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Domino Michael-aldol annulation of cycloalkane-1,3-diones with enals affords a general route to 6-hydroxybicyclo[3.3.1]nonane-2,9-diones and 2-hydroxybicyclo[3.2.1]octane-6,8-diones, notably in one-pot procedures under convenient conditions. The annulation is shown to be compatible with one or more substituents at six positions of the bicyclo[3.3.1]nonane-2,9-dione scaffold. In some cases, the relative configuration of the product can be controlled by the appropriate choice of solvent, base and temperature for the annulation. In contrast to the chair–chair conformations usually adopted, the bicyclo compounds derived from 2,4,4-trimethylcyclohexane-1,3-dione possessed boat-chair conformations. Oxidation of the annulation products gave the corresponding bicyclo triketones.

The marasmane sesquiterpenoid structure can be found in the skeleton of a variety of natural products bearing interesting bioactivity. The unique fused-5,6,3-tricyclic ring structure, in which the rings are cis-fused and the five- and three-membered rings are mutually trans, provides a synthetic challenge for organic chemists. In this work, we took advantage of the photoinduced decarbonylative rearrangement of bicyclo[2.2.2]octenone to develop a new methodology for construction of the highly functionalized fused-5,6,3-tricyclic ring structure in a concise reaction sequence.

LY379268 and LY354740, two agonists of mGlu2/3 metabotropic glutamate receptors, display different potencies in mouse models of schizophrenia. This differential effect of the two drugs remains unexplained. We performed a proteomic analysis in cultured cortical neurons challenged with either LY379268 or LY354740. Among the few proteins that were differentially influenced by the two drugs, Rab GDP dissociation inhibitor-β (Rab GDIβ) was down-regulated by LY379268 and showed a trend to an up-regulation in response to LY354740. In cultured hippocampal neurons, LY379268 selectively down-regulated the α isoform of Rab GDI. Rab GDI inhibits the activity of the synaptic vesicle-associated protein, Rab3A, and is reduced in the brain of schizophrenic patients. We examined the expression of Rab GDI in mice exposed to prenatal stress ("PRS mice"), which have been described as a putative model of schizophrenia. Rab GDIα protein levels were increased in the hippocampus of PRS mice at postnatal days (PND)1 and 21, but not at PND60. At PND21, PRS mice also showed a reduced depolarization-evoked [(3)H]d-aspartate release in hippocampal synaptosomes. The increase in Rab GDIα levels in the hippocampus of PRS mice was reversed by a 7-days treatment with LY379268 (1 or 10 mg/kg, i.p.), but not by treatment with equal doses of LY354740. These data strengthen the validity of PRS mice as a model of schizophrenia, and show for the first time a pharmacodynamic difference between LY379268 and LY354740 which might be taken into account in an attempt to explain the differential effect of the two drugs across mouse models.

Medium-sized ynolides were prepared by the Lewis acid-mediated fragmentation of bicyclic γ-silyloxy-β-hydroxy-α-diazolactones in which the Cβ–Cγ bond is the ring fusion bond. Although these lactone fragmentation substrates reacted somewhat less efficiently than their carbocyclic counterparts, the fragmentation provided 11-membered ynolides in up to 84% yield. Unlike prior fragmentations of similar substrates, elevated temperatures were required to obtain optimum yields of the ynolide products. The ynolides reported herein have ring sizes of 10 or 11, which are the smallest reported to date.

A simple and effective method for the synthesis of 7-oxabicyclo[2.2.1] heptanes and 8-oxabicyclo[3.2.1]octanes from acetonyl C-glycoside substrates is described, which involves an intramolecular cyclization reaction through a nucleophilic substitution at C-5 or C-6 of C-glycosides by a 2′-enamine intermediate formed in the presence of pyrrolidine. Because anomeric epimerization occurs under these conditions, C-glycoside substrates with either anomeric configuration were converted to the same product(s) in same stereoselectivity and similar chemical yield. © 2013 American Chemical Society.

Acid treatment of densely substituted 2-silyl-1,2-dihydropyridines provides a new and convenient entry to reactive azomethine ylides that can (1) be protonated and reduced with high stereoselectivity to give piperidines, (2) participate in [3 + 2] dipolar cycloaddition to give tropanes, and (3) undergo a Nazarov-like 6-π electrocyclization that upon reduction give 2-azabicyclo[3.1.0] systems.

