Effect of platinum derivatives on the inducible and repressible liver microsomal enzyme systems in the rat: inhibition of zoxazolamine-hydroxylase and induction of dimethyl-nitrosamine demethylase isoenzymes by cis-dichlorodiamine platinum (cis-PtCl2(NH3)2) and ammonium hexachloroplatinum (PtC16(NH4)2)]

Two platinum derivatives, cis-PtCl2(NH3)2 and PtCl6(NH4)2 have been studied for their effects on the Rat on cytochrome P450 in hepatic parenchyma on zoxazolamine-hydroxylase, a typical inducible system and on the two isoenzymes of dimethyl-nitrosamine demethylase, typical repressible systems. The inhibitory effect of PtCl6(NH4)2 on zoxazolamine-hydroxylase activity, previously shown by the authors, has been confirmed. The cis-PtCl2(NH3)2 also significantly inhibits zoxazolamine-hydroxylase activity. On the other hand, both of the platinum derivatives decrease cytochrome P450 level and enhance the dimethyl-nitrosamine metabolism. These various effects and their relationship are discussed.     

Oxidative photochemical decarboxylation of zaragozic acid A

A unique decomposition reaction of the novel squalene synthase inhibitors called zaragozic acids has been studied. Under very mild conditions, e.g. by merely exposing their solutions to air and visible light at ambient temperature, these compounds, characterized by the 2,8-dioxabicyclo[3.2.1]octane-4,6,7-trihydroxy-3,4,5-tricarboxylic acid core, rapidly decompose. As relatively stable intermediates in the cascade of decomposition, the biologically active 2,8-dioxabicyclo[3.2.1]octane-6,7-dihydroxy-4-keto-5-caroxylic acid (or 3,4-decarboxy-4-dehydro) derivatives of these compounds have been isolated in ca. 20% yield. Derivatization on the highly reactive 4-carbonyl group yields stable derivatives, several of which are potent inhibitors of squalene synthase. Further decomposition results in the elimination of C3 and C4 atoms and the carboxylic acid on C5, the oxidation of C5 to carboxylic acid and the liberation of the oxo group on C1. Specific results obtained with zaragozic acid A, a key representative of the family of these potent cholesterol-lowering agents, are presented in this study.     

Studies on the interaction of the mistletoe lectin I with carbohydrates

Summary Carbohydrates and modified derivatives of D-galactose have been studied for their capacity to inhibit the hemagglutination of human erythrocytes by mistletoe lectin I. Inhibition data suggest that unmodified hydroxyl groups at the C-2, C-3, and C-4 position of the D-galactopyranosyl ring are essential for binding to the active sites of the lectin.     

Pectinoacetals A-C: novel sterol hemiacetals from the gorgonianCtenocella pectinata

Three polyhydroxylated sterol hemiacetals, pectinoacetals A-C (1–3) have been isolated as their acetyl derivatives (4–6) from the acetic anhydride treated organic extract of the Indo-Pacific gorgonianCtenocella pectinata. These natural products were found to undergo very rapid epimerization at the C-18 chiral center and thus exist only as an equilibrium mixture of two diastereomers. The structure assignments are based on spectral studies and chemical modifications of the natural products.     

Modifikationen der Nebennierenrindenfunktion in vitro durch 3- und 4-Pyridinderivate

Summary Within a new series of 3- and 4-monosubstituted pyridin derivatives, some have been found to modify qualitatively and quantitatively the adrenocortical function in vitro as preferential inhibitors of aldosterone or cortisol and as stimulators of corticosterone and cortisol respectively.

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Mitteilung IV «Über die adrenale Steroidbiosynthese in vitro».     

Über pharmakodynamisch interessante Aminoalkylderivate von Acridan- und Phenthiazinhomologen

Summary The synthesis of aminoalkyl derivatives of 1-aza-2, 3; 5,6-dibenzocycloheptadiene (homoacridane) and 1-aza-4-thia-2, 3; 5,6-dibenzocycloheptadiene (homophenothiazine) is described. Salts of these bases possess high antihistamine and local anaesthetic activity.     

Indoxyl derivatives of drug metabolites

Summary Indoxyl derivatives were detected as minor products among the urinary metabolites of two trial drugs, a benzodiazepine (GP 55 129) and a benzophenone (CGP 11 952). Their structures were elucidated by NMR and mass spectroscopy. Presumably, metabolites containing potential aldehyde functions react spontaneously with endogenous indoxyl. Such derivatives have not hitherto been encountered in drug metabolism.     

Indoxyl derivatives of drug metabolites

Indoxyl derivatives were detected as minor products among the urinary metabolites of two trial drugs, a benzodiazepine (GP 55 129) and a benzophenone (CGP 11 952). Their structures were elucidated by NMR and mass spectroscopy. Presumably, metabolites containing potential aldehyde functions react spontaneously with endogenous indoxyl. Such derivatives have not hitherto been encountered in drug metabolism.     

Dérivés trifluorométhylés des [1]benzothiopyrano[4,3-b]indoles et des 6H-[1]benzothiopyrano-[4,3-b]quinoléines

Summary Some fluoro derivatives of [1]benzothiopyrano[4,3-b]indoles and 6H[1]benzothiopyrano[4,3-b] quinolines have shown carciuogenic activities in regard to the fluorine position; we thought it interesting to prepare some trifluoromethyl analogs of there compounds to study the biological activities and to compare with other compounds of the same family. In the present work, we report the synthesis of 7-trifluoromethyl and 8-trifluoromethyl [1]thiochroman-4-one and some [1]benzothiopyrano[4,3-b]indoles and quinolines substitued in 3 or 4 position which have been obtained from these two ketones.     

