University of Bordeaux

In the frame of this research program, carried out at the Institute of Molecular Sciences (ISM) at the University of Bordeaux (UB), we propose a strategy directed towards the first total synthesis of leucophyllidine, a cytotoxic alkaloid recently isolated from L. griffithii. From the retrosynthetic analysis of the target, two fragments where identified that will be prepared then connected in the last stage of the synthesis, following a biomimetic approach. The “North-fragment” will be synthesized relying on a coupling between a key-aldehyde moiety and tryptamine through a Pictet-Spengler reaction/lactamization cascade. The “South-fragment” will be elaborated using a Friedländer-type condensation between a piperidinone, and an ortho-aminobenzonitrile. The key-aldehyde and the piperidinone will be elaborated using a unified strategy, including a novel stereoselective free-radical carbo-oximation process, which will install quaternary centers present in North and South fragments. Incorporation of the vinyl motif on the naphthyridine ring, through a Suzuki coupling, should complete the synthesis of the south-fragment. Both fragments will finally be connected, following a biomimetic Mannich-type strategy, which should provide sufficient quantities of this potent anticancer agent and analogues for future biological screening. Key objectives of this research program are the development of an access to new plant anticancer drugs for potential clinical use and the training of future leading experts in the field of natural product–derived drugs discovery, a domain in which Europe must remain competitive in the 21st century as cancer-related diseases are rapidly increasing with population’s life expectancy.

The design and precise construction of biomimetic self-assembling systems in aqueous solution is a challenging yet potentially highly rewarding endeavor, contributing to the development of new biomaterials, catalysts, drug-delivery systems and tools for the manipulation of biological processes. A high level of sophistication with control over morphologies and functions has been achieved by engineering self-assembling peptide-based building units. Although peptides possess a number of specific advantages including synthetic availability, modularity, one difficulty resides in precisely controlling the rules relating primary sequence and secondary structure. Alternatively, opportunities exist to develop bottom-up approaches using non-natural oligomers also referred to as foldamers, with predictable and well-defined folding patterns. Advances in foldamer chemistry bode well for their use as building units for the precise construction of nanometer scale assemblies and for possible applications. This project will move a step forward towards the realization of this mission, by developing protein-like quaternary arrangements under sequence based control using amphiphilic helical foldamers in aqueous conditions. The applicant has been trained in the synthesis of folded oligoamides and more importantly has acquired a high level of expertise in the design and structural characterization of peptide-based assemblies. He will join and bring his expertise to a host laboratory in France that has pioneered the development of urea-based helical foldamers. Secondment in one established European group with prominent expertise in X-ray crystallography techniques and biological structure determination will provide the appropriate combination of knowledge required for this multidisciplinary study. This approach will be a milestone in the design of foldamer-based quaternary architectures and may lead to new functional nanostructures.

The concentration of carbon dioxide (CO2) in the atmosphere depends on carbon cycle processes, i.e. sources and sinks of carbon. The future evolution of the carbon sinks is not well known, which inhibits robust quantification of future atmospheric CO2 concentration and the resulting climate change. Understanding warm past periods is essential to constrain climate models and accurately predict future changes. During the last million years, warmer periods, called interglacials, happened every ~100,000 years. CO2 levels measured in interglacials before the mid-Bruhnes event (MBE), a large climate shift taking place ~430,000 years ago, are lower than the CO2 in interglacials after the MBE. The cause for this drastic evolution is still unexplained, resulting in uncertainty in the carbon cycle response to global warming. To resolve that issue, we propose to combine data and model simulations including new key processes. We suggest that a major mechanism was a slower circulation during interglacials before the MBE, resulting in more ocean carbon storage and lower atmospheric CO2. We also hypothesize that sea-level changes played a considerable role by altering carbon sinks from land vegetation and shallowing ocean carbonate sedimentation. We will include these mechanisms in a state-of-the-art climate model applicable to long timescales, and compare its modified behaviour with paleoclimate data and more complex models used for projections. This will provide a step change in our understanding of the impact of ocean circulation and sea-level changes on the carbon cycle. It will benefit the European and international scientific community by shedding new light on these processes, and by setting the basis to include these new mechanisms in climate models used for projections. The excellence of the experienced researcher in carbon cycle modelling combined with the expertise in ocean modelling and paleoclimate data from the host institution will ensure the success of this project.

Mounting evidence suggests that early life factors have an important impact on the occurrence of late-life neurological diseases. From a public health perspective this is of particular relevance for dementia, the prevalence of which is increasing drastically, with no available preventive treatment, and epidemiological data suggesting that pathological processes may begin many years before clinical diagnosis. MRI-defined structural brain phenotypes are powerful intermediate markers for dementia, and can already show measurable alterations in young and middle-aged adults. These include global and regional brain volumes, gray matter volume and cortical thickness, and markers of white matter integrity. The SEGWAY project aims to: (i) explore the heritability and genetic determinants of structural brain phenotypes in young adults in their early twenties participating in the i-Share study, the largest ongoing student cohort; (ii) take a lifetime perspective by examining the shared genetic contribution to structural brain alterations in young adulthood (i-Share) and late-life, among participants of a large French population-based study (3C-Dijon); (iii) explore the interaction between genetic variants and vascular risk factors with established impact on structural brain phenotypes, in both age groups; (iv) examine the clinical significance of genetic risk variants for structural brain alterations by testing their association with cognitive performance in young and older adults. Replication and of our findings will be sought in the multigenerational Framingham Heart Study and other independent samples. Identifying common biological mechanisms underlying both early and late-life structural brain changes would provide important information on the mechanisms and timecourse of brain aging throughout a lifetime and could be of major importance for identifying of molecular drug targets and characterizing high risk populations most likely to benefit from early interventions.