Cilj ove doktorske disertacije bio je razvoj sintetičke metodologije za dobijanje funkcionalizovanih bicikličnih ketona čijom daljom transformacijom bi bilo moguće sintetisati prirodne proizvode korialstonin i korialstonidin. Sintezu pomenutih ketona moguće je ostvariti intramolekulskom Heck-ovom reakcijom vinil-halogenida i alil-alkoholne grupe odgovarajućeg polifunkcionalizovanog ciklopentenskog derivata. Kako bi dobili uvid u faktore koji kontrolišu regioselektivnost procesa, intramolekulsku Heck-ovu reakciju najpre smo proučavali na model sistemu čijom ciklizacijom može nastati biciklični keton (azabiciklo[4.2.1]nonan). U zavisnosti od načina ciklizacije koji u odnosu na alilnu alkoholnu funkcionalnu grupu može biti egzo i endo, postoji mogućnost dobijanja regioizomernih proizvoda. Tokom ovih istraživanja utvrdjeno je da priroda grupa koje su vezane za ciklopentenov prsten (etarska ili alkoholna) utiču na regioselektivnost ciklizacije, pri čemu je moguće dobiti strukturno različite proizvode pod istim uslovima. Ciklični alilni alkoholi koji imaju zaštićenu -OH grupu u obliku etra ciklizovani su na egzo-način. Nezaštićena alkoholna grupa vodi nastanku endo-proizvoda ciklizacije tj. bicikličnog ketona. Proučavani su faktori koji usmeravaju ovaj korak sa ciljem razvoja metodologije koja omogućava kontrolisanu sintezu bicikličnih derivata. Razvijeni sintetički pristup primenjen je na odgovarajući cis-ciklizacioni prekursor sa alilalkoholnom grupom u cilju sinteze bicikličnog skeleta (azabiciklo[3.2.1]oktanon) prirodnih proizvoda korialstonina i korialstonidina. Proučavanjem reakcionog puta utvrđeno je da se ciklizacija odvijala na endo-način pri čemu su dobijena tri proizvoda u relativno dobrom prinosu. Ovom ciklizacijom očekivani proizvod nije dobijen. Iz tog razloga ciklični alilni alkohol je podvrgnut oksidaciji, a potom ciklizaciji pod reduktivnim Heck-ovim uslovima. Kao jedan od proizvoda ove ciklizacije dobijen je biciklični keton koji ima azabiciklo[3.2.1]oktanski skelet. U drugom delu istraživanja razvijen je sintetički pristup policikličnim derivatima indola koji imaju N-vinilnu grupu. Proučavane su reakcije uvođenja vinilne grupe na azotov atom indolnog prstena, kao i mogućnost anelacije dobijenih derivata reakcijom RCM... The aim of this doctoral thesis was the development of synthetic methodologies for the preparation of functionalised bicyclo ketones whose further transformation would enable the synthesis of natural product: corialstonidine and corialstonine. These ketones could be synthesized by an intramolecular Heck reaction of a vinyl halogenide and an allyl alcohol moiety of an appropriate polyfunctionalised cyclopentene derivative. To get insight into the elements controlling the regioselectivity the intramolecular Heck reaction was first examined on a model system whose cyclization results in the bicyclo[4.2.1]nonanon skeleton. Depending on the mode of cyclization, which in relation to the allyl alcohol functional groups can be exo and endo, regioisomeric products may be obtained. During this research it was found that the nature of substituents of the cyclopentene ring (ether or alcohol moieties) affects the regioselectivity of the cyclization, leading to different structural products under the same conditions. Cyclic allylic alcohols that have a protected OH group in the form of ether are cyclized in the exo manner. The unprotected alcohol group generates endo cyclization products i.e. bicyclic ketones, whose structure is the basis for the skeletons of corialstonidine and corialstonine. Factors that direct this step were studied with the aim of developing a methodology that would allow the controlled synthesis of bicyclic derivatives. The developed synthetic approach was applied to a corresponding cyclic allylic alcohol to synthesise azabicyclo[3.2.1]octane, a key intermediate in the synthesis of natural products corialstonidine and corialstonine. The study of the reaction pathway revealed that the cyclization is carried out in the endo manner giving three products in relatively good yield. The expected product was not obtained. For this reason, the cyclic allylic alcohol was oxidized, and then subjected to cyclization under reductive Heck conditions. One of the products of this cyclization was a bicyclic keton, possessing the azabicyclo[3.2.1]octane skeleton. In the second part of the research, a synthetic approach to polycyclic indole derivatives with the N-vinyl group was developed. Methods for introducing vinyl groups on the nitrogen atom of the indole ring were studied, as well as the possibility of annelating the obtained derivatives using RCM...

Photochemical oxa-di-π-methane rearrangement of bicyclo[3.2.1]octanoid scaffolds affords multifunctional, donor-acceptor cyclopropanes. A related photochemical reaction of an iminium ether substrate uncovered an unprecedented aza-di-π-methane rearrangement of a β,γ-unsaturated iminium. Donor-acceptor cyclopropanes have been evaluated as substrates for reactions generating several new chemotypes.

