Hydrolysis of N-phenylacetyl-α-methyl-α-amino acids by benzylpenicillinacylase

Summary Enzymatic hydrolysis of several racemic N-phenylacetyl--methyl--amino acids containing an additinal aliphatic, aromatic or polar substitutent on the chiral carbon atom, has been studied by using benzylpenicillincylase fromEscherichia coli A.T.C.C. 9637. Both the rate of hydrolysis and the stereoselectivity were found to be considerably lower than in the case of natural -amino acids. Steric and electronic factors in the side chains influencing the stereoselectivity are discussed.     

The effect of D-6-methyl-8-[β-isopropylaminoethyl] ergoline-I on the lactation in nursing rats

D-6-Methyl-8-[-isopropylaminoethyl] ergoline-I [VÚFB-10726], beginning from the dose of 0.05 mg/kg p.o., suppresses lactation through the inhibition of prolactin secretion in nursing rats.     

Preliminary note on certain pharmacological properties of 3β, 16α-dihydroxyallopregnan-20-one

Zusammenfassung 3, 16- Dihydroxyallopregnan-20-one hat die Eigenschaft, bei der Mehrzahl adrenopriver, salzbelasteter Ratten im Harn eine Natrium-Mehrausscheidung hervorzurufen.     

Luteolytic potency of 16-phenoxy-derivatives of prostaglandin F2α

Summary The binding of 16-phenoxy derivatives of prostaglandin (PG) F₂ to rat luteal membranes, and also their abortifacient potency in pregnant rats, have been studied. Competitive binding studies with various PG-analogues were performed in ovaries of juvenile rats pretreated with PMSG and HCG, and in parallel studies the abortifacient potency of these substances was tested, in pregnant rats. It was observed that this class of derivatives bound to the PGF₂ receptor as well as, or even better than the parent compound PGF₂. Modifications in the carboxyl group at C-1 yielded derivatives with a higher affinity for the receptor, in decreasing order of effectiveness as follows:-COOR>COOH>OH. The data obtained from the binding studies also compared well with data on the abortifacient potency in pregnant rats. It is concluded that the addition of a phenoxy group to either the lower or upper side chain of PGF₂ may augment the binding to the receptor as well as the biological responses induced by the post receptor effect.     

α-andβ-activity of O-methylated derivatives of norepinephrine and epinephrine

Summary Metanephrine, iso-metanephrine, normetanephrine and isonormetanephrine were tested for - and -activity on various tissues obtained from rats, guinea-pigs and cats. It was found that methylation of the hydroxyl groups of norepinephrine or epinephrine in either the 3-or 4-position markedly reduces or abolishes -and -activity with the exception of the nictitating membrane of the cat. This receptor seems to show a tissue difference.Acknowledgment. W. H. V. would like to thank the Federal Republik of Germany for the U. S. Senior Scientist Award which enabled him to work at the Department of Pharmacology, University of Mainz, and to conduct part of this work. W. H. V. would also like to thank Prof. Dr E. Muscholl, Mainz, for his hospitality, help and advice during this stay.     

The rate of cleavage ofβ-mercaptopyruvate by rapidly dividing cells

Zusammenfassung Quantitative Analysen des-mercaptobrenztraubensäure-spaltenden Enzyms zeigen, dass Zellen, die sich in aktivem mitotischem Prozess befinden (bzw. Krebszellen und Gewebekulturen), dieses Enzym in viel geringerem Masse enthalten als « normale » Zellen. Da dieses Enzym in dem anaeroben Stoffwechsel von Zystein eine wichtige Rolle spielt, lässt sich vermuten, dass sich der Zysteinstoffwechsel der Tumorzelle quantitativ von dem der Normalzelle unterscheidet.

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Supported by U.S. Public Health Grants H-2897, C-3211 and by a grant of the American Cancer Society (70-4612-24).     

The oxidative metabolism ofα-chlorohydrin and the chemical induction of spermatocoeles

Summary -Chlorohydrin (I) is oxidatively metabolized to -chlorolactic acid (III) and oxalic acid (IV). Deposition of calcium oxalate within the renal tubules is responsible for the toxic effects of-chlorohydrin and a similar action on the epididymis or epididymal blood vessels could initiate the formation of spermatocoeles from this and other male antifertility agents.     

