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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Les composés organiques volatiles (COVs) sont produits de façon massive chaque jour, et contribuent fortement à la dégradation de la qualité de vie. Pour cette raison, de nombreuses techniques ont été développées pour leur destruction. Parmi celles-ci, l'adsorption présente l'avantage d'être simple et de revaloriser les composés capturés. Elle est industriellement réalisée sur les charbons actifs ou les zéolites. Dans cette thèse, nous étudions les Metal Organic Frameworks (MOFs) comme possibles matériaux adsorbants. Les MOFs sont des matériaux à la fois constitués de parties organiques et inorganiques dont on peut moduler la structure à souhait par un processus de design. L'objectif principal de cette thèse est de dégager les interactions microscopiques gouvernant les phénomènes d'adsorption des COVs dans les MOFs. Pour cela, nous avons utilisé une approche à la fois théorique (DFT+D, Monte-Carlo classique) et expérimentale (gravimétrie, DRIFT, DRUV, adsorption d'azote, DRX).La première partie a montré le comportement des alcanes linéaires adsorbés dans trois MOFs différents (MIL-47, MIL-125 et UiO-66), ainsi que dans ces MOFs fonctionnalisés. Dans le cadre de l'adsorption d'alcanes interagissant exclusivement par interactions vdW, la forme et la taille des pores du MOF sont des facteurs gouvernant l'adsorption. Toutefois, les alcanes sont des molécules flexibles qui peuvent se replier sous contrainte du confinement au sein des MOFs. Ce repliement est un phénomène primordial pour mieux comprendre l'adsorption des alcanes. Selon le milieu, les alcanes peuvent être linéaires ou repliés, et ainsi montrer des différences dans les quantités adsorbées et les sites d'adsorption préférentiels (et donc de leur enthalpie d'adsorption). Ce repliement est basé sur le compromis énergétique entre le coût lié au repliement, et au gain d'énergie apporté par ce repliement. Les alcanes interagissent faiblement avec les structures, mais cette faible énergie pourrait être suffisante pour modifier très légèrement la structure du MOF. La deuxième partie a montré le comportement de l'adsorption d'acétone dans le Cu-BTC. Le Cu-BTC est un MOF particulier qui peut présenter des sites acides de Lewis après activation thermique. Dans ce cas, l'acétone étant une molécule polaire, elle peut établir à la fois des interactions électroniques et de vdW. L'étude IR in-situ couplée à une approche quantique ont permis de relier les fréquences de vibrations du C=O de l'acétone avec leur position dans le Cu-BTC en termes de site d'adsorption. De plus, cette étude a montré que le site préférentiel de l'acétone représente un cas limite, entre les interactions purement vdW et les interactions électroniques. / Volatile Organic compounds (VOCs) are massively produced each day, and contribute strongly to a degradation of quality of life. For this purpose, several techniques were developed for their removal. Among these, adsorption has the advantage to be simple and allow further re-use of captured compounds. Industrially, adsorption is made on activated carbons or zeolites. In this thesis, we investigated the possibility of taking Metal Organic Frameworks (MOFs) as adsorbents. MOFs are materials constituted by both organic and inorganic which can be precisely modulated through a design process. The main objective of this work is to give insights about microscopic interactions controlling adsorption phenomena between VOCs and MOFs. Consequently, we used an approach based both on theoretical (DFT+D, classic Monte-Carlo) and experimental (gravimetric, DRIFT, DRUV, azote adsorption, XRD) aspects.The first part shows the behavior of linear alkanes inside three different MOFs (MIL-47, MIL-125 et UiO-66) in their pure and functionalized forms. Alkanes adsorption is mainly driven by vdW forces, thus, shape and pore size are the most important factors to be taken into account. However, alkanes are flexible molecules which can be folded under constraint of confinement effect within MOFs. This folding is a phenomenon of prime importance while considering study of alkanes. Depending on the environment, alkanes can be linear or folded, and subsequently show differences for quantity adsorbed or preferential adsorption sites (and their isosteric heat of adsorption). This folding is based on an energetic compromise between cost associated to folding and the gain consequent of this folding. Moreover, alkanes interact weakly with MOF, but this energy could be sufficient to modify slightly MOF structure. The second part shows the behavior of acetone adsorption inside Cu-BTC. Cu-BTC is a particular MOF which reveals Lewis acid sites upon thermal activation. In this case, acetone is a polar molecule which can interact with MOF via electronic and vdW interactions. The in situ IR study, compared to quantum approach, allows to make a link between the frequency of C=O stretching of acetone and the position of acetone inside Cu-BTC. Moreover, acetone adsorption appears to be a limit case between a preferential adsorption driven by electronic forces at Lewis acid site and by vdW forces inside a small cage.