Cilj ove doktorske disertacije bio je razvoj sintetičke metodologije za dobijanjefunkcionalizovanih bicikličnih ketona čijom daljom transformacijom bi bilo moguće sintetisatiprirodne proizvode korialstonin i korialstonidin. Sintezu pomenutih ketona moguće je ostvaritiintramolekulskom Heck-ovom reakcijom vinil-halogenida i alil-alkoholne grupe odgovarajućegpolifunkcionalizovanog ciklopentenskog derivata.Kako bi dobili uvid u faktore koji kontrolišu regioselektivnost procesa, intramolekulskuHeck-ovu reakciju najpre smo proučavali na model sistemu čijom ciklizacijom može nastatibiciklični keton (azabiciklo[4.2.1]nonan). U zavisnosti od načina ciklizacije koji u odnosu naalilnu alkoholnu funkcionalnu grupu može biti egzo i endo, postoji mogućnost dobijanjaregioizomernih proizvoda. Tokom ovih istraživanja utvrdjeno je da priroda grupa koje su vezaneza ciklopentenov prsten (etarska ili alkoholna) utiču na regioselektivnost ciklizacije, pri čemu jemoguće dobiti strukturno različite proizvode pod istim uslovima. Ciklični alilni alkoholi kojiimaju zaštićenu -OH grupu u obliku etra ciklizovani su na egzo-način. Nezaštićena alkoholnagrupa vodi nastanku endo-proizvoda ciklizacije tj. bicikličnog ketona. Proučavani su faktori kojiusmeravaju ovaj korak sa ciljem razvoja metodologije koja omogućava kontrolisanu sintezubicikličnih derivata.Razvijeni sintetički pristup primenjen je na odgovarajući cis-ciklizacioni prekursor sa alilalkoholnomgrupom u cilju sinteze bicikličnog skeleta (azabiciklo[3.2.1]oktanon) prirodnihproizvoda korialstonina i korialstonidina. Proučavanjem reakcionog puta utvrđeno je da seciklizacija odvijala na endo-način pri čemu su dobijena tri proizvoda u relativno dobrom prinosu.Ovom ciklizacijom očekivani proizvod nije dobijen. Iz tog razloga ciklični alilni alkohol jepodvrgnut oksidaciji, a potom ciklizaciji pod reduktivnim Heck-ovim uslovima. Kao jedan odproizvoda ove ciklizacije dobijen je biciklični keton koji ima azabiciklo[3.2.1]oktanski skelet.U drugom delu istraživanja razvijen je sintetički pristup policikličnim derivatima indolakoji imaju N-vinilnu grupu. Proučavane su reakcije uvođenja vinilne grupe na azotov atomindolnog prstena, kao i mogućnost anelacije dobijenih derivata reakcijom RCM... The aim of this doctoral thesis was the development of synthetic methodologies for thepreparation of functionalised bicyclo ketones whose further transformation would enable thesynthesis of natural product: corialstonidine and corialstonine. These ketones could besynthesized by an intramolecular Heck reaction of a vinyl halogenide and an allyl alcohol moietyof an appropriate polyfunctionalised cyclopentene derivative.To get insight into the elements controlling the regioselectivity the intramolecular Heckreaction was first examined on a model system whose cyclization results in thebicyclo[4.2.1]nonanon skeleton. Depending on the mode of cyclization, which in relation to theallyl alcohol functional groups can be exo and endo, regioisomeric products may be obtained.During this research it was found that the nature of substituents of the cyclopentene ring (ether oralcohol moieties) affects the regioselectivity of the cyclization, leading to different structuralproducts under the same conditions. Cyclic allylic alcohols that have a protected OH group in theform of ether are cyclized in the exo manner. The unprotected alcohol group generates endocyclization products i.e. bicyclic ketones, whose structure is the basis for the skeletons ofcorialstonidine and corialstonine. Factors that direct this step were studied with the aim ofdeveloping a methodology that would allow the controlled synthesis of bicyclic derivatives.The developed synthetic approach was applied to a corresponding cyclic allylic alcohol tosynthesise azabicyclo[3.2.1]octane, a key intermediate in the synthesis of natural productscorialstonidine and corialstonine. The study of the reaction pathway revealed that the cyclizationis carried out in the endo manner giving three products in relatively good yield. The expectedproduct was not obtained. For this reason, the cyclic allylic alcohol was oxidized, and thensubjected to cyclization under reductive Heck conditions. One of the products of this cyclizationwas a bicyclic keton, possessing the azabicyclo[3.2.1]octane skeleton.In the second part of the research, a synthetic approach to polycyclic indole derivativeswith the N-vinyl group was developed. Methods for introducing vinyl groups on the nitrogenatom of the indole ring were studied, as well as the possibility of annelating the obtainedderivatives using RCM...

Among the deoxyribozymes catalyzing the ligation of two RNA substrates, 7S11 generates a branched RNA containing a 2',5'-linkage. We have attached the small fluorogenic probe Bimane to the triphosphate terminated RNA substrate and utilized emission intensity and anisotropy to follow structural rearrangements leading to a catalytically active complex upon addition of Mg(2+). Bimane coupled to synthetic oligonucleotides is quenched by nearby guanines via photoinduced electron transfer. The degree of quenching is sensitive to changes in the base pairing of the residues involved and in their distances to the probe. These phenomena permit the characterization of various sequential processes in the assembly and function of 7S11: binding of Mg(2+) to the triphosphate moiety, release of quenching of the probe by the 5'-terminal G residues of R-RNA as they engage in secondary base-pair interactions, local rearrangement into a distinct active conformation, and continuous release of the Bimane-labeled pyrophosphate during the course of reaction at 37°C. It was possible to assign equilibrium and rate constants and structural interpretations to the sequence of conformational transitions and catalysis, information useful for optimizing the design of next generation deoxyribozymes. The fluorescent signatures, thermodynamic equilibria and catalytic function of numerous mutated (base/substituted) molecules were examined. peerReviewed

