Palladium-Catalyzed Coupling of 3-Halo-Substituted Coumarins, Chromenes, and Quinolones with Various Nitrogen-Containing Nucleophiles

International audienceAn efficient and general palladium‐catalyzed coupling reaction between 3‐bromocoumarins, 3‐bromoquinolin‐2(1H)‐ones, and 3‐iodo‐2H‐chromenes with a variety of nitrogen‐containing nucleophiles (azole, amide, lactam, sulfonamide, aniline, amine, and urea) is described. The reaction proceeded rapidly and cleanly in dioxane providing the coupling products in good to excellent yields. The chemoselectivity of this reaction was also studied with polyhalocoumarins. Under optimized conditions, these underwent a site‐selective amination at the C‐3–Br bond, regardless of the nature of the nitrogen‐containing nucleophile used

Rosaceae, Brassicaceae and pollen beetles: exploring relationships and evolution in an anthophilous beetle lineage (Nitidulidae, Meligethes-complex of genera) using an integrative approach

Background: Meligethes are pollen-beetles associated with flowers of Rosaceae as larvae. This genus currently consists of 63 known species in two subgenera, Meligethes and Odonthogethes, predominantly occurring in the eastern Palaearctic. We analyzed 74 morphological and ecological characters (169 states) of all species, as well as of 11 outgroup species from 7 Meligethinae genera (including Brassicogethes), to investigate their phylogeny. We also conducted a parallel molecular analysis on 9 Meligethes, 9 Odonthogethes, 3 Brassicogethes and 2 Meligethinus species based on DNA sequence data from mitochondrial (COI, 16S) and nuclear (CAD) genes. Results: Morphological phylogenetic reconstructions supported the monophyly of the whole genus and clades corresponding to purported subgenera Meligethes s.str. and Odonthogethes. Main species-groups were mostly confirmed, however some unresolved polytomies remained. Molecular data placed members of Brassicogethes (including 42 mostly W Palearctic species associated with Brassicaceae) as sister to Odonthogethes, with this clade being sister to Meligethes s.str. This phylogenetic scenario suggests that monophyletic Meligethes s.str., Odonthogethes and Brassicogethes should be regarded alternatively as three subgenera of a monophyletic Meligethes, or three genera in a monophyletic genus-complex, with mutually monophyletic Brassicogethes and Odonthogethes. Molecular analyses estimated the origin of this lineage at ca. 14–15 Mya from a common stem including Meligethinus. Conclusions: We hypothesize that the ancestor of Meligethes specialized on Rosaceae in the Middle Miocene (likely in Langhian Age) and subsequently radiated during Late Miocene and Plio-Pleistocene maintaining a trophic niche on this plant family. This radiation was primarily due to geographic isolation in E Asiatic mountain systems. Combined evidence from morphology, ancestral state parsimony reconstruction of host-plant associations and molecular evidence suggested that Rosoideae (Rosa spp.) represented the ancestral hosts of Meligethes s.str., followed by an independent shift of ancestral Odonthogethes (ca. 9–15 Mya) on Rubus (Rosoideae) and members of Rosaceae Spiraeoideae. Other ancestral Odonthogethes probably shifted again on the unrelated plant family Brassicaceae (maybe 8–14 Mya in S China), allowing a rapid westward radiation of the Brassicogethes clade

Relationship between tree-related microhabitats and the captures obtained using different trap methods for large threatened saproxylic beetles

Osmoderma eremita and Cerambyx cerdo are saproxylic beetle species, included in the IUCN Red List and in the EU/92 Habitats Directive. Their occurrence has been recorded, through appropriate traps, in several localities in Italy, including urban and peri-urban parks, mostly associated with veteran trees. In this study, traps were tested over 17 veteran oak trees in the Castelporziano Presidential Estate (Latium, Rome province, central Italy) and the abundance of sampled saproxylic beetles was related to the growing stock volume (GSV) and the abundance of microhabitats. Moreover, we compared three different trapping methods: a trap designed to monitor C. cerdo (CC), and two traps designed for monitoring O. eremita, i.e., the Black Cross Window Trap (BCWT) and the Black Bottle Traps (BBT). We found that larger trees hosted a great variety of microhabitats, in particular cavities, which abundance was correlated with the number of specimens sampled, especially O. eremita species. Both classic traps (i.e., CC traps and BCWT) and the herein-introduced BBT variants were effective for capturing large saproxylic beetles. In this work, we underline the importance of the preservation of veteran trees to the occurrence of threatened saproxylic beetles, and we contributed to (i) extending general knowledge of the habitat preferences of saproxylic beetles and (ii) improving new cost-effective trapping system variants

