The effect of charatoxin, 4-methylthio-1,2-dithiolane, on the frog sartorius neuromuscular junction

The insecticide 4-methylthio-1,2-dithiolane, named charatoxin, blocks the frog muscular twitches elicited through the neuromuscular junction. The activity level and the course of inhibition is comparable to that of 4-dimethyl-amino-1,2-dithiolane, nereistoxin.     

Changes in glycosaminoglycan sulfation and protein kinase C subcellular distribution during differentiation of the human colon tumor cell line Caco-2

During the spontaneous differentiation (day 5 to day 15 of the culture) of Caco-2 cells, the sulfation of cell layer glycosaminoglycans increased, whereas protein kinase C activity was concomitantly redistributed from the membrane to the cytosol. The protein kinase C activators, 4 beta-phorbol 12 beta-myristate, 13 alpha-acetate and 1,2-dioctanoylglycerol inhibited glycosaminoglycan sulfation. By contrast, 4 alpha-phorbol 12, 13 didecanoate was ineffective. These results suggest that membrane-bound PKC may exert a modulatory effect on glycosaminoglycan sulfation, and this effect is gradually attenuated as Caco-2 cell differentiation progresses.     

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.     

Oxytoxins, bioactive molecules produced by the marine opisthobranch mollusc Oxynoe olivacea from a diet-derived precursor

The ethereal extract of the mucous secretion from the opisthobranch mollusc Oxynoe olivacea was examined and found to contain two novel ichthyotoxic compounds, named oxytoxin 1 and 2 (1,2). The structures of 1 and 2 are closely related to the metabolites previously isolated from the alga Caulerpa prolifera. The activity of the most stable compound was studied in order to investigate the possibility of a further biological role for these metabolites, which represent an uncommon example of bioactive molecules produced in vivo from a dietary precursor.     

1,2-di-n-butylhydrazine dihydrochloride carcinogenesis in mice

Summary A solution of 0.0625% 1,2-di-n-butylhydrazine dihydrochloride (1,2-DBH) was given continuously in the drinking water of 6-week-old randomly bred albino Swiss mice for the remainder of their lives. The treatment gave rise to tumors of the lungs, lymphoreticular tissue and kidneys.     

Anticonvulsant action of YG 19-256 in baboons with photosensitive epilepsy.

YG 19-256, 4-(1,3,4,9b-tetrahydro-5 methyl-2H-indeno[1,2-c]pyridine-2-yl)-2-butanone methane sulphonate, 1-3 mg/kg i.v., abolished or reduced photically-induced myoclonic responses for 1.5-6.5 h in baboons, Papio papio, without producing signs of acute neurological toxicity.     

Chitin in the epidermal cuticle of a vertebrate (Paralipophrys trigloides,Blenniidae, Teleostei)

Lectin binding, endo-chitinase binding and enzymatic degradation studies show that the epidermal cuticle of the bony fishParalipophrys trigloides (Blenniidae) is chitinous. This is the first evidence that a vertebrate species possesses a chitinous tissue. Recently aXenopus gene has been identified which has significant sequence similarity to the catalytic domain of yeast chitin synthase III, a chitin producing enzyme^1,2. Taken together these two findings imply that chitin synthesis capability may be a basic vertebrate feature.     

Comparison of the effects of imidazo[1,2-a]pyridine-2-carbamates and benzimidazole-2-carbamates on the development of Hymenolepis nana in Tribolium confusum

The anthelmintic properties of several imidazo[1,2-a]pyridine carbamates and benzimidazole carbamates against Hymenolepis nana are compared. The results of this study, coupled with previous work, indicate that methyl 6-(trichloroethenyl)-imidazo[1,2-a]pyridine-2-carbamate has the potential of being a broad spectrum anthelmintic effective against both nematodes and cestodes.     

Transplacentar induction of neurogenic malignomas by 1,2-diethyl-hydrazine,azo-, and azoxy-ethane in rats

Zusammenfassung Schwangere Ratten erhielten am 15. Tage post coitum eine einmalige i.v. Injektion von 1,2-Diäthyl-hydrazin bzw. von Azoxyäthan oder wurden einmal 1 h lang Azoäthan-Dämpfen exponiert. 107 von 114 aufgezogenen Nachkommen starben mit malignen Tumoren im Gehirn, Rückenmark und peripheren Nervensystem.

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This paper is dedicated to Prof. Dr. h.c.A. Butenandt on the occasion of his sixty-fifth birthday.

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The authors are indebted to the Deutsche Forschungsgemeinschaft for generous support.     

