Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents & metal coordination-controlled and bifunctional catalysis toward tertiary β-Ketols

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours.

Stable oxygen and carbon isotope ratios of Globigerinoides obliquus of quantitative range chart of the ostracodes in the Pliocene-Pleistocene interval of ODP Hole 107-654A

Deep-water benthic ostracodes from the Pliocene-Pleistocene interval of ODP Leg 107, Hole 654A (Tyrrhenian Sea) were studied. From a total of 106 samples, 40 species considered autochthonous were identified. Detailed investigations have established the biostratigraphic distribution of the most frequent ostracode taxa. The extinction levels of Agrenocythere pliocenica (a psychrospheric ostracode) in Hole 654A and in some Italian land sections lead to the conclusion that the removal of psychrospheric conditions took place in the Mediterranean Sea during or after the time interval corresponding to the Small Gephyrocapsa Zone (upper part of early Pleistocene), and not at the beginning of the Quaternary, as previously stated. Based on a reduced matrix of quantitative data of 63 samples and 20 variables of ostracodes, four varimax assemblages were extracted by a Q-mode factor analysis. Six factors and eight varimax assemblages were recognized from the Q-mode factor analysis of the quantitative data of 162 samples and 47 variables of the benthic foraminifers. The stratigraphic distributions of the varimax assemblages of the two faunistic groups were plotted against the calcareous plankton biostratigraphic scheme and compared in order to trace the relationship between the benthic foraminifers and ostracodes varimax assemblages. General results show that the two populations, belonging to quite different taxa, display almost coeval changes along the Pliocene-Pleistocene sequence of Hole 654A, essentially induced by paleoenvironmental modifications. Mainly on the base of the benthic foraminifer assemblages (which are quantitatively better represented than the ostracode assemblages), it is possible to identify such modifications as variations in sedimentation depth and in bottom oxygen content.

Mineral and foraminifer composition of sediments across the Paleocene/Eocene Thermal Maximum from ODP Leg 198 sites

The Paleocene/Eocene Thermal Maximum (PETM) was a transient interval of global warming ~55 m.y. ago associated with transformation of ecosystems and changes in carbon cycling. The event was caused by the input of massive amounts of CO2 or CH4 to the ocean-atmosphere system. Rapid shoaling of the lysocline and calcite compensation depth (CCD) is a predicted response of CO2 or CH4 input; however, the extent of this shoaling is poorly constrained. Investigation of Ocean Drilling Program (ODP) Sites 1209-1212 at Shatsky Rise, which lies along a depth transect, suggests a minimum lysocline shoaling of ~500 m in the tropical Pacific Ocean during the PETM. The sites also show evidence of CaCO3 dissolution within the sediment column, carbonate "burn-down" below the level of the carbon isotope excursion, and a predicted response to a rapid change in deepwater carbonate saturation. Close examination of several foraminiferal preservation proxies (i.e., fragmentation, benthic/planktonic foraminiferal ratios, coarse fraction, and CaCO3 content) and observations of foraminifers reveal that increased fragmentation levels most reliably predict intervals with visually impoverished foraminiferal preservation as a result of dissolution. Low CaCO3 content and high benthic/planktonic ratios also mirror intervals of poorest preservation.

Massic magnetic susceptibility and CaCO3 content at the P. ohmi and T. hugii zones from the Rio Argos X.Ag-1 section, southeastern Spain

An orbital floating time scale of the Hauterivian-Barremian transition (Early Cretaceous) is proposed using high-resolution magnetic susceptibility measurements. Orbital tuning was performed on the Río Argos section (southeast Spain), the candidate for a Global boundary Stratotype Section and Point (GSSP) for the Hauterivian-Barremian transition. Spectral analyses of MS variations, coupled with the frequency ratio method, allow the recognition of precession, obliquity and eccentricity frequency bands. Orbitally-tuned magnetic susceptibility provides minimum durations for ammonite biozones. The durations of well-constrained ammonite zones are assessed at 0.78 myr for Pseudothurmannia ohmi (Late Hauterivian) and 0.57 myr for Taveraidiscus hugii (Early Barremian). These results are consistent with previous estimates from the other reference section (Angles, southeast France) and tend to show that the Río Argos section displays a complete succession for this time interval. They differ significantly from those proposed in the Geologic Time Scale 2008 and may help to improve the next compilation. The Faraoni Oceanic Anoxic Event, a key Early Cretaceous oceanographic perturbation occurring at the P. ohmi/P. catulloi subzone boundary has a duration estimated at 0.10-0.15 myr, which is similar to previous assessments.

