Implication of C-5, C-6 unsaturation as a key structural factor in steroidal alkaloid-induced mammalian teratogenesis

Hamster teratogenicity induced upon oral administration of steroidal alkaloids (solanidanes, spirosolanes and jervanes) appears to relate very closely to the presence or absence of C-5, C-6 unsaturation in the alkaloid, which may be more important than molecular configuration at C-22 and placement of the nitrogen atom with regard to the plane of the steroid.     

Zum Mechanismus derβ-Lysin-Mutase-Reaktion

Summary Using tritium labelled substrates it is shown that in the rearrangement of (S) --lysine to 3,5-diaminohexanoic acid catalysed by-lysine mutase a stereospecific hydrogen migration from C-5 to C-6 of the substrate occurs. When the reaction is carried out in the presence of [5-³H]-coenzyme B₁₂, the heavy isotope is transferred both to C-6 of 3, 5-diaminohexanoate and to C-5 of-lysine. In the latter the labelled atom occupies the same diastereotopic position as the H atom that is transferred to C-6 of the product.     

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.     

Spontaneous morphine withdrawal from the rat spinal cord

A characteristic and reproducible sign of narcotic withdrawal is the naloxone induced increase in arterial pressure. In morphine-dependent rats allowed to undergo spontaneous withdrawal (6-24 h) and then transected at the spinal C-1 level, arterial pressure was maintained at a significantly higher level than either spinal-transected nondependent controls or morphine-dependent, spinal-transected rats pithed from C-1 to L-4. These findings indicate that the morphine-dependent spinal cord, independent of supraspinal influences, is able to exhibit an autonomic component of spontaneous withdrawal.     

Oviposition-deterring pheromone inRhagoletis cerasi L.: Purification and determination of the chemical constitution

Summary An oviposition-deterring pheromone (ODP) of the European cherry fruit flyRhagoletis cerasi L. was isolated from faeces using cellulose and several reverse phase TLC and HPLC procedures. The biological activity was evaluated by means of behavior tests and by electrophysiological recordings from tarsal contact chemoreceptors. The compound was structurally characterized as a N[15(-glucopyranosyl)oxy-8-hydroxypalmitoyl]-taurine by spectroscopic means. The configurations of C-8 and C-15 of the fatty acid constituent remain to be established by synthetic work.     

Antimutagenic unusual amino acids from plants

Summary Five unusual amino acids were identified as antimutagens against spontaneous mutation ofSalmonella typhimurium TA100: L-azetidine-2-carboxylic acid (1) from Liliaceae plants, -(methylenecyclopropyl)glycine (2) fromLitchi chinensis seeds, and 2-amino-4-methylhex-5-ynoic acid (3), hypoglycin A (4), and (2S, 4R)-2-amino-4-hydroxyhept-6-ynoic acid (5) fromEuphoria longana seeds. The absolute stereochemistry of5 was determined by its chiral synthesis from L-allylglycine, proving that5 is the C-4 epimer of the amino acid previously isolated from dried longan seeds.This work was partly supported by a Grant-in-Aid form the Ministry of Education, Science, and Culture, Japan, No. 57740283 (to HK).     

Antifungal properties of taxol and various analogues

The antimitotic agent taxol was tested for toxicity towards fungi from different taxonomic groups and found to be particularly active against oomycete fungi. In germinating zoospore cysts of the oomycetePhytophthora capsici the mechanism of action of taxol was shown to involve inhibition of mitosis, presumably resulting from an effect on microtubules. Various taxol analogues with deleted A-ring C-13 side chain substituents were tested for toxicity towardsP. capsici andAphanomyces cochlioides to provide insight into structural features required for activity. The importance of the side chain was shown by the much lower activity as compared to taxol of analogues lacking all or part of the side chain. The effect of stereochemistry at the C-2 position on fungitoxicity towards oomycetes was similar to that reported previously on mammalian microtubule assembly.     

7-alpha-Hydroxylation of 5 alpha-androstane-3 beta, 17 beta-diol in human normal and hyperplastic prostates]

Incubation of 4-14C-5 alpha-androstane-3 beta, 17 beta-diol with human normal and hyperplastic prostate minces led to the NADPH-dependent production of a major polar radiometabolite which was identified as 5 alpha-androstane-3 beta, 7 alpha, 17 beta-triol and proved the presence of a 3 beta-hydroxysteroid-7 alpha-hydroxylase in prostate. Such evidences may bring new leads for the study of the mechanisms of androgenic steroid action in the prostate gland.     

7 alpha-Hydroxylation of 5 alpha-androstane-3 beta, 17 beta-diol in normal and hyperplastic human prostate]

Incubation of 4-14C-5 alpha-androstane-3 beta, 17 beta-diol with human normal and hyperplastic prostate minces led to the NADPH-dependent production of a major polar radiometabolite which was identified as 5 alpha-androstane-3 beta, 7 alpha, 17 beta-triol and proved the presence of a 3 beta-hydroxysteroid-7 alpha-hydroxylase in prostate. Such evidences may bring new leads for the study of the mechanisms of androgenic steroid action in the prostate gland.     