Induction of autotomy in the American bird grasshopperSchistocerca americana (Drury) by the ecdysone agonist RH-5849 and investigation of its mode of action

The non-steroidal ecdysone agonist RH-5849 (1,2-dibenzoyl-l-tert-butylhydrazine) was found to be an effective neurotoxicant on injection into the American bird grasshopper,Schistocerca americana (Drury). Treated grasshoppers became immediately hyperactive, followed by loss of coordination, paralysis and eventually death. We also discovered that this compound induced bilateral autotomy of the metathoracic legs during the early stages of intoxication. However, no evidence of ecdysonergic or morphogenetic activities was observed. Synergism studies with neurotoxins of known mode of action suggested that RH-5849 has a mechanism of action similar to that of 4-amino pyridine, which blocks potassium channels.     

Fatty acid modulation of antiestrogen action and antiestrogen-binding protein in cultured lymphoid cells

Nonsteroidal antiestrogens reversibly and specifically inhibited the proliferation of two estrogen receptor-negative lymphoid cell lines (EL4 and Raji) in a dose-dependent manner. [3H]Thymidine incorporation of concanavalin A-stimulated primary splenocytes was also inhibited by 10(-6) M clomiphene (1-[4-(2-diethylaminoethoxy)phenyl]-1,2-diphenyl-2-chloroethylene). The antiproliferative effect could be prevented by the simultaneous presence in the growth medium of 10(-5) M linoleic acid or 10(-5) M arachidonic acid but not by 10(-6) M estradiol. Both lymphoid cell lines had high affinity antiestrogen-binding sites whose affinity could be altered by conditions of growth. Growth of EL4 cells in RPMI 1640 medium supplemented with charcoal-pretreated 5% fetal calf serum (charcoal-stripped medium) resulted in significantly higher affinity (Kd 0.54 nM +/- 0.11 nM; n = 6) than growth in medium supplemented with untreated serum (complete medium) (Kd = 1.68 nM +/- 0.48 nM; n = 6) (p less than 0.001). This change in affinity was partly due to removal of fatty acids from the growth medium by charcoal pretreatment, since addition of 10(-5) M linoleic acid or 10(-5) M gamma-linolenic to charcoal-stripped medium decreased the affinity of the antiestrogen-binding protein. In contrast, growth in 10(-5) M stearic acid or 10(-5) M oleic acid did not significantly alter the affinity of the antiestrogen-binding protein, whereas 10(-5) M palmitic acid significantly increased its affinity. The same fatty acids were also tested for their intrinsic effects on EL4 cell proliferation. Oleic, linoleic and gamma-linolenic acids were growth stimulatory while stearic and palmitic acids were not. Thus linoleic and gamma-linolenic acids whose presence in the growth medium was associated with decreased affinity of [3H]tamoxifen (1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1(Z)-ene) binding to the intracellular antiestrogen-binding protein were also growth stimulatory. Unsaturated fatty acids have previously been shown to inhibit binding of [3H]tamoxifen to the antiestrogen-binding protein in a cell-free system. The present observations demonstrate that unsaturated fatty acids also modify the affinity of the antiestrogen-binding protein in intact cells.     

Comparison of the effects of imidazo[1,2-a]pyridine-2-carbamates and benzimidazole-2-carbamates on the development ofHymenolepis nana inTribolium confusum

Summary The anthelmintic properties of several imidazo[1,2-a]pyridine carbamates and benzimidazole carbamates againstHymenolepis nana are compared. The results of this study, coupled with previous work, indicate that methyl 6-(trichloroethenyl)-imidazo[1,2-a]pyridine-2-carbamate has the potential of being a broad spectrum anthelmintic, effective against both nematodes and cestodes.Acknowledgments. We are indebted to Miss Marianne Hardy for excellent technical assistance. Our sincere thanks are extended to the Merck, Sharp & Dohme and Hoechst companies for the compounds tested in the present study.     

Radical catalysis of B12 enzymes: structure,mechanism, inactivation,and reactivation of diol and glycerol dehydratases

Enzymatic radical catalysis is defined as a mechanism of catalysis by which enzymes catalyze chemically difficult reactions by utilizing the high reactivity of free radicals. Adenosylcobalamin (coenzyme B12) serves as a cofactor for enzymatic radical reactions. The recent structural analysis of adenosylcobalamin-dependent diol dehydratase revealed that the substrate 1,2-propanediol and an essential potassium ion are located inside a (beta/alpha)8 barrel. Two hydroxyl groups of the substrate coordinate directly to the potassium ion which binds to the negatively charged inner part of the cavity. Cobalamin bound in the base-on mode covers the cavity to isolate the active site from solvent. Based on the three-dimensional structure and theoretical calculations, a new mechanism for diol dehydratase is proposed in which the potassium ion plays a direct role in the catalysis. The mechanisms for generation of a catalytic radical by homolysis of the coenzyme Co-C bond and for protection of radical intermediates from undesired side reactions during catalysis are discussed based on the structure. The reactivating factors for diol and glycerol dehydratases have been identified. These factors are a new type of molecular chaperone which participate in reactivation of the inactivated holoenzymes by mediating ATP-dependent exchange of the modified coenzyme for free intact coenzyme.     