HSP90 et cancer (synthèse et évaluation biologique d'analogues originaux de la novobiocine)

Les résistances aux traitements actuels contre le cancer incitent à trouver de nouvelles cibles thérapeutiques. Une de ces cibles, la protéine chaperon Hsp90 (Heat Shock Protein) impliquée dans la maturation de protéines clientes oncogènes intervenant dans le cycle cellulaire, se révèle très intéressante car son inhibition induit la dégradation des protéines oncogènes par la voie du protéasome. À ce jour, de nombreux inhibiteurs de la Hsp90 sont rapportés dans la littérature, la plupart d entre eux se lient au site ATPasique N-terminal. La novobiocine, en revanche, inhibe l activité du chaperon en se fixant sur un deuxième site ATPasique, très controversé, situé à niveau de son domaine C-terminal. L objectif de cette thèse a été la synthèse et l évaluation biologique d analogues originaux de la novobiocine. Deux stratégies ont été envisagées : d une part une étude RSA et d autre part une méthode in silico à travers un criblage virtuel.Resistance to current treatments of cancer encourages finding new therapeutical targets. Heat Shock Protein 90 (Hsp90) is a molecular chaperon, which regulates the folding of many client protein associated with all the six hallmarks of cancer, and helps maintaining their proper conformation. Consequently, Hsp90 has become an exciting new target in cancer drug discovery since the inhibition of its ATPase activity leads to the depletion of these client proteins via the proteasomal pathway. Several inhibitors of the Hsp90 folding machinery have been reported, most of them binding to the N-terminal ATP binding site. Recently, novobiocin has been shown to bind to a second putative ATP binding site on the C-terminal region. This work reports the synthesis and biological evaluation of original novobiocin derivatives. Two main strategies have been undertaken: RSA study and virtual screening.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges

International audienceCarbon-14 (14 C) is a gold standard technology routinely utilized in pharmaceutical and agrochemical industries for tracking synthetic organic molecules and provide their metabolic and safety profiles. While the state of the art has been dominated for decades by traditional multi-step synthetic approaches, the recent emergency of late-stage carbon isotope labeling has provided new avenues to rapidly access to carbon-14 labeled biologically relevant compounds. In particular, the development of carbon isotope exchange has represented a fundamental paradigm change, opening the way to unexplored synthetic transformations. In this Perspective, we discuss the recent developments in the field with a critical assessment of the literature. We subsequently discuss research directions and future challenges within this rapidly evolving field

Assessment of the role of hydrogen to produce high-temperature heat in the steel industry

The iron and steel industry is a major source of industrial greenhouse gas emissions, accounting for 7-9% of global energy-related CO2 emissions. Current steel production routes are therefore expected to undergo a profound decarbonisation process in the coming decades. This work aims to shed light on the role of hydrogen in decarbonising the supply of high-temperature heat in the steel sector by means of an optimisation framework. The model includes on-site hydrogen production using a low-temperature electrolyser integrated with a compression and storage system and gas burners, which can be fed with hydrogen and/or natural gas to cover the process heat demand. The assessment also takes advantage of real thermal load profiles of a scrap-based electric arc furnace steel plant. A sensitivity analysis is conducted on the electricity, natural gas and carbon prices. Cost-optimal maps are then derived to unveil the combination of energy and carbon prices at which hydrogen becomes convenient for heat production in the steel industry. A general relationship to define the cost-effectiveness of hydrogen is also given. The results show that, at current carbon prices (about 100 €/tCO2), the use of hydrogen becomes economically convenient when the electricity price is less than 0.4-0.6 times the natural gas price. In scenarios with electricity prices lower than about 0.10 €/kWh, as could occur with on-site renewable electricity generation, hydrogen cost falls below 6.5 €/kgH2, leading to cost savings of up to 60-70% compared to a natural gas-based configuration. Finally, when total CO2 emissions (direct + indirect) are considered, hydrogen becomes environmentally beneficial if the electricity carbon intensity is below 123 gCO2/kWh