Integrated stratigraphy of the Messinian across the North Atlantic Ocean

The Messinian was a time of major climatic and paleoceanographic change during the late Cenozoic. It is well known around the Mediterranean region because of the giant anhydritelgypsum sequence and the suggested desiccation of the Mediterranean Sea. However, this interval is less constrained outside the Mediterranean region, where several paleoceanographic changes could have taken place because of the desiccation. Hence, we present an integrated stratigraphic framework for future Messinian paleoceanographic studies, determination of the effect of the Mediterranean desiccation on deep-water paleoceanography, and comparison of intra-Mediterranean paleoceanographic changes with those in the open oceans during the Messinian Stage. Four DSDP/ODP Holes (552A, 646B, 608, and 547A) from the North Atlantic Ocean and one land borehole from Morocco have been studied to integrate bio-, magneto-, and stable isotope Messinian stratigraphy with high resolution sampling. Our results produce the best assessment of the Tortonian/Messinian boundaries in all holes because they do not rely on any one signal. In paleomagnetic Subchronozone C3An1r in the Sale borehole and DSDP Site 609, a S/D coiling direction change of Neogloboquadrina pachyderma/acostaensis appears to indicate PMOW entering the northeastern Atlantic Ocean, at least reaching 50°N. Diachrony and synchrony of some important Messinian planktic foraminifera from these Atlantic DSDP/ODP holes and the Sale borehole, such as the LO of Gq. dehiscens, the LO of Gt. Eenguaensis, the FO and LO of Ct. conomiozea, the FO of Gt. margaritae s.s., the FO of Gt. puncticutata, and the FO of Gt. crassaformis are discussed for understanding some of the paleoceanographic changes. This integrated stratigraphic framework presented here allows much better North Atlantic correlations at this critical point in Messinian geologic history.

Stable carbon and oxygen isotope ratios of bulk sediment from DSDP Hole 62-463 (Appendix A)

In order to elucidate early Aptian marine paleotemperature evolution across the period of enhanced organic carbon (Corg)-burial [Oceanic Anoxic Event (OAE) 1a], stable isotope analyses were performed on pelagic limestones at Deep Sea Drilling Project Site 463, central Pacific Ocean. The delta18O data exhibit a distinct anomaly by ~-2? spanning the OAE 1a interval (i.e., a ~6 m-thick, phytoplanktonic Corg-rich unit constrained by magneto-, bio- and delta13C stratigraphy). Elucidation of paleotemperature significance of the delta18O shift is made by taking account of recent Sr/Ca evidence at the same section, which revealed that geochemical signals in carbonate-poor lithologies are relatively unaltered against burial diagenesis. By discriminating delta18O values from carbonate-poor samples (CaCO3 contents=5-30 wt.%), it appears that an abrupt rise in seasurface temperatures (SSTs) by 8 °C (=-1.7? shift in delta18O) occurred immediately before OAE 1a, whereas a cooling mode likely prevailed during the peak Corg-burial. In terms of its stratigraphic relationship as to the Corg-rich interval and to a pronounced negative delta13C excursion, as well as its timescale, the observed SST rise resembles those associated with the Paleocene-Eocene thermal maximum and, more strikingly, Jurassic Toarcian OAE. This observation is consistent with the hypothesis that these paleoenvironmental events were driven by a common causal mechanism, which was likely initiated by the greenhouse effect via massive release of CH4 or CO2 from the isotopically-light carbon reservoir and terminated by a negative productivity feedback.

Polarity chron boundaries and interval sedimentation rates of ODP Leg 162 sites

Magnetic polarity stratigraphies for Sites 980-984 are based on shipboard measurements from the pass-through magnetometer after alternating field (AF) demagnetization at a peak field of 25 mT and shore-based stepwise AF demagnetization of discrete samples. The characteristic magnetization component was determined after AF demagnetization removed the steep downward drill-string-related magnetic overprint. Peak AF fields in the 20-30 mT range were required to resolve the component, carried by magnetite, that was used to produce unambiguous Pliocene-Pleistocene magnetic stratigraphies at all five sites. At Sites 980 and 983, magnetic stratigraphies were resolved to the base of the recovered advanced hydraulic piston corer (APC) section, which lies in the Matuyama Chron (1r.2r) and Olduvai Subchron (2n), respectively. At Sites 981 and 982, magnetization intensities decrease sharply in the normal polarity zone corresponding to the Gauss Chron (2An), and magnetic stratigraphies below this level could not be resolved. At Site 984, the resolution of magnetic stratigraphy was curtailed at ~250 meters below seafloor (Olduvai Subchron) by core deformation at the base of the APC section and in the underlying extended core barrel section. As the magnetic stratigraphies at all four sites are unequivocal, polarity chron interpretations can be made without aid from the biostratigraphy. Mean sedimentation rates within polarity chrons have been calculated and Pliocene-Pleistocene biomagnetostratigraphic correlations tested.