Effects of isoxazolyl-naphthoquinoneimines on growth and oxygen radical production in Trypanosoma cruzi and Crithidia fasciculata

Several 4-(aminomethylisoxazolyl)-1,2-naphthoquinones inhibited growth and DNA synthesis in Trypanosoma cruzi and stimulated O2 uptake and O2-. generation by the parasite epimastigotes and their mitochondrial and microsomal membranes; these results support the idea that oxygen radicals play a role in quinone toxicity. Maximal effects on respiration and O2-. generation were observed with antimycin-inhibited cells. Similar results as well as stimulation of H2O2 production were obtained with Crithidia fasciculata despite the presence of catalase in this organism.     

Lipopeptaibols, a novel family of membrane active, antimicrobial peptides

Lipopeptaibols are members of a novel group of naturally occurring, short peptides with antimicrobial activity, characterized by a lipophilic acyl chain at the N-terminus, a high content of the turn/helix forming α-aminoisobutyric acid and a 1,2-amino alcohol at the C-terminus. The amino acid sequences range from 6 to 10 residues and the fatty acyl moieties from 8 to 15 carbon atoms. The peptide portion of lipopeptaibols can be shorter than those of the nonlipidated peptaibols that range from 10 to 19 amino acid residues. The longest peptides fold into a mixed 3₁₀/α helix, whereas the shortest peptides tend to adopt a β-turn/sheet structure. Using solution methodologies, a series of analogues of trichogin GA IV was synthesized which allowed determination of the minimal lipid chain and peptide main-chain lengths for the onset of membrane activity and exploitation of a number of spectroscopic techniques aimed at determining its preferred conformation under a variety of conditions and investigating in detail its mode of interaction with, and its effect on, the phospholipid membranes. Received 26 January 2001; received after revision 7 March 2001; accepted 15 March 2001     

Anticonvulsant action of YG 19-256 in baboons with photosensitive epilepsy

Summary YG 19-256, 4-(1,3,4,9b-tetrahydro-5 methyl-2H-indeno[1,2-c]pyridine-2-yl)-2-butanone methane sulphonate, 1–3 mg/kg i.v., abolished or reduced photically-induced myoclonic responses for 1.5–6.5 h in baboons,Papio papio, without producing signs of acute neurological toxicity.We thank the Medical Research Council, The Wellcome Trust and the British Epilepsy Association for financial support, and Drs D.M. Loew and H. Weber (Sandoz Ltd) for the gift of YG 19-256.     

New furanoid metabolites fromRhizoctonia solani

Zusammenfassung Zwei neue, furanoide Metaboliten wurden aus einer Kultur vonRhizoctonia solani isoliert und als 2-Furyl-hydroxymethyl-Keton und 1,2-bis-(2-Furoyl)-1,2-Dihydroxyaethan identifiziert und durch Totalsynthese bestätigt.     

4-Hydroxyurazole

Zusammenfassung Durch Hydroxylaminolyse von 1,2-bis (äthoxycarbonyl)hydrazin wurde Natriumsalz von 1-Äthoxycarbonyl-2-hydroxylaminocarbonylhydrazin hergestellt und mit wässeriger Salzsäure auf pH<1 in 4-Hydroxyurazol (N-Hydroxybicarbamimid) synthetisiert.

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This investigation was supported by Contract No. PH43-65-94 with Chemotherapy, National Cancer Institute, National Institutes of Health, U.S. Public Health Service.     

Affinity of 1,2-substituted oxytocin analogues to the uterus receptor: Free-Wilson and Hansch analysis.

The analysis of pA2 values for 1,2-substituted oxytocin analogues suggests a significant resonance effect of p-substituted groups in 2-tyrosine when the hormone binds to its uterus receptor, whereas the N-terminal amino group exerts less clearly characterized effects (participation of its lipophilicity and molecular volume can be assumed.     

化学发光试剂研究新进展

综述了近十年来几种主要化学发光试剂的研究新进展。内容包括鲁米诺类、吖啶酯类、1,2-二氧环乙烷类和洛粉碱类等化学发光试剂的新型衍生物的结构、发光性能和特点。引用文献48篇。