PtCl₂-Catalyzed Rearrangement of Methylenecyclopropanes

Alkylidenecyclopropanes readily convert into cyclobutene derivatives on treatment with catalytic amounts of PtCl2. The reaction is strongly accelerated when performed under an atmosphere of CO (1 atm). The resulting cyclobutenes are isolated in good to excellent yields for substrates bearing aliphatic as well as aromatic substituents R on their olefinic site. If the substituent R, however, is a very electron-rich arene, the cyclobutenes initially formed react further to give dimeric products with a previously unknown 1,2,2a,7a-tetrahydrospiro[cyclobuta[a]indene-7,1‘-cyclobutane skeleton. A mechanism accounting for these experimental observations as well as for a deuterium-labeling experiment is proposed which implies reactive intermediates at the nonclassical cation/carbene interface. Furthermore it is shown that the PtCl2-catalyzed cyclobutene formation can be geared with subsequent ring-opening/ring-closing metathesis (ROM/RCM) events. Finally, a convenient “one pot” method for the preparation of the alkylidenecyclopropane substrates used in this study is presented, which is based on a modified Julia−Kocienski olefination of aldehydes with readily available 1-tert-butyl-1H-tetrazol-5-yl-cyclopropyl sulfone under Barbier conditions

A Rhodium-Catalyzed C−H Activation/Cycloisomerization Tandem

A reaction cascade comprising a rhodium-catalyzed C−H activation, a subsequent hydrometalation of an alkylidene cyclopropane in vicinity, regioselective C−C bond activation of the flanking cyclopropane ring, followed by reductive elimination of the resulting metallacycle, opens a new entry into functionalized cycloheptene derivatives. This crossover of C−H activation and higher order cycloaddition has been performed in two different formats, either using alkylidenecyclopropanes with a lateral vinylpyridine moiety or with a pending aldehyde group as the trigger. The reaction tolerates various functional groups, leaves chiral centers α to the reacting sites unaffected, and proceeds with excellent stereoselectivity. Labeling experiments support the proposed mechanism explaining the observed net cycloisomerization process

Exact performance analysis of dual-hop semi-blind AF relaying over arbitrary nakagami-m fading channels

Relay transmission is promising for future wireless systems due to its significant cooperative diversity gain. The performance of dual-hop semi-blind amplify-and-forward (AF) relaying systems was extensively investigated, for transmissions over Rayleigh fading channels or Nakagami-m fading channels with integer fading parameter. For the general Nakagami-m fading with arbitrary m values, the exact closed-form system performance analysis is more challenging. In this paper, we explicitly derive the moment generation function (MGF), probability density function (PDF) and moments of the end-to-end signal-to-noise ratio (SNR) over arbitrary Nakagami-m fading channels with semi-blind AF relay. With these results, the system performance evaluation in terms of outage probability, average symbol error probability, ergodic capacity and diversity order, is conducted. The analysis developed in this paper applies to any semi-blind AF relaying systems with fixed relay gain, and two major strategies for computing the relay gain are compared in terms of system performance. All analytical results are corroborated by simulation results and they are shown to be efficient tools to evaluate system performance. © 2011 IEEE.published_or_final_versio

Activation of the hsp70 promoter by environmental inorganic and organic chemicals: relationships with cytotoxicity and lipophilicity.