Because fibroblast filamentous actin (F-actin) influences cutaneous interstitial matrix swelling pressure (5), we investigated whether F-actin in fibroblast-derived synoviocytes influences the hydraulic permeability of the trans-synovial interstitial pathway. The study also tested whether F-actin in fenestrated synovial endothelium contributes to the blood-joint barrier in vivo.The clearance of Evans blue-albumin (EVA) from plasma into the knee joint cavity was determined in joint infused with F-actin disrupting cytochalasin D (1-200 microM), latrunculin B (100 microM) or vehicle in anesthetized rabbits. The hydraulic permeability of the lining was determined as the slope relating net trans-synovial flow Q(s) to intra-articular pressure P(j). Synovium was examined histologically after i.v. Monastral blue to assess endothelial leakiness.EVA permeation in vivo was increased up to 25-fold by cytochalasin (p = 0.0002, ANOVA), with an EC(50) of 23 microM (95% confidence limits 13-43 microM). Washout quickly reversed the increase. Latrunculin had a similar effect. F-actin disruption switched Q(s) from drainage (control) to filtration into the cavity at low P(j) in vivo and raised the conductance Q(s)/dP(j) by 2.13 (p = 0.001, ANOVA). Circulatory arrest abolished these effects. Monastral blue revealed numerous endothelial leaks.F-actin is crucial to the barrier function of fenestrated endothelium in situ. No significant effect of synoviocyte F-actin on matrix permeability was detected.

Electrocyclic ring opening of 4,6-fused cyclobutenamides 1 under thermal conditions leads to cis,trans-cyclooctadienones 2-E,E as transient intermediates, en route to 5,5-bicyclic products 3. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving cis,trans-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones.

Polyhetero-bicyclo compounds were synthesized by a regioselective [3+2]-cycloaddition reaction between stable condensed oxaziridines and alkenes, alkynes, and nitriles. These molecules showed considerable antimicrobial activity against several gram-positive bacteria.

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclinical model of schizophrenia (prepulse inhibition).

Objective To evaluate PIK3CA mutational status and c-erbB2 gene amplification in a series of primary uterine serous carcinomas (USC) cell lines. To assess the efficacy of GDC-0980, a potent inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2), against primary USC harboring HER2/neu gene amplification and/or PIK3CA mutations. Study Design Twenty-two primary USC cell lines were evaluated for c-erbB2 oncogene amplification by fluorescence in situ hybridization (FISH) assays and for PIK3CA gene mutations by direct DNA sequencing of exons 9 and 20. In vitro sensitivity to GDC-0980 was evaluated by flow-cytometry-based viability and proliferation assays. Downstream cellular responses to GDC-0980 were assessed by measuring phosphorylation of the 4-EBP1 protein by flow-cytometry. Results Five of 22 (22.7%) USC cell lines contained oncogenic PIK3CA mutations although 9 (40.9%) harbored c-erbB2 gene amplification by FISH. GDC-0980 caused a strong differential growth inhibition in FISH+ USC when compared with FISH− (GDC-0980 IC 50 mean ± SEM = 0.29 ± 0.05 μM in FISH+ vs 1.09 ± 0.20 μM in FISH− tumors, P = .02). FISH+ USC harboring PIK3CA mutations were significantly more sensitive to GDC-0980 exposure when compared with USC cell lines harboring wild-type PIK3CA ( P = .03). GDC-0980 growth-inhibition was associated with a significant and dose-dependent decline in phosphorylated 4-EBP1 levels. Conclusion Oncogenic PIK3CA mutations and c-erbB2 gene amplification may represent biomarkers to identify patients harboring USC who may benefit most from the use of GDC-0980.

Recent studies have suggested that the reaction of stabilised Criegee Intermediates (CIs) with sulfur dioxide (SO(2)), leading to the formation of a carbonyl compound and sulfur trioxide, is a relevant atmospheric source of sulfuric acid. Here, the significance of this pathway has been examined by studying the formation of gas phase products and aerosol during the ozonolysis of β-pinene and 2-butene in the presence of SO(2) in the pressure range of 10 to 1000 mbar. For β-pinene at atmospheric pressure, the addition of SO(2) suppresses the formation of the secondary ozonide and leads to highly increased nopinone yields. A complete consumption of SO(2) is observed at initial SO(2) concentrations below the yield of stabilised CIs. In experiments using 2-butene a significant consumption of SO(2) and additional formation of acetaldehyde are observed at 1 bar. A consistent kinetic simulation of the experimental findings is possible when a fast CI + SO(2) reaction rate in the range of recent direct measurements [Welz et al., Science, 2012, 335, 204] is used. For 2-butene the addition of SO(2) drastically increases the observed aerosol yields at higher pressures. Below 60 mbar the SO(2) oxidation induced particle formation becomes inefficient pointing to the critical role of collisional stabilisation for sulfuric acid controlled nucleation at low pressures. peerReviewed

A general strategy is developed for the stereoselective synthesis of C-substituted morpholine derivatives using intramolecular reductive etherification reaction. The method is extended to the first stereoselective total synthesis of (�)-chelonin C. � 2011 American Chemical Society.