Antimutagenic unusual amino acids from plants

Five unusual amino acids were identified as antimutagens against spontaneous mutation of Salmonella typhimurium TA100: L-azetidine-2-carboxylic acid (1) from Liliaceae plants, alpha-(methylenecyclopropyl)glycine (2) from Litchi chinensis seeds, and 2-amino-4-methylhex-5-ynoic acid (3), hypoglycin A (4), and (2S,4R)-2-amino-4-hydroxyhept-6-ynoic acid (5) from Euphoria longana seeds. The absolute stereochemistry of 5 was determined by its chiral synthesis from L-allylglycine, proving that 5 is the C-4 epimer of the amino acid previously isolated from dried longan seeds.     

Spontaneous morphine withdrawal from the rat spinal cord

Summary A characteristic and reproducible sign of narcotic withdrawal is the naloxone induced increase in arterial pressure. In morphine-dependent rats allowed to undergo spontaneous withdrawal (6–24 h) and then transected at the spinal C-1 level, arterial pressure was maintained at a significantly higher level than either spinal-transected nondependent controls or morphine-dependent, spinal-transected rats pithed from C-1 to L-4. These findings indicate that the morphine-dependent spinal cord, independent of supraspinal influences, is able to exhibit an autonomic component of spontaneous withdrawal.This study was supported by the Medical Research Service of the Veterans Administration. A preliminary report of aspects of this work appeared in Soc. Neurosci. Abs.10 (1984) 1113.     

Biological activity of enantiomerically pure forms of insect juvenile hormone I and III inBombyx mori

Summary Biological activity of enantiomerically pure juvenile hormones was assayed by topical application on allatectomizedBombyx fourth instar larvae. JHs tested were (10R)-JH I [methyl (2E,6E,10R,11S)-10,11-epoxy-3,11-dimethyl-7-ethyl-2,6-tridecadienoate], (10S)-JH I [methyl (2E, 6E, 10S, 11R)-10,11-epoxy-3,11-dimethyl-7-ethyl-2,6-tridecadienoate], (10R)-JH III [methyl (2E,6E,10R)-10,11-epoxy-3,7,11-trimethyl-2,6-dodecadienoate] and (10S)-JH III [methyl (2E,6E,10S)-10,11-epoxy-3,7,11-trimethyl-2,6-dodecadienoate]. Among these compounds, natural (10R)-JH I was most active and the dose needed to induce 50% larval molting was 0.04 g/larva; it was approximately 12,000 times more active than unnatural (10S)-JH I. Though natural (10R)-JH III showed slight biological activity, it was only one three-thousandth of that of (10R)-JH I. Unnatural (10S)-JH III exhibited no biological activity at the levels assayed.     

Neuartige Umwandlungen bei den Steroiden

Summary The problem of an efficient partial synthesis of the important corticosteroidal hormone, aldosterone, involves the ability to obtain steroids with functional groups at C-18. Thus, naturally occuring steroid alkaloids, holarrhimine and conessine, were degraded to nitrogen-free 18-hydroxysteroids.In order to find other more efficient methods of synthesis, attempts were made to effect direct functionalization of the unactivated angular methyl group 18 in steroids. This was achieved by known and by novel intramolecular substitution procedures.In the course of these investigations, conessin-type compounds, novel pentacarbocyclic steroids with four-and five-membered E ring as well as novel 18,20-oxido steroids were synthesized from pregnane derivatives. The lead tetraacetate oxidation of 20-hydroxypregnanes, leading to ether formation between C-18 and C-20, ultimately provided the key step for the first partial synthesis ofnat.-aldosterone. The latter work was carried out in close collaboration with the research group of the Pharmaceutical Department of CIBA Ltd., Basle.

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Erweiterte Fassung eines am 6. 5. 59 in der Zürcher Chemischen Gesellschaft sowie am 11. 6. 59 in der CIBA AG., Basel, vom Seniorautor gehaltenen Vortrages.     

Some aspects of the NMR-spectra of aporphine and phenanthrene alkaloids

Summary The C-11 proton of an aprophine possessing a C-1,2 methylenedioxy group falls relatively upfield between 7.47 and 7.86. Additionally, the i.c.s. for the two protons of the methylenedioxy group is large (4–12 Hz). The presence of a methylenedioxy at C-3,4 in a phenanthrene alkaloid also results in an upfield shift ( 8.95–9.00) of the C-5 proton.This project was supported by NIH research grant No. HL-12971, awarded by the National Heart and Lung Institute, PHS/DHEW.     

