Semi-synthesis and proposed structure of platelet-activating factor (P.A.F.): PAF-acether an alkyl ether analog of lysophosphatidylcholine]

We have studied the molecular structure of platelet-activating factor" (P.A.F.), a mediator of inflammation obtained from blood leukocytes, macrophages, and platelets themselves. We have semi-synthetized a substance that possesses all the known physicochemical and biological characteristics of P.A.F. from hog leukocytes. This was performed by successive methylation, hydrogenation, and acetylation of lysophosphatidylethanolamine plasmalogen. We therefore propose the following structure for P.A.F.: 1-0-alkyl-2-acetyl-glyceryl-3-phosphorylcholine. This molecular structure is not yet described among the numerous substances capable of inducing platelet aggregation and release.     

Monovalent cation conductance in liposomes induced by ionophore A23187

Summary In the absence of divalent cations, ionophore A23187 supports low rates of monovalent cations loss (Na⁺>K⁺) from unilamellar liposomes containing the sulfate salts. Monovalent cation efflux is optimal when a pH gradient (interior alkaline) is applied. The maximum observed rate of 0.56 ngion K⁺·min^–1·nmole^–1 A23187 is insufficient to account for the rates of K⁺ efflux induced by the ionophore in mitochondria (150 ngion K⁺·min^–1·nmole^–1 A23187). These studies therefore support the concept that A23187 induces loss of K⁺ from mitochondria by removal of regulating divalent cations from an endogenous K⁺/H⁺ exchanger.These studies were supported in part by United States Public Health Services Grant HL09364.     

Inhibition of neural tube closure by ionophore A23187 in chick embryos

Summary Ionophore A23187 inhibited closure of the chick neural tube through its effects on cytoskeletal components.This study was supported in part by grants from the Research Council and the Charles and Johanna Busch Memorial Fund of Rutgers University. Ionophore A23187 was provided through the courtesy of Dr R.L. Hamill, Lilly Research Laboratories, Indianapolis, Indiana, USA.     

A new one-step synthesis of hexahydrocannabinoid analogs

Summary A one-step synthesis of hexahydrocannabinoid analogs (HHC) is described making use of the condensation of phenolic ketones and aldehydes with citronellal in the presence of pyridine.Grateful thanks are accorded to Drs L. Chopard and S. Selvavinayakam for spectral measurements and Dr I. Fleming for useful discussion.R. Mechoulam and Y. Gaoni, Recent advances in the chemistry of Hashish, in: Progress in the Chemistry of Organic natural products, vol. 25, p. 175. Ed. L. Zechmeister. Springer Verlag, Wien 1967; R. Mechoulam, Marijuana Chemistry and Pharmacology, metabolism and clinical effects. Academic Press, New York 1973; R. Mechoulam, N. K. McCallum and S. Burstein, Chem. Rev.76, 75 (1976).     

Inhibition of neural tube closure by ionophore A23187 in chick embryos.

Ionophore A23187 inhibited closure of the chick neural tube through its effects on cytoskeletal components.     

Muscle damage induced by the ionophore A23187 can be prevented by prostaglandin inhibitors and leupeptin

Frog skeletal muscle incubated in vitro with the ionophore A23187 shows extensive morphological alterations. Myofilament disruption, presumably mediated by excess intracellular calcium, can be partially prevented by preincubating the muscle with inhibitors of prostaglandin synthesis and the lysosomal thiol protease inhibitor leupeptin.     

Muscle damage induced by the ionophore A23187 can be prevented by prostaglandin inhibitors and leupeptin

Summary Frog skeletal muscle incubated in vitro with the ionophore A23187 shows extensive morphological alterations. Myofilament disruption, presumably mediated by excess intracellular calcium, can be partially prevented by preincubating the muscle with inhibitors of prostaglandin synthesis and the lysosomal thiol protease inhibitor leupeptin.The author would like to thank Dr R. J. Walter for helpful comments and Ms V. Kriho for valuable technical assistance     

Tumorigenic potential of endoperoxide analogs

Summary The endoperoxide analogs known as U-46619 and U-44069 significantly enhanced the carcinoma formation and cellular atypicality initiated by a chemical carcinogen in mice. Studies of DNA radioactivity demonstrated that endoperoxides exerted their cocarcinogenic action by stimulating DNA synthesis. Thus, they play an important role in tumor cell proliferation.     

Activity of precocene analogs onLocusta migratoria migratorioides (R. and F.)

Summary Several analogs of precocene have been synthesized and evaluated as potential inhibitors of juvenile hormone onLocusta migratoria. Only 5,7-dimethoxy-2,2-dimethylchromene was active; its ED₅₀ and LD₅₀ were measured and compared to those of precocene I and II.Acknowledgments. This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada and the Ministère de l'Education du Québec. We are grateful to Gaston Grégoire for rearing the insects.     

Synthesis of ochratoxins TA and TC,analogs of ochratoxins A and C

Zusammenfassung Zwei Ochratoxinanaloge, Ochratoxin T_A (OT_A) und T_C (OT_C) wurden aus Ochratoxin- chemisch synthetisiert indem Phenylalanin und sein Äthylester im Molekül durch Tyrosin und Tyrosinäthylester substituiert wurden. Der Hühnerembryonentest ergab, dass OT_C etwas toxischer und OT_A etwas weniger toxisch ist als Ochratoxin A (OA).     

Analgesic activity of certain tripeptide-beta-phenethylamide analogs

Studies of the analgesic effect of tripeptide-beta-phenethylamides are described, and their structure-activity relationship is discussed. SD-25, which has a methyl group at R2, and a hydroxymethyl group at R3 of beta-phenethylamide, was the most potent one of the 8 analogs tested.     

Fluorinated analogs of insect sex pheromones

Summary The syntheses of fluorinated mimics of pheromones ofSpodoptera littoralis, Diparopsis castanea, Laspeyresia pomonella, Bombyx mori andThaumetopoea pityocampa are described. These analogs showed biological activities similar to those of the natural pheromones in laboratory assays (EAG).We gratefully acknowledge Comisión Asesora de Investigación Cientifica y Técnica for financial support (Grant No. 3296/79) and Consejo Superior de Investigaciones Cientificas for predoctoral and postdoctoral fellowship (to G.F. and M.R.). We also thank Mr J. Baltá and Ms R. Murgó for their collaboration in the EAG work.     

Acetyl-coenzyme A synthetase (AMP forming)

Acetyl-coenzyme A synthetase (AMP forming; Acs) is an enzyme whose activity is central to the metabolism of prokaryotic and eukaryotic cells. The physiological role of this enzyme is to activate acetate to acetyl-coenzyme A (Ac-CoA). The importance of Acs has been recognized for decades, since it provides the cell the two-carbon metabolite used in many anabolic and energy generation processes. In the last decade researchers have learned how carefully the cell monitors the synthesis and activity of this enzyme. In eukaryotes and prokaryotes, complex regulatory systems control acs gene expression as a function carbon flux, with a second layer of regulation exerted posttranslationally by the NAD⁺/sirtuin-dependent protein acetylation/deacetylation system. Recent structural work provides snapshots of the dramatic conformational changes Acs undergoes during catalysis. Future work on the regulation of acs gene expression will expand our understanding of metabolic integration, while structure/function studies will reveal more details of the function of this splendid molecular machine.Received 4 December 2003; received after revision 2 March 2004; accepted 16 March 2004