The gas-phase ozonolysis of cyclic-alkenes (1-methyl-cyclohexene, methylene-cyclohexane, α-pinene, β-pinene) is studied with respect to the pressure dependent formation of secondary organic aerosol (SOA). We find that SOA formation is substantially suppressed at lower pressures for all alkenes under study. The suppression coincides with the formation of ketene (α-pinene, 1-methyl-cyclohexene), ethene (1-methyl-cyclohexene) and the increased formation of CO (all alkenes) at lower reaction pressures. The formation of these products is independent of the presence of an OH scavenger and explained by an increased chemical activation of intermediate species in the hydroperoxide channel after the OH elimination. These findings underline the central role of the hydroperoxide pathway for SOA formation and give insight into the gas-phase ozonolysis mechanism after the stage of the Criegee intermediate chemistry. peerReviewed

An automated, silicon-based microreactor system has been developed for rapid, low-volume, multidimensional reaction screening. Use of the microfluidic platform to identify transformations of densely functionalized bicyclo[3.2.1]octanoid scaffolds will be described.

Background The honeybee has to detect, process and learn numerous complex odours from her natural environment on a daily basis. Most of these odours are floral scents, which are mixtures of dozens of different odorants. To date, it is still unclear how the bee brain unravels the complex information contained in scent mixtures. Methodology/Principal Findings This study investigates learning of complex odour mixtures in honeybees using a simple olfactory conditioning procedure, the Proboscis-Extension-Reflex (PER) paradigm. Restrained honeybees were trained to three scent mixtures composed of 14 floral odorants each, and then tested with the individual odorants of each mixture. Bees did not respond to all odorants of a mixture equally: They responded well to a selection of key odorants, which were unique for each of the three scent mixtures. Bees showed less or very little response to the other odorants of the mixtures. The bees' response to mixtures composed of only the key odorants was as good as to the original mixtures of 14 odorants. A mixture composed of the other, non-key-odorants elicited a significantly lower response. Neither an odorant's volatility or molecular structure, nor learning efficiencies for individual odorants affected whether an odorant became a key odorant for a particular mixture. Odorant concentration had a positive effect, with odorants at high concentration likely to become key odorants. Conclusions/Significance Our study suggests that the brain processes complex scent mixtures by predominantly learning information from selected key odorants. Our observations on key odorant learning lend significant support to previous work on olfactory learning and mixture processing in honeybees.

symmetricaland display excellent reaction kinetics in strain-promotedcycloaddition reactions. Functionalized derivatives of BCNwere applied in the labeling of proteins and glycans, as well asin the three-dimensional visualization of living melanomacells.Based on the known reactivity enhancement of cyclo-propane fusion

Bisiklik terpenler doğal madde olmalarının yanı sıra organik kimyada da önemli bileşik sentezlerinde kullanlmaktadır. Bu bileşikler özellikle biyolojik aktif madde sentezi ve boyar maddeler gibi yaygın kullanıma sahiptir. Özellikle ?-pinenin sentezi ile ilgili güncel çalışmalar devam etmektedir. Ticari öneme sahip ?-pinen türevlerinin etkili yollarla yapılan sentez çalışmaları gittikçe önem kazanmaktadır. ?-Pinen bileşiği, tat ve koku monoterpenoidlerinin üretimi için substrat olarak kullanılan doğal bir monoterpendir. ?-Pinenin asit katalizli hidrasyonu ve asetillenmesi parfüm ve farmasöptik endüstride uygulanabilir değerli terpenik alkoller ve esterlerin önemli sentez yollarındandır.?-Pinen bileşiği üzerine literatür çalışmalarında düzenlenme ürünlerinin oldukça büyük miktarlarda oluştuğu görülmektedir. Çalışmamız da ?-pinen bileşiğinin türevlendirilmesi için etkin ve seçici bir yöntemle brominasyonunu hedeflendi. Farklı parametreler sonucunda düzenlenme ürünleri yanı sıra normal katılma ürünleri de elde edildi. Bu sentez yöntemi ile elde edilen bileşiklerin ileride yapılacak çalışmalara ışık tutması beklenmektedir.Anahtar kelimeler: Fotobrominasyon, ?-pinen, bisiklik monoterpenler, Wagner-Meervein düzenlenmesi Bisyclic terpenes are the natural substances and they are used in organic chemistry for synthesis of important compound. Especially like biological active-substance synthese and like colorants the bisyclic terpenes have a common usage. Especially the current studies about ?-pinene have been going on. The synthese performances which belong to ?-pinene-derivatives, that have a commercial importance, have been gaining importance. The compound of ?-pinene is a natural monoterpene which is used as a substrate for the production of flavour and flavor- monoterpenoids. The hydration and the asetoxylation of ?-pinene with the acid catalysis are the important ways for the synthesis of the terpenic alcohols and esters, which can be used in the perfume industry and pharrmasoptik industry.It can be seen that the arrangement productions about the literature workings on the compound of ?-pinene , are widely formed. In our work, we aimed the bromination with an effective and selective method for the derivation of ?-pinene-compound. After the different parameters applied the arrangement products and also normalcontribution productions. It is hoped that compounds obtained this method will trigger some future works.Key Words: Photobromination, ?-pinene, bisyclic monoterpenes, Wagner-Meervein rearrangement 93