La rose est la fleur la plus vendue au monde. Elle a une place prépondérante en horticulture et dans l'industrie des parfums, c’est pourquoi des études visant à préciser les mécanismes cellulaires d’émission du parfum ont été entreprises. Des travaux antérieurs ont permis d'émettre une hypothèse selon laquelle le parfum serait véhiculé par des vésicules lipidiques. Nos observations ont montré que dans les pétales de roses, les vésicules sont composées d'une matrice centrale où se concentrent les triglycérides entourés d'une membrane à un seul feuillet phospholipidique. Ces caractéristiques étayent la théorie selon laquelle les vésicules lipidiques purifiées de pétales de rose sont des oléosomes. Cependant, l’oléosine, protéine marqueur de ce compartiment, n'a pas été identifiée. Ces vésicules sembleraient être impliquées dans le stockage des enzymes des voies de biosynthèse des parfums et des parfums eux-mêmes. Le gène RhPAAS, impliqué dans la voie de biosynthèse du 2-phényléthanol, a également été étudié. Des travaux préliminaires montrent que le QTL majeur expliquant la présence de 2-phényléthanol chez Rosa wichuraiana et le gène RhPAAS sont localisés sur le même locus dans le groupe de liaison B7. La modulation de l'expression du gène RhPAAS a donc été une hypothèse pour expliquer la présence ou l’absence de 2-phényléthanol dans la population HW. Au stade BJO, seuls les descendants produisant beaucoup de 2-phényIéthanoI, expriment RhPAAS. Le transcrit est accumulé au stade BJO dans les pétales c'est-à-dire avant le maximum d’émission du parfum. L’allèle a1 lié à la production du 2-phényléthanol a été identifié tandis qu’un autre allèle a2 s'exprime uniquement chez les roses produisant très peu de 2-phényléthanol / The rose is the most sells flower around the world and it has a prominent place in horticulture and in the perfume industry, which is why studies to clarify the cellular mechanisms of perfume emission have been undertaken. Previous work has enabled to deliver a hypothesis is that the scent would be mediated by lipid vesicles. Our observations showed that the vesicles are composed of a central matrix with a TG concentrate surrounded by a single sheet phospholipid membrane. These patterns support the theory that oil bodies purified from rose petals are oleosomes. However, the oleosin, a marker protein of this compartment has not been identified. The vesicles appear to be involved in the storage of biosynthetic pathways enzymes of perfumes, and fragrances themselves. The RhPAAS gene, involved in the biosynthesis of 2-phenylethanol, was also studied. Preliminary work showed that the major QTL explaining the presence of 2-phenylethanol to Rosa wichuraiana and the RhPAAS gene are localized on the same locus in linkage group B7. The modulation of gene expression RhPAAS has been a hypothesis to explain the presence or absence of 2-phenylethanol in the population HW. Indeed, at BJO stage, only the descendants producing much 2-phenylethanol, expresses RhPAAS. The transcript is accumulated in petals at BJO stage that is to say before the maximum emission of fragrance. The a1 allele linked to the production of 2-phenylethanol was identified while another allele is expressed only in roses producing few 2-phenylethanol

Editorial

Como parte importante de la sociedad, las universidades forman un grupo activo que trabaja en la investigaciòn y el desarrollo de iniciativas que combaten el COVID-19

Background: Cancer patients are at higher risk of infection and severity of Coronavirus Disease-19 (COVID-19). Management of patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is challenging due to the scarce scientific information and treatment guidelines. In this work, we present our Institutional experience with our first 100 patients with oncological malignancies and COVID-19. Patients and methods: We conducted a cross-sectional study of the first 100 patients hospitalised at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru) who were positive for SARS-CoV-2 by reverse transcriptase (RT)-PCR during the period 30 March to 20 June. Clinicopathological variables of the oncological disease as well as risk factors, management and outcomes to COVID-19 were evaluated. Results: The mean age was 43.5 years old (standard deviations: ±24.8) where 57% were male patients. In total, 44%, 37% and 19% were adult patients bearing solid tumours, adults with haematologic malignancies and paediatric patients, respectively. Hypertension was the most frequent comorbidity (23%) followed by chronic lung disease (10%). COVID-19-associated symptoms included cough (65%), fever (57%) and dyspnoea (56%). Twelve percent of patients were asymptomatic. Nosocomial infections were more frequent in paediatric patients (84.2%) than in adult