Isolierung von 4α-methyl-5α-stigmasta-7,24(28)-dien-3β-ol ausSolanum tuberosum sowie über die Identität dieser Verbindung mitα 1-Sitosterin

Summary The sterol fraction from leaves of the potato plant,Solanum tuberosum, was found to contain a minor constituent, the structure of which has been established as 4-methyl-5-stigmasta-7,24(28)-diene-3-ol (I). This sterol is most probably identical with ₁-sitosterol and has the same constitution as citrostadienol, differing only in the configuration of the ^{24 (28)}-double bond.

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Sterine und Triterpenoide. III. Mitteilung. — II. Mitteilung s. 3.     

On the mineralocorticoid and hypertensogenic properties of 16β-Hydroxy-Dehydroepiandrosterone

Summary Dosages of either 1 or 2 mg daily of 16-hydroxy-dehydroepiandrosterone, given to mononephretomized, salt-loaded female rats, had no detectable effect upon saline consumption, blood pressure, kallikrein excretion or heart and kidney weight. Its alleged mineralocorticoid properties, as judged by these criteria, were not demonstrable.This study was supported by a grant No. HL 15319 from the United States Public Health Service.     

Synthese von 5α- und 5β-Androstan-17β-ol-3-on-17-acetat aus Hyodesoxycholsäure

Summary 5- and 5-androstane-17-ol-3-one-17-acetate have been prepared from 5-androstane-6, 17-diol-3-one-17-acetate by a synthesis involving directedHuang-Minlon-reduction.Separation of 5-androstane-17-ol-3-one from its 5-isomer could readily be achieved by crystallisation of their 3-ethylenketals from acetone.     

The structure of human interferon-β: implications for activity

Interferons (IFNs) are potent extracellular protein mediators of host defence and homoeostasis. This article reviews the structure of human IFN-β (HuIFN-β), in particular in relation to its activity. The recently determined crystal structure of HuIFN-β provides a framework for understanding of the mechanism of differentiation of type I IFNs by their common receptor. Insights are generated by comparison with the structures of other type I IFNs and from the interpretation of existing mutagenesis data. The details of the observed carbohydrate structure, together with biochemical data, implicate the glycosylation of HuIFN-β, which is uncommon among type I IFNs, as an important factor in the solubility, stability and, consequently, activity of the protein. Finally, these structural implications are discussed in the context of the clinical use of HuIFN-β. Received 12 June 1998; received after revision 16 July 1998; accepted 16 July 1998     

The effect ofβ-aminopropionitrile (BAPN) on bacteria

Zusammenfassung Alle untersuchten Bakterien waren gegenüber BAPN entweder ganz unempfindlich oder zeigten nur eine unspezifische Wachstumsverminderung. Diese Bakterien scheinen zum Studium lathyrogenischer Substanzen ungeeignet. Die Annahme, dass BAPN auf Mucopolysacchariden wirkt, konnte durch diese Untersuchung nicht gestützt werden.

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This work was supported by Research Grant A-4002 from the National Institute of Arthritis and Metabolic Diseases, U.S. Public Health Service. We are also grateful to Abbott Laboratories, North Chicago (Illinois) for generous gifts of mono--aminopropionitrile (BAPN) fumarate.     

The steric course of hydrogenation of Δ4 and Δ5 steroids

Zusammenfassung Bei der katalytischen Hydrierung von Steroiden mit Doppelbindung in 4-Stellung entstehen überwiegend A/B-cis-Verbindungen, während Doppelbindung in 5 vor allem A/B-trans liefert. Dieser Unterschied wird mit Hilfe der Konstellationsanalyse erklärt: die als Zwischenformen angenommenen Komplexe aus Substrat, Wasserstoff und Katalysator weisen unterschiedliche sterische Hinderung auf.

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Based in part on a portion of the Ph. D. Thesis of the author, University of Wisconsin, 1951.     