International audienceStress proteins (heat shock proteins, HSPs) have been proposed as general markers of cellular aggression and their use for environmental monitoring is often suggested. The aim of this work was to study the potency of various environmentally relevant organic and inorganic chemicals to induce the expression of the HSP70 marker. For this purpose, we used an established HeLa cell line containing the chloramphenicol acetyl transferase (CAT) gene under the control of the hsp70 promoter. The screening of three metallic and 15 organic chemicals revealed differences in their capacities to induce the hsp70 promoter. The three metals tested (cadmium, zinc and mercury) were able to induce a stress response. Some organochlorine compounds (chlorophenol derivatives, tetrachlorohydroquinone, 3, 4-dichloroaniline, ethyl parathion and 1-chloro-2,4-dinitrobenzene) induced a response, whereas other common halogenated pesticides or aromatic hydrocarbons (e.g. benzo(a)pyrene, 2, 4-dichlorophenoxyacetic acid, endosulfan, diuron, 4-nonylphenol) did not. The potency to induce hsp70 was significantly correlated to the octanol-water partition coefficient (log K(ow)) of the inducing chemicals, except for 1-chloro-2,4-dinitrobenzene and ethyl parathion. Cytotoxicity assays run in parallel to the induction measurements revealed that the three metals were effective at non cytotoxic doses whereas all organic compounds, except tetrachlorohydroquinone and 1-chloro-2,4-dinitrobenzene, induced the promoter at cytotoxic doses. These results suggest that hsp70 is induced by different mechanisms of toxicity. We propose that this model can be used in mechanistic studies for the detection of toxic effects of certain pollutants

Effects of human pharmaceuticals on cytotoxicity, EROD activity and ROS production in fish hepatocytes.

Pharmaceuticals are found in the aquatic environment but their potential effects on non-target species like fish remain unknown. This in vitro study is a first approach in the toxicity assessment of human drugs on fish. Nine pharmaceuticals were tested on two fish hepatocyte models: primary cultures of rainbow trout hepatocytes (PRTH) and PLHC-1 fish cell line. Cell viability, interaction with cytochrome P450 1A (CYP1A) enzyme and oxidative stress were assessed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrasodium bromide tetrazolium (MTT), 7-ethoxyresorufin-o-deethylase (EROD) and dichlorofluorescein (DCFH-DA) assays, respectively. The tested drugs were clofibrate (CF), fenofibrate (FF), carbamazepine (CBZ), fluoxetine (FX), diclofenac (DiCF), propranolol (POH), sulfamethoxazole (SFX), amoxicillin (AMX) and gadolinium chloride (GdCl(3)). All substances were cytotoxic, except AMX at concentration up to 500 microM. The calculated MTT EC(50) values ranged from 2 microM (CF) to 651 microM (CBZ) in PLHC-1, and from 53 microM (FF) to 962 microM (GdCl(3)) in PRTH. CF, FF, and FX were the most cytotoxic drugs and induced oxidative stress before being cytotoxic. Compared to hepatocytes from human and dog, fish hepatocytes seemed to be more susceptible to the peroxisome proliferators (PPs) CF and FF. In PLHC-1 cells none of the tested drugs induced the EROD activity whereas POH appeared as a weak EROD inducer in PRTH. Moreover, in PRTH, SFX, DiCF, CBZ and to a lesser extend, FF and CF inhibited the basal EROD activity at clearly sublethal concentrations which may be of concern at the biological and chemical levels in a multipollution context

Integration of Dirac-Jacobi structures

We study precontact groupoids whose infinitesimal counterparts are Dirac-Jacobi structures. These geometric objects generalize contact groupoids. We also explain the relationship between precontact groupoids and homogeneous presymplectic groupoids. Finally, we present some examples of precontact groupoids.Comment: 10 pages. Brief changes in the introduction. References update

Total Synthesis of Iejimalide A-D and Assessment of the Remarkable Actin-Depolymerizing Capacity of These Polyene Macrolides

A concise and convergent total synthesis of the highly cytotoxic marine natural products iejimalide A−D (1−4) is reported, which relies on an effective ring-closing metathesis (RCM) reaction of a cyclization precursor containing no less than 10 double bonds. Because of the exceptional sensitivity of this polyunsaturated intermediate and its immediate precursors toward acid, base, and even gentle warming, the assembly process hinged upon the judicious choice of protecting groups and the careful optimization of all individual transformations. As a consequence, particularly mild protocols for Stille as well as Suzuki reactions of elaborate coupling partners have been developed that hold considerable promise for applications in other complex settings. Moreover, a series of non-natural “iejimalide-like” compounds has been prepared, differing from the natural lead in the polar head groups linked to the macrolide's N-terminus. With the aid of these compounds it was possible to uncover the hitherto unknown effect of iejimalide and analogues on the actin cytoskeleton. Their capacity to depolymerize this microfilament network rivals that of the latrunculins which constitute the standard in the field. Structural modifications of the peptidic terminus in 2 are thereby well accommodated, without compromising the biological effects. The iejimalides hence constitute an important new class of probe molecules for chemical biology in addition to their role as promising lead structures for the development of novel anticancer agents

