Erythropoietic effects of PGE2 and 2 endoperoxide analogs

Summary The erythropoietic effects in exhypoxic polycythemic mice of two endoperoxide analogs were assessed and compared with PGE₂. The 9a, 11a epoxymethano analog (U-44069) was found to be a much more potent erythropoietic stimulus than the 11a,9a analog (U-46619) or PGE₂.This work was supported by a Senior Research Grant-in-Aid from the American Heart Association-Louisiana (DMG) and USPHS Grant No. AM 13211 (JWF).     

Tumorigenic activity of cloned polyoma virus DNA in newborn rats

Summary The proximal portion of the polyoma virus early region as well as the complete viral genome were cloned in pBR322. Recombinant plasmids induced tumors in newborn rats but only after linearization of the DNA by various restriction endonucleases.This work was financed by grant MA-6731 from the Medical Research Council and by a grant from the National Cancer Institute of Canada.     

Tumorigenic effect of topical mechlorethamine,BCNU and CCNU in mice

Summary Mice were painted with mechlorethamine (HN2), carmustine (BCNU) and lomustine (CCNU) for up to 33 weeks. HN2 was a potent carcinogen, producing squamous cell carcinomas in 9 of 33 mice in 1 series. BCNU was a weak carcinogen. CCNU produced no tumors in 1 series.Supported in part by PHS grant CA-14825 from the National Cancer Institute.     

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.     

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.     

Caffeine analogs: biomedical impact

Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer’s disease, asthma, cancer, diabetes, and Parkinson’s disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms. Received 31 January 2007; received after revision 7 April 2007; accepted 26 April 2007     

The enzymatic degradation of phyllocaerulein and analogs

Riassunto Vengono riportate e discusse alcune differenze osservate durante la degradazione con subtilisina dei 2 peptidi naturali ceruleina e phylloceruleina.     

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).     

Enzymatic processing of pheromones and pheromone analogs

Summary Pheromone perception requires rapid enzymatic degradation of the active chemical signal in the sensory hairs. Three insects are used to illustrate chemical approaches to studying the degradation of pheromones by antennal enzymes. First, hydrolysis of acetate and haloacetate esters is examined in the diamondback moth,Plutella xylostella. Second, aldehyde oxidation and the selective inhibition of the oxidase and dehydrogenase activities are described for the tobacco budworm moth,Heliothis virescens. Finally, a stereochemical analysis of the epoxide-hydrase catalyzed addition of a water molecule to the oxirane ring of disparlure is described for the gypsy moth,Lymantria dispar.     

New Amphenone analogs as adrenocortical inhibitors

Zusammenfassung 2-Methyl-1,2-bis-(3-pyridyl)-1-propanon (Su 4885) hemmt beim Hund die Ausscheidung von 17-OH-Steroiden aus den Nebennieren und hemmtin vitro ähnlich wie Amphenon den ACTH-Effekt auf Ratten-, Meerschweinchen-und Hunde-Nebennieren.In situ bei der Ratte hat es jedoch keine Amphenon-Wirkung, von dem es sich auch sonst unterscheidet.     

Antidiuretic activities of substance P and its analogs

Summary Substance P (SP) and analogs, including 5 nucleoside (ARA or HRA)-peptides, were examined for antidiuretic activity in ethanolized rats. The activity was potent in the analogs embodying the C-terminal hexapeptide, weak in the nucleoside-pentapeptide, and negligible in the nucleoside-tetrapeptide. In addition, the activity was increased by acylation of the hexapeptide. The antidiuretic potencies were also compared with the hypotensive potencies.This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan, and by a grant from the Imanaga Foundation, Nagoya, Japan.     

Semi-synthesis of A23187 (calcimycin) analogs

Summary The cleavage of A23187 to give a synthon (4) and the semi-synthesis from (4) of 2 Des-N-methylamino A23187 isomers (7a,b) are described. The antibiotic activities of the acids analogous to A23187(1), (2), (7a), (7b) are compared.Acknowledgment. The authors are very grateful to Drs G. Dauphin and J.Y. Lallemand for the NMR-spectra at 400 MHz performed in Gif-sur-Yvette, To Dr J.G. Gourcy and Mrs G. Kergomard for technical assistance.     