patients (16.0%). Patients with uncontrolled oncological disease were most frequent (72%). Anaemia was present in 67% of patients, 68% had lymphopenia, 62% had ferritin value > 500 mcg/L, 85% had elevated lactate dehydrogenase (LDH), 83% D-dimer > 500 ng/mL and 80% C-Reactive Protein > 8 mg/L. The most common complication was acute respiratory failure (42%). Overall fatality rate was 39% where the main cause of mortality was acute respiratory distress syndrome (64.1%). Conclusion: Paediatric patients had better outcomes than adult populations, and a high number of asymptomatic carriers and nosocomial infection, early diagnosis are recommended. Considering oncological treatments 30 days before COVID-19 diagnosis, our data did not reveal an increased mortality. / Revisión por pares

Indiana University-Purdue University Indianapolis (IUPUI) / During 2020, the Indiana State Department of Health conducted a longitudinal study of novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus, the cause of COVID-19 disease, to understand the number of past and current infections as well as the prevalence of disease in the State of Indiana by conducting a survey to participants as well as administering testing for exposure to SARS-COV-2. The study consisted of 3 waves of testing, each spread months apart, consisting of a random sample and a non-random sample. The non-random sample was used to ensure the sample population was representative of the state of Indiana and was used as stratum in the logistic regression model, allowing for the adjustment for nonresponse. These finding indicate that persons of non-White race and persons of Hispanic ethnicity had highest risk of exposure to the virus. Understanding the disparity in health in various racial and ethnic populations and addressing how different communities are impacted by the pandemic, as well as working with the community is paramount when attempting to mitigate a pandemic. In addition, understanding the data from the ambient pandemic when instituting measures to mitigate the spread of viruses is also extremely important for managing health emergencies such as the COVID-19 pandemic.

After implementing a reliable mass spectrometry based kinetic study the indole conjugation with different organometallic indoles led to questions about the electronical and sterical influences on reactivity. The substitution pattern of the ferrocene functionalized indoles at the six-membered ring determines the electron density on the C3 atom, which reacts with the formed Schiff base. Since the experimental results showed the exact opposite trend, covalent docking studies were performed elucidating the importance of surface interactions. These studies were in harmony with the experimental results and determined lysine 33 as most preferable conjugation site as well as substitution in 6-position as most favourable pattern. The amine motif in compounds 6, 7 and 8 proofed to be easily fragmented by the ESI method used. The amide linker in 10 remains intact but shows a lower conversion. Those two inherent characteristics are however preferable for well-defined and site-specific bioconjugation. The synthesis and evaluation of piano stool complex derivatives with manganese and rhenium metal centre 15, 16, 18 and 22 gave additional guidance by the interpretation of applicable structural motifs. The electron-withdrawing carbonyl groups lead to the hindrance of fulvene formation and thus to no fragmentation as seen with the ferrocene group. The total conversion is low compared to 8, only 22 shows a good enough conversion to mainly monoconjugate of 45% and a possible radio-labelling application as 99mTc analogue. As consequence manganese complexes with a stable facial tricarbonyl unit and a tridentate chelator with 4-, 5- and 6-substituted aminomethylindole conjugated through an amide bond were synthesized and consecutively evaluated. The resulting organometallic indole derivatives 29, 30 and 31 all showed a total conversion around 40% similar to 16, but at the same time a rate constant in the range of 10-4 s-1 like the organic indole. Besides the similar conversion, the rate constants followed the trend of the 6-substituted derivative as fastest and then 5- and 4- substituted derivative with decreasing reactivity. For underlining the usage as technetium label for the best out of the series 31, a rhenium analogue was prepared. The resulting compound 32 was especially interesting, because the conversion was even higher than the 70% of 8 with a total of 88%. Additionally, the rate constant was a tenfold higher as well. This rendered compound 32 as best possible 99mTc analogue for further application as radio-label. After the success of 32 and realizing the sterical benefits resulting from the flexible