Studies on Iejimalide B: Preparation of the Seco Acid and Identification of the Molecule's "Achilles Heel"

Limitations of models in total synthesis are illustrated by a study towards the potent cytotoxic macrolide iejimalide B. Although the Yamaguchi protocol allowed for the esterification of elaborate segments, attempted macrolactonization of the seco acid met with failure (see scheme, Boc= tert-butyloxycarbonyl). The assembly of the seco acid involves some of the most advanced applications of the Julia olefination known to date

Palladium-Catalyzed Synthesis of α-Carbonyl-α′-(hetero)aryl Sulfoxonium Ylides:Scope and Insight into the Mechanism

Despite recent advances, a general method for the synthesis of α-carbonyl-α′-(hetero)aryl sulfoxonium ylides is needed to benefit more greatly from the potential safety advantages offered by these compounds over the parent diazo compounds. Herein, we report the palladium-catalyzed cross-coupling of aryl bromides and triflates with α-carbonyl sulfoxonium ylides. We also report the use of this method for the modification of an active pharmaceutical ingredient and for the synthesis of a key precursor of antagonists of the neurokinin-1 receptor. In addition, the mechanism of the reaction was inferred from several observations. Thus, the oxidative addition complex [(XPhos)PhPdBr] and its dimer were observed by 31P{1H} NMR, and these complexes were shown to be catalytically and kinetically competent. Moreover, a complex resulting from the transmetalation of [(XPhos)ArPdBr] (Ar = p-CF3–C6H4) with a model sulfoxonium ylide was observed by mass spectrometry. Finally, the partial rate law suggests that the transmetalation and the subsequent deprotonation are rate-determining in the catalytic cycle

Anti-androgens act jointly in suppressing spiggin concentrations in androgen-primed female three-spined sticklebacks - Prediction of combined effects by concentration addition

This is the post-print version of the final paper published in Aquatic Toxicology. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2013 Elsevier B.V.Increasing attention is being directed at the role played by anti-androgenic chemicals in endocrine disruption of wildlife within the aquatic environment. The co-occurrence of multiple contaminants with anti-androgenic activity highlights a need for the predictive assessment of combined effects, but information about anti-androgen mixture effects on wildlife is lacking. This study evaluated the suitability of the androgenised female stickleback screen (AFSS), in which inhibition of androgen-induced spiggin production provides a quantitative assessment of anti-androgenic activity, for predicting the effect of a four component mixture of anti-androgens. The anti-androgenic activity of four known anti-androgens (vinclozolin, fenitrothion, flutamide, linuron) was evaluated from individual concentration-response data and used to design a mixture containing each chemical at equipotent concentrations. Across a 100-fold concentration range, a concentration addition approach was used to predict the response of fish to the mixture. Two studies were conducted independently at each of two laboratories. By using a novel method to adjust for differences between nominal and measured concentrations, good agreement was obtained between the actual outcome of the mixture exposure and the predicted outcome. This demonstrated for the first time that androgen receptor antagonists act in concert in an additive fashion in fish and that existing mixture methodology is effective in predicting the outcome, based on concentration-response data for individual chemicals. The sensitivity range of the AFSS assay lies within the range of anti-androgenicity reported in rivers across many locations internationally. The approach taken in our study lays the foundations for understanding how androgen receptor antagonists work together in fish and is essential in informing risk assessment methods for complex anti-androgenic mixtures in the aquatic environment.European Commission and Natural Environment Research Council