Two series of bicyclic oxime ethers viz, 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one O-benzyloximes 13-24 and 2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1]nonan-9-one O-benzyloximes 31-36 were synthesized and stereochemistry was established by their spectral (1D and 2D NMR) and crystal studies. Synthesized oxime ethers were screened for their in vitro antimicrobial activity against a set of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, Escherichia coli and Klebsiella pneumoniae) and fungi (Candida albicans, Candida-51, Rhizopus sp., Aspergillus niger and Aspergillus flavus) by twofold serial dilution method, respectively, using Ciprofloxacin and Amphotericin B as standards. Most of the molecules expressed promising antimicrobial profile against the tested pathogens and even a few compounds 16, 21, 22, 33 and 34 were better than standard drugs. � 2009 Elsevier Ltd. All rights reserved.

Accessory β-subunits modulate the pharmacology of ion channel blockers. The aim was to investigate differences in effects of the antiarrhythmic agent and open-channel blocker tedisamil on transient outward current I to (Kv4.3) when coexpressed with β-subunits potassium voltage-gated channel, Isk-related family, member 1 (KCNE1), potassium voltage-gated channel, Isk-related family, member 2 (KCNE2), or dipeptidyl-aminopeptidase-like protein 6 (DPP6) which modulate I to kinetics. Tedisamil inhibited I to with IC50 values of 16 μM for Kv4.3+KChIP2, 11 μM in the presence of KCNE1, and 14 μM for KCNE2. Values were higher in the presence of DPP6 or DPP6+KCNE2 (35 and 26 μM). K d values of tedisamil binding and rate constants were not affected by KCNE or DPP6. I to kinetics were accelerated by KCNE and DPP6, inactivation to a larger extent with DPP6. Tedisamil did not affect activation time course but apparently accelerated inactivation in all channel subunit combinations tested. Deletion of the intracellular domain of KCNE2 or DPP6 resulted in slowing of kinetics and increased tedisamil sensitivity (IC50 4 and 7 μM). It is concluded that apparent effects of DPP6 and deletion mutants (KCNE2 and DPP6) are due to the acceleration or slowing effects of the β-subunits on I to kinetics.

An altered glutamatergic input at corticostriatal synapses has been shown in experimental models of Parkinson's disease (PD). In the present work, we analyzed the membrane and synaptic responses of striatal neurons to metabotropic glutamate (mGlu) receptor activation in two different mouse models of inherited PD, linked to mutations in PINK1 or Parkin genes. Both in PINK1 and Parkin knockout ((-/-)) mice, activation of group I mGlu receptors by 3,5-DHPG caused a membrane depolarization coupled to an increase in firing frequency in striatal cholinergic interneurons that was comparable to the response observed in the respective wild-type (WT) interneurons. The sensitivity to group II and III mGlu receptors was tested on cortically-evoked excitatory postsynaptic potentials (EPSPs) recorded from medium spiny neurons (MSNs). Both LY379268 and L-AP4, agonists for group II and III, respectively, had no effect on intrinsic membrane properties, but dose-dependently reduced the amplitude of corticostriatal EPSPs. However, both in PINK1(-/-) and Parkin(-/-) mice, LY379268, but not L-AP4, exhibited a greater potency as compared to WT in depressing EPSP amplitude. Accordingly, the dose-response curve for the response to LY379268 in both knockout mice was shifted leftward. Moreover, consistent with a presynaptic site of action, both LY379268 and L-AP4 increased the paired-pulse ratio either in PINK1(-/-) and Parkin(-/-) or in WT mice. Acute pretreatment with L-dopa did not rescue the enhanced sensitivity to LY379268. Together, these results suggest that the selective increase in sensitivity of striatal group II mGlu receptors represents an adaptive change in mice in which an altered dopamine metabolism has been documented.

A novel and general method has been developed for the stereoselective construction of 5-hydroxymethyl azabicyclic ring skeletons based on epoxide-initiated cationic cyclization of azides. The key cyclization reaction was systematically studied with the model compound, 3-(1-oxa-spiro[2.4]hept-4-yl)propyl azide 3a, and EtAlCl 2 was found to be an ideal choice as the catalyst. The generality of this transformation was further tested with different ring sizes, where six- and seven-membered epoxyazides 3b,c underwent smooth cyclization to give 5-hydroxymethyl azepine 4b and 5-hydroxymethyl azocine 4c, respectively, as a single detectable diastereomer. This novel methodology was elegantly applied in the stereoselective total synthesis of indolizidine alkaloids 167B and 209D. Further, the enantioselective total synthesis of natural and unnatural indolizidine alkaloids 167B and 209D was accomplished by using Sharpless asymmetric dihydroxylation as a key step.

