Selective Environmentally Benign Synthesis of Isotope Labeled Compounds: Introduction of Deuterium into Compounds of Medicinal Relevance

Deuterium (2H) is a less abundant isotope of hydrogen that possesses an additional neutron resulting in significant differences in the properties of a 1H-containing-molecule compared to its 2H homologues. Deuterium labeled organic compounds are valuable in medicinal chemistry as they offer widespread applications. For instance, in imaging deuteratium labeling can serve as biological tracers, thus, deuterated drugs can provide better understanding of the metabolic pathways; they can also help localize the metabolites of the drug and assess their toxicity. While metabolic enzymes easily transform drug molecules to metabolites that the body can excrete, the introduction of deuterium to drugs appears to strengthen the resistance of drugs toward metabolism. In fact, the carbon-deuterium bond is known to be six to ten times stronger than its C-1H counterpart. The higher the stability, the longer the drug remains intact, which allows lower dosage, potentially causing fewer side effects. Due to the carbon-deuterium bond strength, deuterated drugs can also prevent the formation of toxic metabolites observed with its hydrogen-containing homologue. There are several known methods for the introduction of deuterium to organic compounds; most methods, however, do not conform to the recent expectations and standards of sustainable synthesis. Therefore, a green synthesis of deuterated organic compounds would be an important advance in producing these compounds in an environmentally sustainable way. Thus, we have turned our attention to the Al-H2O system that is commonly applied for hydrogenation reactions. Replacing the H2O with its deuterated version D2O in the system constitutes an easy, economic and safe source of deuterium. The application of either the commercially available Ni-Al alloy or Al in combination with Pd, a common hydrogenation catalyst, for the H-D exchange of compounds with reactive C-H bonds was performed, while yielding no harmful byproducts. The low reactivity of the aluminum metal was significantly enhanced by the application of ultrasonic irradiation prior to the reaction. The H-D exchange reaction was carried out under microwave irradiation and achieved good yields in no more than 1h. The success of the method was demonstrated by applying a broad variety of compounds from essential amino acids to actual drug compounds

Theoretical and Experimental Analysis of the Antioxidant and Anti-amyloid Features of Synthetic Resveratrol Mimics

Diaryl hydrazones, possessing similar structure to the popular red wine antioxidant resveratrol, have been previously identified as multitarget compounds interfering with several processes associated with the pathogenesis of Alzheimer’s disease (AD). These compounds exhibited particularly strong inhibition of the amyloid beta (A) peptide self-assembly, including blocking the formation of fibrils and oligomers, species that are widely accepted to be neurotoxic. The molecules were also powerful free radical scavengers and thus have a potential to defend against oxidative stress. In order to learn more about the mode of action of the compounds, theoretical and experimental studies have been carried out. First, the structural, energetic and electronic features of the core structure have been elucidated by density funtional theory (DFT) calculations. The DFT results identified the most likely form of the compounds, which was applied to a broad range of calculations using substituted derivates. Based on the structural information several characteristics such as logP, H-binding energy, HOMO-LUMO energies and band gap and electron densities were calculated. The compounds were subjected to three different antioxidant assays (DPPH, ABTS and ORAC). The % radical scavenging has been analyzed as a function of the above determined structural parameters in order to identify the role of the energetic and electronic features in the antioxidant activity. The analysis of the same parameters as potential markers to the anti-amyloid activity has also been carried out. Isotope labeling via H-D exchange and in situ hydrazone-radicals as well as hydrazone-A complex formation, applying 1H-NMR and HRMS, have also been used to experimentally observe the potential role of various tautomeric forms and the partially delocalized electron structure of the hydrazones

Development of Environmentally Benign Sustainable Synthetic Methods for Biologically Active Compounds and Synthetic Building Blocks

The goal of the present work was to develop organic syntheses that comply with the principles of green chemistry, as alternatives to the traditional method that often have a significant environmental impact. Notably, the principle of catalysis was exploited, water was employed as a green solvent, and safe methods were carefully designed. Four projects are described which demonstrate that the environmentally-friendly features of synthetic methods do not necessarily compromise performances. In fact, the eco-friendly methods reported afford high yields and selectivities. The first project describes a novel environmentally benign approach based on microwave-assisted solid phase diazotization to convert o-phenylenediamines to substituted benzotriazoles, useful in the dye and pharmaceutical industry. The reaction was carried out in solid phase under microwave irradiation, taking advantage of the strong microwave absorption capability of K-10 montmorillonite that acted as a catalyst and medium in one. Excellent yields were obtained for a broad range of phenylenediamines; the catalyst was recyclable, the reaction occured with high efficiency and does not produce any harmful waste. The second project outlines an efficient and environmentally benign deprotection of a broad range of benzyl (Bn), benzyloxycarbonyl (Cbz) and Allyloxycarbonyl (Alloc) protected amines, alcohols and amino acids with the M-Al-H2O (M=Ni, Pd) system. The reactions were performed in water under mild conditions. The efficient in situ generation of hydrogen from water and Al is utilized by the hydrogenation catalysts (Ni or Pd) thus facilitating the hydrogenolysis of the protecting groups. Good to excellent yields were obtained for the deprotection of a variety of protected amines, alcohols and amino acids demonstrating the versatility and the practicality of the method. The third project is based on a similar system using D2O in lieu of H2O to introduce deuterium without the need for the explosive deuterium gas. D2 gas was generated in situ while the commercially available palladium catalyst assisted the H-D exchange reaction. The chemo/regioselective H-D exchange of amino acids and synthetic building blocks yielded promising results. The importance of isotope labeled compounds in medicinal chemistry, notably their use as improved drug candidates and biological probes, makes this efficient and selective method of great interest. Last, the simple and straightforward catalyst-free synthesis of diarylhydrazones is reported. The structure of the newly synthesized molecules resemble the structure of resveratrol, well-known for its antioxidant properties. The presence of nitrogen atoms in the hydrazones are believed to provide better bioavailability than resveratrol making them good candidates for dietary supplement