New Catalytic Reactions using CO2_2 for Radiolabeling of Tracers

International audienceCO$_2$, well known as a greenhouse gas responsible for global warming and considered as a cheap, non-toxic, renewable C1 building block, is by far the most accessible primary source of carbon for all radiolabeled compounds. However, its kinetic and thermodynamic stability significantly restrains potential applications. Broader availability of secondary labeled carbon sources would therefore grant access to a wide array of highly functionalized bioactive tracers. Indeed, $^{14}$C labelled compounds are commonly required during the development process of drugs where as $^{11}$C molecules are key radiotracers for positron emission tomography (PET) imaging.In this context, we have been investigating CO$_2$ reduction into methoxy derivatives followed by a Suzuki cross-coupling to generate anisoles moieties. Selective borane mediated organocatalytic CO2 reduction into OMe synthons has been previously disclosed by our group. However, very few couplings between methanol derivatives and aryl halides have been reported to date. Inspired by Novak’s work, an innovative, efficient palladium catalyzed cross-coupling between methoxyboranes and aryl bromides has been developed under mild conditions. Working in a double chamber set-up allows both reactions to becompatible. This strategy is further expected to be tested on therapeutic targets and ideally transposed to $^{14}$C and $^{11}$C isotope

Modern Strategies for Carbon Isotope Exchange

International audienceAbstract In contrast to stable and natural abundant carbon‐12, the synthesis of organic molecules with carbon (radio)isotopes must be conceived and optimized in order to navigate through the hurdles of radiochemical requirements, such as high costs of the starting materials, harsh conditions and radioactive waste generation. In addition, it must initiate from the small cohort of available C‐labeled building blocks. For long time, multi‐step approaches have represented the sole available patterns. On the other side, the development of chemical reactions based on the reversible cleavage of C−C bonds might offer new opportunities and reshape retrosynthetic analysis in radiosynthesis. This review aims to provide a short survey on the recently emerged carbon isotope exchange technologies that provide effective opportunity for late‐stage labeling. At present, such strategies have relied on the use of primary and easily accessible radiolabeled C1‐building blocks, such as carbon dioxide, carbon monoxide and cyanides, while the activation principles have been based on thermal, photocatalytic, metal‐catalyzed and biocatalytic processes

Investigation on the stoichiometry of carbon dioxide in isotope-exchange reactions with phenylacetic acids

International audienceThe functionalization of carbon dioxide (CO$_2$) as a C1 building block has attracted enormous attention. Carboxylation reactions, in particular, are of major interest for applications in isotope labeling. Due to the inexpensive nature of CO$_2$, information about its stoichiometric use is generally unavailable in the literature. Because of the rarity and limited availability of CO$_2$ isotopomers, this parameter is of concern for applications in carbon-isotope labeling. We investigated the effects of the stoichiometry of labeled CO$_2$ on carbon isotope exchange of phenyl­acetic acids. Both thermal and photocatalytic procedures were studied, providing insight into product outcome and isotope incorporation. Preliminary results on isotope-dilution effects of carbonate bases in photocatalytic carboxylation reactions have also been obtained

Fluorogenic iminosydnones: bioorthogonal tools for double turn-on click-and-release reactions

International audienceIn this article, we report the synthesis and use of iminosydnone-based profluorophores as bioorthogonal cleavable linkers for imaging applications. These linkers react with cycloalkynes via subsequent [3+2] cycloaddition and retro Diels-Alder reactions, allowing simultaneous release of two dyes in biological media