Chemical components of the rectal gland secretions of maleDacus cucurbitae,the melon fly

Summary The volatile constituents of the rectal gland secretion of maleDacus cucurbitae have been shown to contain 2-methoxy-N-3-methylbutyl acetamide together with 2 other amides, 3 pyrazine derivatives and 2-ethoxybenzoic acid. Excised male rectal glands have been demonstrated to elicit strong responses from female melon flies.Acknowledgment. We thank Dr P. Howse for valuable discussions and advice.     

Milanjilactones A and B,two novel cytotoxic norditerpene dilactones fromPodocarpus milanjianus Rendle

Summary Two new cytotoxic norditerpene dilactones, milanjilactones A(3) and B(4) have been isolated from the stem bark ofPodocarpus milanjianus Rendle and characterized, on the basis of spectroscopic evidence, as 1,2-dehydro derivatives of nagilactones F(1) and G(2).The authors acknowledge the technical assistance of Ms Teresa K. Lightner. Part 11 in the series Potential Antitumor Agents.     

The role of cysteine in the detoxification of an herbicide]

The methyl 2-chloro-3 (4-chlorophenyl) propionate is quickly hydrolysed through coleoptiles of wheat (coleoptile test). Then, depending on the concentration of the compounds, one observes mainly a further degradation (at 0,01 mM) of the acid or conjugation (at 0,1 mM) of it with cystein in vivo. This second type of physiological neutralisation appears to be more efficient than the catabolism which give derivatives of benzoic acid.     

A cholinergic modulator.

Soluble proteins obtained from presynaptic cholinergic vesicles have been tested regarding their effects to modify postsynaptic spike generation. The results suggest that these proteins (or derivatives, incl. glycopeptides) may act as modulators in increasing the effectiveness and duration of postsynaptic spike generation. They may partake in generation of homosynaptic (posttetanic) potentiation.     

Fructose-1,6-diphosphate reduces acute ECG changes due to doxorubicin in isolated rat heart

Doxorubicin (DXR) (0.17 x 10(-4) M) induces an acute cardiotoxicity in isolated rat heart; there is a progressive widening of the S alpha T segment, with a decrease in force derivatives and in the coronary flow. Concurrent perfusion with fructose-1,6-diphosphate (FDP) (10(-5)-10(-4) M) dose-dependently reduces the S alpha T enlargement but fails to affect the reduction in force derivatives and coronary flow. The target of cardiac protection by FDP might be the ionic mechanisms underlying the action potential configuration.     

Propriétés antiacétylcholinestérasiques du diiodométhylate debis-(diméthylamino-3-phénoxy)-1-3 propane,de ses dérivés phénoliques et des esters carbamiques correspondants

Summary Thein vitro anti-acetylcholinesterase properties ofbis-(dimethylamino-3-phenoxy)-1-3 propane dimethiodide (2842 CT) of two phenolics derivatives (3443 CT and 3116 CT) and of the two corresponding carbamic esters (3152 CT et 3113 CT) have been compared using human red blood corpuscles as enzyme source; under specified conditions, the Cl-50 are respectively 8 × 10^–7 M for 2842 CT, 3.5 × 10^–9 for the two phenolic compounds, and 1.5 × 10^–9 for the carbamic esters. The potencies of these phenols are very close to those of the carbamates, being a bit higher or lower depending on the concentration of the inhibitor and on the time of the readingThe two phenolic compounds, like 2842 CT, react readily with the enzyme contrarily to the carbamic esters which combine slowly. On the other hand the inhibition by the phenolic derivatives is as stable against washing as that by the carbamates. The carbamates, but not the phenols, show the slow displacement phenomenon.Some of these characteristics are compatible with the hypothesis that carbamic compounds could act through liberated phenolic functions but others indicate that carbamic groups have a role of their own.     

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.     

Sur des œstrogènes dérivés du triphényléthylène

Summary A series of derivatives of triphenylethylene have been tested and some of them found to possess interesting oestrogenic properties; the relations between chemical constitution and oestrogenic activity have been discussed.     

Defensive secretions of Nematinae larvae (Symphyta - Tenthredinidae)

Summary The composition of the defensive secretion of larvae of 8 Nematinae species is reported. 7 derivatives have been identified: benzaldehyde, (E)-2-hexenol, (E)-2-hexenal, (E)-4-oxo-2-hexenal, geranial, neral andcis, trans-dolichodial.Maître de recherches du Fonds National de la Recherche Scientifique.We gratefully acknowledge the Fonds National de la Recherche Scientifique for financial support. We express our sincere thanks to Professor B. Zwanenburg and Dr J. M. J. Verlaak for helpful suggestions.     

Über den biologischen Abbau eines Glutarsäureimids

Summary In view of the therapeutic interest glutarimides have been found recently, the metabolism of -Phenyl--ethyl-glutarimide and 3-Phenyl-3-ethyl-2-piperidone have been studied by feeding experiments upon dogs. Both derivatives were degraded to -phenyl glutarimide, the ethyl side chain was thereby very probably eliminated by oxidation.     

Luteolytic potency of 16-phenoxy-derivatives of prostaglandin F2 alpha

The binding of 16-phenoxy derivatives of prostaglandin (PG) F2 alpha 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 alpha receptor as well as, or even better than the parent compound PGF2 alpha. 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 greater than COOH greater than 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 alpha may augment the binding to the receptor as well as the biological responses induced by the post receptor effect.