Chronic and acute exposure to organophosphate (OP) pesticides may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. It is suggested that other brain proteins are involved. Effects of commonly used organophosphate pesticides on rat neuronal α4β2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. Several OP pesticides, e.g., parathion-ethyl, chlorpyrifos and disulfoton, inhibited the ACh-induced ion current with potencies in the micromolar range. The potency of inhibition increased with increasing concentrations of the agonist ACh. Comparison of the potency of nAChR inhibition with the potency of AChE inhibition demonstrated that some OPs inhibit nAChRs more potently than AChE. Binding experiments on α 4β2 nAChRs showed that the OPs noncompetitively interact with nAChRs. The inhibitory effects on nAChRs are adequately described and explained by a sequential two-step mechanism, in which rapidly reversible OP binding to a separate binding site leads to inhibition followed by a stabilization of the blocked state or receptor desensitization. It is concluded that OPs interact directly with neuronal α4β2 nAChRs to inhibit the agonist-induced response. This implicates that neuronal α4β2 nAChRs are additional targets for some OP pesticides. © Society of Toxicology 2004; all rights reserved. Chemicals / CAS: chlorpyrifos, 2921-88-2; dipeptidyl carboxypeptidase, 9015-82-1; disulfoton, 298-04-4; parathion, 3270-86-8, 56-38-2, 597-88-6; Bicyclo Compounds, Heterocyclic; Cholinesterase Inhibitors; epibatidine, 140111-52-0; Insecticides; Ligands; Nicotinic Agonists; Nicotinic Antagonists; Organophosphorus Compounds; Pyridines; Receptors, Nicotinic

We have recently discovered bicyclic furopyrimidines as potent and selective inhibitors of VZV. In order to investigate the structural requirements for antiviral activity we have succesfully synthesised some 3′-chloro and 5′-chloro derivatives. The compounds have been tested against VZV and CMV, but displayed no significant in vitro activity.

Bazı bisiklik endoperoksit bileşiklerinin (1, 2...) yapıları, proton ve karbon iti çekirdeklerinin spin-örgü rölaksasyon zamanları ve C- H etkileşme sabitleri spektral yöntemlerle incelendi. Bileşiklerin yapıları İD ve 2D NMR spektroskopisi ile belirlenirken, proton ve karbon çekirdeklerinin spin-örgü rölaksasyon zamanları inversion-recovery yöntemi kullanılarak ölçüldü. Bileşiklerin karbon ve proton arasındaki etkileşme sabitleri (Jch) aralıklı geniş bantlı ışınlandırma (gated decoupling) yöntemi ile belirlenerek, hibrit orbitallerindeki s orbitalinin oranı tesbit edildi. 30 J o 4 ^78 e``` ı 7 1 T^ 1 POH i/^ /L OOH OCOCH3 H,COv O H3CO 8 COOEt 11 SUMMARY n i The spin-lattice relaxation times Ti of individual nuclei C, H and C-H coupling constants (Jch) of the bicyclo-endoperoxide compounds (1, 2...) were studied by 1-1 1 spectral methods. The spin-lattice relaxation times Ti of individual nuclei C, H was measured by inversion-recovery method while the structures of the compounds were obtained by ID and 2D NMR spectroscopy. C-H coupling constants (Jch) were achieved by means of gated-decoupling method and relative of the s orbital which exists in the hybrid orbital was also assigned with C-H coupling constants. 30 / 7L 4 ^78 6 1 ^7 1 v. / L OH POH r /L OOH,/ >/ 0,CH3 /L // HoCO. O H3CO 8 COOEt 184

1. The relation between changes in the cerebral cortical concentration of allopregnanolone and gamma-aminobutyric acid (GABA) type A receptor function after intracerebroventricular injection of this neurosteroid was investigated in male rats. 2. Intracerebroventricular administration of allopregnanolone (1.25 to 15 micrograms) produced a maximal increase (100 fold at the highest dose) in cortical allopregnanolone concentration within 5 min; the concentration remained significantly increased at 15 and 30 min, before returning to control values by 60 min. 3. The same treatment induced a rapid and dose-dependent decrease in the binding of t-[35S]-butylbicyclophosphorothionate ([35S]-TBPS) to cerebral cortical membranes measured ex vivo, an effect mimicked by the benzodiazepine midazolam but not by the 3 beta-hydroxyepimer of allopregnanolone. The time course of changes in [35S]-TBPS binding paralleled that of brain allopregnanolone concentration. 4. In a dose-dependent manner, allopregnanolone both delayed the onset of convulsions and inhibited the increase in [35S]-TBPS binding to cortical membranes induced by isoniazid. The potency of allopregnanolone in inhibiting [35S]-TBPS binding in isoniazid-treated rats was approximately four times that in control animals. 5. The ability of allopregnanolone to decrease [35S]-TBPS binding in isoniazid-treated rats also correlated with its anticonvulsant activity against pentylenetetrazol-induced seizures as well as its inhibitory effect on the increase in [35S]-TBPS binding induced by foot shock. 6. The results indicate that the in vivo administration of allopregnanolone enhances the function of GABAA receptors in rat cerebral cortex and antagonizes the inhibitory action of stress and drugs that reduce GABAergic transmission.