Die Konstitution der Salamander-Alkaloide

Summary Four alkaloids have been isolated from the skin gland of the Feuer- and Alpensalamander (Salamandra maculosa andatra Laur.). The structure, stereochemistry and absolute configuration of the principal alkaloid, samandarin, have been elucidated by chemical, optical, and X-ray-crystallographic methods. The basic structure of samandarin is derived from 5-androstan by the insertion between C-2 and C-3 of ring A of an NH group which, along with an oxygen bridge between C-1 and C-3, constitutes an oxazolidine ring; at C₁₆ there is a-hydroxyl group. By virtue of its origin and constitution samandarin occupies a unique position among alkaloids.

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Nach der am 15. Juni 1960 in der Aula der Universität Zürich gehaltenen zweitenPaul-Karrer-Vorlesung. Der Vortrag ist zum Teil gekürzt, Ergebnisse der letzten Zeit sind in die vorliegende Fassung eingearbeitet worden.     

Comparative study of oxalate oxidase in three genotypes ofSorghum vulgare

Summary The presence of an oxalate oxidase (EC 1.2.3.4) has been demonstrated in 15,000×g supernatants prepared from 10-day-old seedlings of three genotypes ofSorghum vulgare: grain sorghum hybrid (CSH-5), grain-cum-forage sorghum (PC-6) and forage sorghum (PC-1). The specific activity of the enzyme in the different tissues of seedlings was found to be present in the order leaves > stems > roots in PC-6 and PC-1, but this order was reversed in CSH-5. A comparison of the different properties of the leaf enzyme of these three genotypes of sorghum revealed that the enzyme has maximum activity in the acidic pH range from 4.0 to 5.0 and in the temperature range from 37°C to 40°C. The enzyme was stimulated by Cu²⁺ and Fe²⁺. The rate of H₂O₂ formation in the enzyme reaction was linear up to 5 min and was stoichiometrically related to oxalate consumption. The enzyme is unaffected by Na⁺ at physiological concentration (0.15 M). The superiority of this enzyme over moss and other plant enzymes for enzymic determination of urinary oxalate is discussed.     

Occurrence of tetrodotoxin in the starfishAstropecten latespinosus

Summary A toxin causing paralysis was detected in the starfishAstropecten latespinosus. The toxin was purified by a method consisting of charcoal treatment and chromatography on CM-Sephadex C-25 and Bio-Rex 70. The toxin was identified as tetrodotoxin by its behavior in thin-layer chromatography and electrophoresis and its¹H-NMR spectrum.Acknowledgment. This work was in part supported by a research fund from the Ministry of Agriculture, Forestry and Fisheries of Japan.     

The metabolism of dibenz[b,f]-1,4-oxazepine (CR): In vivo hydroxylation of 10,11-dihydrodibenz[b,f]-1,4-oxazepin-11-(1OH)-one and the NIH shift

Summary Studies of the in vivo metabolism of 10,11-dihydrodibenz[b,f]-1,4-oxazepin-11-(1OH)-one (2) specifically deuteriated at C-7 implicate an arene oxide intermediate during the conversion to 7-hydroxy-2 (4) as evidenced by the observation of the NIH shift.     

Phosphoramidon enhances allatostatin-mediated inhibition of juvenile hormone biosynthesis in the corpora allta of the cockroach,Diploptera punctata

Use of the enkephalinase inhibitor phosphoramidon in the in vitro radiochemical assay for juvenile hormone biosynthesis enhanced allatostatin-mediated inhibition of hormone production by corpora allata of the cockroach,Diploptera punctata. Significant increases in inhibition in day 2 virgin female CA by AST 1 (at 10^–7 M) and AST 4 (10^–8–10^–7 M) were observed in the presence of phosphoramidon (10^–5M or greater). No significant increases in inhibition were seen in CA from day 6 mated females with AST 4 (10^–9–10^–7M) and phosphoramidon combined. Phosphoramidon alone had no effect on JH biosynthesis. Analysis of allatostatin content of the CA, as determined by ELISA, revealed that addition of phosphoramidon to the medium increased the endogenous allatostatin conten in CA of virgin and mated females. The similarity in primary structure between allatostatins and enkephalin-like peptides and their similar distribution makes it probable that phosphoramidon acts by preventing breakdown of allatostatins within the CA.     

Stereochemical course of pheromone biosynthesis in the arctiid moth,Creatonotos transiens

Summary The biosynthetic conversion of a pyrrolizidine alkaloid (heliotrine,IV) to a male moth pheromone (hydroxydanaidal,III) is found to proceed with inversion of configuration at the remaining asymmetric center (C-7).Acknowledgments. The partial support of this research by a grant from the N.I.H. (AI-12020) and by the Deutsche Forschungsgemeinschaft (SFB4-B6) is acknowleded with pleasure.Please address correspondence regarding the chemical aspects of this communication to either T.W. Bell (Stony Brook) or J. Meinwald (Ithaca); inquiries regarding biological aspects should be sent to M. Boppré (Regensburg) or D. Schneider (Seewiesen).