tridentate ligand-system, substitution at the five-membered ring was explored. The complexes 33, 34 and 35 are based on indole-2-carboxylic acid and with the difference of the length of the alkyl spacer between amide and complex to probe for the influence and sterical hindrance, but all three derivatives showed no conjugation which excludes functionalization in 2-position. As the C3 is used for the actual bioconjugation, the last possible derivatization was realized on the indole-N1 by using 1-(3-bromopropyl)indole as building block during the synthesis of the ligand-system. The corresponding manganese 36 and rhenium 37 complexes both showed similar properties of a moderate conversion like 22 and a rate constant in the range of 10-5 s-1. In conclusion the rhenium complex 32 with the 6-substitution pattern at the tridentate indole-bearing ligand remains the most promising structure. The here developed liquid chromatography coupled mass spectrometry-based assay for the determination of inhibitory activity of drug candidates against the 3CLpro of the sever acute respiratory syndrome coronavirus type 2 was successfully implemented and especially designed to give, due to the available absorption spectra and corresponding mass traces, further insight in the otherwise through fluorescence resonance energy transfer-based assays neglected influences on the inhibition results. Starting with a literature-known quinolone containing covalent inhibitor 42 an N1-methylated derivative 43 and their analogues 44 and 45 in which the benzoic acid was exchanged for ferrocene carboxylic acid were synthesized. The inhibition of 3CLpro was evaluated by the concentration of initial 15mer peptide left after incubation and for that purpose the for 280 nm defined molar attenuation coefficient of (26.41±0.59) L*mol-1*cm-1 determined and used. The results showed a reaction of DL dithiothreitol with the less stable benzoic acid esters leading to a moderate inhibitory effect. The methylation in N1-position showed an increase in stability. The methylated and with ferrocene carboxylic acid functionalized derivative showed a complete inhibition during the timeframe of the assay. In search of a fluorescent and therefore traceable inhibitor, 4 hydroxycoumarin was used to synthesize the analogue with benzoic acid 49 and ferrocene carboxylic acid 50. Both derivatives were less stable than their analogues but exhibited the same trend of a more stable ferrocene-derived compound, which exerted a higher inhibition as well. After preparing and testing the model thioester 53 and showing an inactivation of the established inhibitor ebselen, it was concluded that the reaction with DL dithiothreitol reduces the concentration of active intact inhibitor and therefore decreases the inhibition rate during the assay. The next step was proofing the reducing agent as non-essential for the fast assay conducted in a timeframe of 5 min to circumvent the negative influence of DL dithiothreitol. By excluding every inhibition-altering part, the resulting method is the perfect tool for precise statements in relation of inhibitory activity. Then the inhibition assay was repeated for ebselen and the best out of the here introduced organometallic inhibitors 45. Both give equivalent results of a complete inhibition during the measurement. The implemented liquid chromatography coupled mass spectrometry-based assay has many advantages over the fluorescence resonance energy transfer-based assays in which all the information and insight accumulated by the evaluation of uv/vis traces and mass spectra are not available leading to wrong or deviating results regarding the inhibitory capacity of inhibitor candidates. / Nach der erfolgreichen Implementierung einer auf Massenspektrometrie basierenden Methode, um kinetische Studien über die Indolkonjugation durchzuführen, kamen Fragen über die elektronischen und sterischen Einflüsse auf die Reaktivität auf. Das Substitutionsmuster der Ferrocen-funktionalisierten Indole am sechsgliedrigen Ring bestimmt die Elektronendichte am C3-Atom, welches wiederum mit der zuvor entstandenen Schiffbase reagiert. Da die experimentellen Daten einen der Elektronendichte entgegengesetzten Trend aufwiesen, wurden Docking-Studien durchgeführt, um die Einflüsse der Wechselwirkungen mit der Proteinoberfläche näher zu beleuchten. Diese entsprachen den experimentellen Werten und zeigten, dass Lysin 33 die bevorzugte Konjugationsstelle ist und dass die Substitution in 6-Position die energetisch günstigste darstellt. Das sekundäre Amin der Verbindungen 6, 7 und 8 wurde unter den ESI-Bedingungen leicht fragmentiert. Die Amid-Bindung von 10 dagegen bleibt intakt und ein langsamerer Umsatz, welcher für einen wohl definierten Umsatz sorgt, wurde beobachtet. Die Synthese