Preparation of Deuterium Labeled Compounds by Pd/C-Al-D2O Facilitated Selective H-D Exchange Reactions

The chemo/regioselective H-D exchange of amino acids and synthetic building blocks by an environmentally benign Pd/C-Al-D2O catalytic system is described. Due to the importance of isotope labeled compounds in medicinal chemistry and structural biology, notably their use as improved drug candidates and biological probes, the efficient and selective deuteration methods are of great interest. The approach is based on selective H-D exchange reactions where the deuterium source is simple D2O. D2 gas is generated in situ from the reaction of aluminum and D2O, while the commercially available palladium catalyst assists the H-D exchange reaction. The high selectivity and efficiency, as well as the simplicity and safe nature of the procedure make this method an environmentally benign alternative to current alternatives

Tourismes, patrimoines, identités, territoires

L’approche des tourismes présentée dans cet ouvrage qui recueille les communications des participants au colloque Tourismes Patrimoines Identités et Territoires, organisé par l’Université de Perpignan Via Domitia, fait une large place aux facteurs humains souvent négligés au profit d’un raisonnement réduit à l’économie. Les territoires y sont pensés comme des espaces dotés d’identités que les patrimoines illustrent et les coprésences liées aux tourismes permettent en remettant souvent en cause le mythe d’autochtonie ou le « noble mensonge » de Socrate c’est à dire la croyance des « dirigeants eux-mêmes et (des) militaires, ensuite (du) reste de la cité, qu’ils avaient été modelés sous la terre et qu’une fois que leur fabrication avait été terminée, la terre, qui est leur mère, les avait mis au monde ; et qu’à présent ils doivent délibérer au sujet du pays où ils sont, et le défendre contre quiconque l’attaque, comme si c’était là leur mère et leur nourrice, et penser aux citoyens comme à des frères nés comme eux de la terre ». Ils apparaissent comme un compromis entre un aspect affectif et un aspect rationnel : tout à la fois espaces fonctionnels, et lieux de pouvoir. L’ouvrage s’adresse aux étudiants des différentes filières de formation aux métiers du tourisme et à l’ensemble des acteurs du secteur touristique soucieux de développement durable, respectueux des identités et des patrimoines

Morphology, distribution and phenotype of polycystin kidney disease 2-like 1-positive cerebrospinal fluid contacting neurons in the brainstem of adult mice

The mammalian spinal cord and medulla oblongata harbor unique neurons that remain in contact with the cerebrospinal fluid (CSF-cNs). These neurons were shown recently to express a polycystin member of the TRP channels family (PKD2L1) that potentially acts as a chemo- or mechanoreceptor. Recent studies carried out in young rodents indicate that spinal CSF-cNs express immature neuronal markers that appear to persist even in adult cells. Nevertheless, little is known about the phenotype and morphological properties of medullar CSF-cNs. Using immunohistochemistry and confocal microscopy techniques on tissues obtained from three-month old PKD2L1:EGFP transgenic mice, we analyzed the morphology, distribution, localization and phenotype of PKD2L1(+) CSF-cNs around the brainstem and cervical spinal cord central canal. We show that PKD2L1(+) CSF-cNs are GABAergic neurons with a subependymal localization, projecting a dendrite towards the central canal and an axon-like process running through the parenchyma. These neurons display a primary cilium on the soma and the dendritic process appears to bear ciliary-like structures in contact with the CSF. PKD2L1(+) CSF-cNs present a conserved morphology along the length of the medullospinal central canal with a change in their density, localization and dendritic length according to the rostro-caudal axis. At adult stages, PKD2L1(+) medullar CSF-cNs appear to remain in an intermediate state of maturation since they still exhibit characteristics of neuronal immaturity (DCX positive, neurofilament 160 kDa negative) along with the expression of a marker representative of neuronal maturation (NeuN). In addition, PKD2L1(+) CSF-cNs express Nkx6.1, a homeodomain protein that enables the differentiation of ventral progenitors into somatic motoneurons and interneurons. The present study provides valuable information on the cellular properties of this peculiar neuronal population that will be crucial for understanding the physiological role of CSF-cNs in mammals and their link with the stem cells contained in the region surrounding the medullospinal central canal