macrophages and extracellular fluids and synthesis of [3H] eicosanoids after incubation of macrophages with traces of the molecular species of lecithin 1-octadecanoyl-2-[3H] eicosatetraenoyl glycerophosphocholine. The three phospholipid analogues developed higher inhibitory effects than mepacrine, dexamethasone or bromophenacyl bromide, at corresponding concentrations in medium.

Summary—Compounds able to inhibit phospholipases A2can be considered as potential anti‐inflammatory drugs. In this respect, the inhibitory effect of the phospholipid analogue 1‐decyl 2‐octyl‐rac‐glycero‐3‐phosphocholine (decyloctyl‐GPC) added to the culture medium of rat peritoneal macrophages stimulated with ionophore A23187 was determined, (a) The substrate of phospholipase A21‐octadecanoyl 2‐[14C]eicosatetraenoyl‐sn‐glycero‐3‐phosphocholine ([14C]20:4‐GPC) was added to the culture medium. In macrophages + extracellular fluids, its hydrolysis at the 2‐position, produced [14C]non‐phosphorous lipids which reached 12% of the dose at 0.14 μM, 73% at 0.9 and > 90% at 1.6 μM; in experiments where macrophages and extracellular fluids were analyzed separately, decyloctyl‐GPC initially added at 4 μM, significantly inhibited the release of [14C]fatty acids and the eicosanoid synthesis, demonstrating its ability to inhibit secreted and/or intracellular phospholipases A2. (b) Extracellular fluids were separated from the macrophages and incubated with [14C]20:4‐GPC: 48% of the dose was hydrolyzed by extracellular fluid‐associated secreted phospholipase A2and decyloctyl‐GPC at 3 μM, reduced this hydrolysis by 50%. (c) [3H]arachidonic acid ([3H]20:4) was added to the culture medium and was esterified in the macrophage membrane phospholipids. Activation of intracellular phospholipase A2induced the release of [3H] fatty acids and eicosanoid synthesis. These releases were inhibited by 50% with decyloctyl‐GPC added at 4 μM. (d) [3H]20:4 and [14C]20:4‐GPC were added to the culture medium of the macrophages. [3H] and [14C] fatty acids and eicosanoids were released in macrophages or extracellular fluids. They were significantly reduced by the phospholipid analogue added at 4 μM. It is concluded that secreted and intracellular phospholipases A2were both inhibited by decyloctyl‐GPC which extensively reduced the 20:4 release from exogenous and membrane phospholipids and therefore eicosanoid synthesis.

AbstractWe report here a new family of antibiotic with fungicidal and antibacterial activity. The syntheses of five 7-amino and 7-aminoalkylcholesterol derivatives are described.

Activated macrophages exposed to the association of eicosapentanoic acid 20:5n-3 and a synthetic non hydrolysable phospholipid analogue maintained a discrete synthesis of active eicosanoids. 20:4n-6 splited from the internalized 20:4–GPC was accumulated in cells and extracellular fluids. This combination thus represents a novel approach to reduce the 20:4n-6 cascade.

This paper reports the studies of components of an undescribed sponge in the genus Pachastrissa sp., collected along the Djibouti coast. The extract showed activity against Candida albicans. Six new bengazoles (1−6) and a new bengamide, named bengamide L (16), in addition to the known bengazoles (7−11), bengamides A (12), B (13), E (14), and F (15), and a lactone (17) are described in this paper. All structures were determined on the basis of spectroscopic studies.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Among a series of aminocholesterol derivatives synthesized, 7-aminocholesterol is the strongest inhibitor of yeast cell growth. Using sterol auxotrophic mutant strains, we showed that this compound inhibits cell proliferation by interfering with ergosterol biosynthesis. The sterol pattern of treated cells revealed that 7-aminocholesterol inhibits Δ8→Δ7-sterol isomerase and Δ14-sterol reductase as morpholine inhibitors. However, the novel feature of this compound is a strong cytotoxicity to yeast.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A new sterol, 7-aminocholesterol, which inhibits growth of Saccharomyces cerevisiae, also displayed antibiotic activity against Gram-positive bacteria. The 50% growth inhibitory concentration against strains of Listeria innocua, L. monocytogenes, Staphylococcus aureus, Enterococcus hirae and Bacillus cereus was 3 μM.