Poisons are common in nature, where they often serve the organism in chemical defense. Such poisons either are produced de novo or are sequestered from dietary sources or symbiotic organisms. Among vertebrates, amphibians are notable for the wide range of noxious agents that are contained in granular skin glands. These compounds include amines, peptides, proteins, steroids, and both water-soluble and lipid-soluble alkaloids. With the exception of the alkaloids, most seem to be produced de novo by the amphibian. The skin of amphibians contains many structural classes of alkaloids previously unknown in nature. These include the batrachotoxins, which have recently been discovered to also occur in skin and feathers of a bird, the histrionicotoxins, the gephyrotoxins, the decahydroquinolines, the pumiliotoxins and homopumiliotoxins, epibatidine, and the samandarines. Some amphibian skin alkaloids are clearly sequestered from the diet, which consists mainly of small arthropods. These include pyrrolizidine and indolizidine alkaloids from ants, tricyclic coccinellines from beetles, and pyrrolizidine oximes, presumably from millipedes. The sources of other alkaloids in amphibian skin, including the batrachotoxins, the decahydroquinolines, the histrionicotoxins, the pumiliotoxins, and epibatidine, are unknown. While it is possible that these are produced de novo or by symbiotic microorganisms, it appears more likely that they are sequestered by the amphibians from as yet unknown dietary sources.

1. The effects of single doses of a novel 5-HT3 receptor antagonist, BRL 46470A (0.1 microgram, 0.01 mg, 1 mg or 50 mg) and lorazepam (2.5 mg) on psychometric performance and the EEG were investigated in a randomised, double-blind, crossover, placebo controlled study of 16 healthy male volunteers. 2. There was strong evidence that lorazepam had a marked effect on the EEG, increasing power in the 1 Hz to 7 Hz and 13 Hz to 20 Hz wavebands, whilst reducing power in the 8 Hz to 12 Hz waveband. Lorazepam also produced an impairment of daytime function as assessed by psychometric performance and subjective measures. 3. In contrast, there was little evidence to suggest that BRL 46470A had any effect on the EEG or that it impaired daytime function.

I- ÖZET Karbenler oldukça aktif ara ürünlerdir. Karbenlerin bu aktif özelliklerinden yararlanarak sikloalkenlerden bisiklo bileşikler oluşturulmaya çalışılmıştır. Daha sonraki basamakta ise oluşturulan bisiklo bileşiklerin arasındaki köprü kırılarak halka genişletilmeye çalışılmıştır. Yapılan deneysel çalışmalarda bisiklo bileşikler oluşturmak için siklopenten, siklohekzen, siklohepten, siklookten ve siklododesen seçilmiştir. Bu bileşiklerin bromoform ve potasyum tertbutoksit ile reaksiyonundan elde edilen bisiklo bileşikleri ayrı ayrı saflaştırılmıştır. Tüm bileşiklerin I.R. ve N.M.R. spektrumları alınarak karşılaştırmalı olarak incelenmiştir. Spektroskopik çalışmalardan amaçlanan ürünlerin oluştuğuna emin olduktan sonra deneylerin ikinci kısmına geçilmiştir. Deneyin ikinci kısmında elde edilen bisiklo bileşiklerini açmak için baz olarak önce dietil amin kullanılmıştır. Daha sonraki çalışmalarda ise dietil amin yerine trietil amin kullanılmış her iki bazın etkisi değişik sıcaklıklarda denenmiş ve her elde edilen ürün saflaştırıldıktan sonra hem T.L.C. leri kontrol edilmiş hem de I.R. spektrumları alınmıştır. Bu çalışmalarda amaçlanan halka genişleme reaksiyonlarının olmadığı görülmüştür. Bu nedenle baz kullanımından-11- vazgeçilerek AgNOs ile halka genişletilmeye çalışılmıştır. Ayrı ayrı kaplarda bisiklo bileşikleri metanol ve su karışımında gümüş nitrat ile çalkalanmış, ürünler saflaştırılarak I.R. spektrumları alınmış ve incelenmiştir. Ayrıca yapılan literatür çalışmaları da bisiklo bileşiklerinin bu tür reaksiyonlara yatkın olduğunu göstermektedir. Bu çalışmanın devam etmesi ileride daha kompleks bileşiklerin elde edilmesine basamak oluşturacaktır. -Ill- SUMMARY Carbenes are very active intermediates. Using their active properties, bicyclo compounds were tried to be made from cycloalkens. In the next step by breaking the bridged bond the ring was tried to be largened. For the experimental work, cyclopenten, cyclo- hexen, cyclohepten, cyclookten and cyclododecen were selec ted to obtain bicyclo compounds. Bicyclo compounds which were obtained from the reaction of these cycloalkenes with bromoform and potossium tert- butoxide were purified. I.R. and N.M.R. spectrums were taken and they were examined carefully for all the compounds. After being sure that all products were correct, we started second part of the expe riment. In the second part of experiment firstly diethyl amin was used as a base to open bicyclo compounds. At the later stages, instead of diethyl amin.tri- ethyl amin was used and effects of them was tested at vari ous temperatures for each bicyclo compounds which was puri fied and cheched with T.L.C. and I.R. In these experiments non of the aimed ring enlargement reaction was observed. As a result AgN03 has been used instead of bases for ring enlargement. Bicyclo compounds were stirred with a.IV- solution of AgNÛ3 in a mixture of water and methanol, pro ducts of these reactions were purified, I.R. spectrum were taken and compared with starting compounds. Moreover, literature search showed that bicyclo compounds tend to give this kind of reactions. The continuation of this research will be a step to obtain more complex compounds in the future. 59