Gramicidin S analogs containing N-methylleucine in place of leucine

Zusammenfassung Nach Methoden der konventionellen Peptidsynthese wurden zwei Gramicidin S Analoga synthetisiert, in denen Leucin durch N-Methylleucin ersetzt ist. Beim antibakteriellen Test sind diese beiden Analoga praktisch gleich wirksam wie Gramicidin S und auch die Konformation dieser zwei Analoga ist derjenigen von Gramidicin S ähnlich.     

Inhibition of angiotensin-converting enzyme by analogs of peptides fromBothrops jararaca venom

Zusammenfassung Nachweis mit Analogen der im Gifte vonBothrops jararaca gefundenen Peptide, dass die Inhihibition des Angiotensins «converting enzyme» von zwei eindeutigen Teilsequenzen dieser Peptide abhängig ist. Die hohe spezifische kompetitive Inhibition, hervorgerufen durch die Peptide vonBothrops jararaca, wird der Bindung ihrer Tripeptidreste vom Carboxyterminus mit dem aktiven Zentrum des Enzyms zugeschrieben, die in gleicher Weise wie die Peptidsubstrate mit dem Enzym gebunden werden. Die Wirksamkeit der Giftpeptide hängt von der Bindung eines zweiten Teiles der Peptide mit dem Enzym ab.     

Comparison of some biological activities of arginine vasotocin and synthetic analogs

Zusammenfassung Nachweis, dass die Substitution in Positionen 3 und 8 im Arginin Vasotocin ([8-Arginin]-Oxytocin) selektive Veränderungen verschiedener biologischer Aktivitäten hervorruft, was am Modell der Oxytocinkonformation diskutiert wird.

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Supported in part by USPHS grant No. AM-13567.

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Neurohypophyseal hormone analogs are denoted in accordance with IUPAC-IUB Tentative Rules on Biochemical Nomenclature, Biochemistry6, 362 (1967) and J. biol. Chem.247, 977 (1972). All optically active amino acids are of thel-configuration unless otherwise noted. Arginine vasopressin, [8-arginine]vasopressin; lysine vasopressin, [8-lysine]vasopressin; AVT, arginine vasotocin, [8-arginine]oxytocin; Mpr, -mercaptopropionic acid.

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Acknowledgment. We thank Dr.Klaus Lübke, Schering AG, West Germany, for generously supplying us with the hormone analogs.     

Oxytocin analogs effective as noncompetitive inhibitors in uterotonic test

Summary Deamino-1-carba-oxytocin analogs with a chemically reactive group in position 4 were demonstrated to act as noncompetitive oxytocin inhibitors in the assay on isolated rat uterus.     

Effects of isaxonine phosphate and analogs on fibroblast metabolism in culture

Human skin fibroblasts in confluent cultures were incubated for 24 h in the presence of isaxonine phosphate (Nerfactor) and several related factors. The incorporation of 14C-proline into secreted proteins and the release of collagen into the medium were inhibited. When the cells were incubated for an additional period of 24 h after thorough washing, protein and collagen syntheses were found to be identical to those of controls, demonstrating that the inhibition of protein synthesis was independent of any toxic effect. When cells were incubated in the presence of both isaxonine and colchicine, the secretion of collagen was more inhibited than by colchicine alone, and proteins accumulated in the cells.     

Effects of isaxonine phosphate and analogs on fibroblast metabolism in culture

Summary Human skin fibroblasts in confluent cultures were incubated for 24 h in the presence of isaxonine phosphate (Nerfactor) and several related factors. The incorporation of¹⁴C-proline into secreted proteins and the release of collagen into the medium were inhibited. When the cells incubated for an additional period of 24 h after thorough washing, protein and collagen syntheses were found to be identical to those of controls, demonstrating that the inhibition of protein synthesis was independent of any toxic effect. When cells were incubated in the presence of both isaxonine and colchicine, the secretion of collagen was more inhibited than by colchicine alone, and proteins accumulated in the cells.