α- andβ-Guttiferins

Zusammenfassung Die Isolierung, Charakterisierung und antibiotischen Eigenschaften von-Guttiferin (I), C₃₃H₃₈O₈ (Smp. 113–115°), aus den Samenhülsen und vom nahe verwandten-Guttiferin (II), C₂₉H₃₆O₆ oder C_33–34H_38–40O₈ (Smp. 86–91°) (möglicherweise identisch mit-Gambogasäure), aus Gummigutt, dem harzigen Sekret vonGarcinia morella, wurden beschrieben und ihre Verwandtschaft zu Morellin und Moreollin, den beiden bekannten Pigmenten der Samenhülsen, dargelegt. Für I wurde eine Partialstruktur vorgeschlagen. Die Bildung derselben komplexen bromhaltigen Säure vom Smp. 199 bis 200° unter der Einwirkung von Natriumhypobromit auf I und II spricht ferner für deren nahe strukturelle Verwandtschaft.     

The interaction of superoxide with nitric oxide destabilizes hypoxia-inducible factor-1α

In renal carcinoma cells (RCC4) hypoxia inducible factor-1 (HIF-1) is constitutively expressed due to a von Hippel Lindau protein deficiency, but can be degraded by calpain, independently of the 26S proteasome, when exposed to hypoxia/nitric oxide (NO). In this study we examined molecular mechanisms to explain calpain activation. The inability of hypoxia/NO to degrade HIF-1α in respiratory-deficient RCC4-ρ0 cells pointed to the requirement for mitochondria-derived reactive oxygen species. A prerequisite for O ₂ ⁻ in combination with NO to destabilize HIF-1α was corroborated in RCC4-p0 cells, when the redox cycler 2,3-dimethoxy-1,4-naphthoquinone was used as a source of superoxide. Degradation of HIF-1α required intracellular calcium transients and calpain activation. Using uric acid to interfere with signal transmission elicited by NO/O ₂ ⁻ blocked HIF-1α degradation and attenuated a calcium increase. We conclude that an oxidative signal as a result of NO/O ₂ ⁻ coformation triggers a calcium increase that activates calpain to degrade HIF-1α, independently of the proteasome. Received 14 August 2007; received after revision 4 October 2007; accepted 22 October 2007     

Identification of 3α, 17α, 21-trihydroxy-5α-pregnane (allotetrahydro-17α-hydroxy-cortexone) and 3α,21-dihydroxy-5α-pregnane (allo-tetrahydro-cortexone) in human urine

Résumé Le 3, 17, 21-trihydroxy 5-pregnane (allo-tétrahydro-17-hydroxy-cortexone) et le 3,21-dihydroxy 5-prégane (allo-tétrahydro-cortexone) ont été identifiés dans l'urine humaine. Ces composés avaient les mêmes migrations chromatographiques avant ou après acétylation ou oxydation que les respectifs stéroïdes de synthèse.     

16-β-methylprednisone from hecogenin

Zusammenfassung Es wird über die Herstellung des 16-Methylprednisons berichtet, welche vom Hecogenin ausgehend über ca. 15 Stufen durchgeführt wird. Als wichtige Zwischenstufe treten 5-Pregn-16-en-3-ol-11, 20-dion-Acetat und 16-Methylen-5-pregnan-3, 17-diol-11, 20-dion auf: letzteres wird durch eine stereospezifische katalytische Reduktion in das entsprechende 16-Methyl-derivat umgewandelt.     

Dependence of 6β-acetoxy-7α-hydroxyroyleanone block of Kv1.2 channels on C-type inactivation

Voltage-gated K⁺ (Kv) channels exhibit slow or C-type inactivation during continuous depolarization. A selective pharmacological agent targeting C-type inactivation is hitherto lacking. Here, we report that 6β-acetoxy-7α-hydroxyroyleanone (AHR), a diterpenoid compound isolated from Taiwania cryptomerioides, can selectively modify C-type inactivation of Kv1.2 channels. Extracellular, but not intracellular, AHR (50 μM) dramatically accelerated the slow decay of Kv currents and left-shifted the steady-state inactivation curve. AHR blocked Kv currents with an IC₅₀ of 17.7 μM. AHR did not affect the kinetics and voltage-dependence of Kv1.2 channel activation. Channel block by AHR was independent of intracellular K⁺ concentration. In addition, effect of AHR was much attenuated in a Kv1.2 V370G mutant defective in C-type inactivation. Therefore, block of Kv1.2 channels by AHR did not appear to involve direct occlusion of the outer pore but depended on C-type inactivation. AHR could thus be a probe targeting Kv channel C-type inactivation gate.