und Evaluation der Halbsandwich-Komplexe 15, 16, 18 und 22 gab zusätzlichen Aufschluss über die strukturellen Einflüsse. Die elektronenziehenden Carbonyle behindern die Bildung der Fulvene, welche für die Ferrocen-Derivate beobachtet worden war. Der Gesamtumsatz ist vergleichsweise gering und nur Substanz 22 zeigt eine annehmbare Konversion von 45% an Monokonjugat auf, welches sie wiederum für den Einsatz als 99mTc-Analog qualifiziert. Als direkte Konsequenz wurden Mangankomplexe mit einer stabilen facialen Tricarbonyl-Einheit und einem Indol beinhaltenden tridentaten Liganden synthetisiert. Dies wurde für die 4-, 5- und 6-Substitution durchgeführt um die Komplexe 29, 30 und 31 zu erhalten. Alle drei zeigten eine Konversion von ungefähr 40% und lagen mit einer Ratenkonstante von 10-4 s-1 in dem Bereich des organischen Indols. Die Ratenkonstanten folgten hingegen wiederum dem Trend der begünstigten 6-Position, gefolgt von der 5- und dann 4-Position. Um einen Verglich zu einer analogen Technetium-Verbindung zu ziehen wurde der beste Komplex 31 als Rhenium-Analog 32 hergestellt. Dies wies den bisher höchsten Gesamtumsatz von 88% auf, welches die Konversion von 70% der Verbindung 8 überschritt. Dadurch qualifizierte sich Verbindung 32 als beste Option für eine Umsetzung als Radiomarker. Nach den Erkenntnissen über die begünstigte Sterik der flexiblen tridendaten Liganden wurde versucht den Erfolg auf den Fünfring zu übertragen. Eine auf Indol-2-säure basierende Reihe an Komplexen (33,34,35) mit unterschiedlich langen Alkyl-Ketten zwischen Indol und Metallkomplex sollte Aufschluss über den sterischen Anspruch geben, allerdings war keine Konjugation für alle drei Derivate zu beobachten. Als Konsequenz wurde die 2-Position für weitere Funktionalisierung nicht weiter berücksichtigt. Die letzte verbliebene Stelle war das Indol-amin selbst, welche durch den Einsatz von 1-(3-bromopropyl)indol bei der Ligandensynthese erfolgreich alkyliert wurde. Der resultierende Mangan- 36 und Rhenium-Komplex 37 zeigten eine mit 22 vergleichbare moderate Konversion und um eine Größenordnung kleinere Ratenkonstante. Durch diese Erkenntnisse verblieb der Rhenium-Komplex 32 weiterhin der beste Kandidat für eine Umsetzung als radioaktiver Marker. Der hier beschriebene liquid chromatography coupled mass spectrometry basierte Assay für die Bestimmung der Inhibitions-Wirkung gegenüber der 3CLpro des sever acute respiratory syndrome coronavirus type 2 wurde erfolgreich etabliert. Durch die zusätzlichen Absorptions , sowie Massenspektren wurden weitere Informationen gewonnen, welche in den oft angewendeten Fluoreszenz-Resonanzenergietransfer Assays vernachlässigt werden und zu Verfälschungen der Inhibitionsergebnisse führen. Ausgehend von dem literaturbekannten kovalenten Inhibitor 42 wurde ein N1-methyliertes Derivat 43 hergestellt. Durch den Austausch von Benzoesäure durch Ferrocensäure wurden die Analoge 44 und 45 erhalten. Die Restkonzentration des 15mer Substrats nach der Inkubation wurde als Maß der Inhibition herangezogen. Hierfür wurde der molare Extinktionskoeffizient bei 280 nm mit (26.41±0.59) L*mol-1*cm-1 bestimmt. Die Methylierung führte zu einer erhöhten Stabilität. Der Wirkstoffkandidat 45 zeigte außerdem eine vollständige Inhibition im Rahmen des durchgeführten Assays. 4-Hydroxycoumarin wurde verwendet, um die fluoreszenten Analoga 49 und 50 herzustellen. Beide waren instabiler, wobei das Ferrocen-Derivat wie zuvor eine erhöhte Inhibition aufzeigte. Nach der Synthese und Auswertung des Assays für eine Thioester Modellverbindung 53 und einer nachgewiesenen Inaktivierung des etablierten Inhibitors Ebselen wurden die Nebenreaktionen mit DL-Dithiothreitol als Ursache für einen Konzentrationsabfall der aktiven und intakten Inhibitoren und infolgedessen verringerte Inhibition angenommen. Als nächstes wurde bewiesen, dass der Zusatz eines Reduktionsmittels wie keinen Einfluss auf die Enzymaktivität während des kurzen Assays hat. So wurden alle Einflüsse auf die Inhibitionswirkung ausgeschlossen und der nun makellose Assay für Ebselen und den hier vorgestellten neuartigen organometallischen Inhibitor 45 wiederholt, welche beide eine vollständige Inhibition aufwiesen.

Introducción: La pandemia por SARS-Cov-2 ha tenido un impacto negativo en múltiples aspectos de la vida humana, tanto en lo físico, psicológico, económico, social y cultural. Las afecciones de la calidad de vida están asociadas al confinamiento y la libertad de salir, de pasar tiempo con sus amigos o familiares, o de realizar actividades; por lo que se ven privados de la mayor parte de su interacción social. El objetivo de este presente artículo es brindar información sobre cómo afecta el confinamiento y aislamiento social por la pandemia a la calidad de vida y salud mental.