Imprimer


The Methodology and Synthesis Group specializes in developping novel methodologies and in the synthesis of biologically relevant molecules and natural products. Methodologies and total syntheses are usually initially applied to carbohydrate targets and structures, but we make a conscious effort to extend these methodologies beyond carbohydrates : the dual label organic chemistry – glycochemistry fully applies to our scientific outlook, as these two aspects are inextricably linked : there is no glycochemistry that is not organic chemistry and no organic chemistry that should not be applied to carbohydrates.

Extending the Modified Julia olefination reaction to the conversion of carbohydrate lactones to exo-glycals led to a general method for the synthesis of enol ethers, which was applied to the total synthesis of Bistramide A, in collaboration with Janet Lord, Jari Yli-Kauhaluoma, and Olivier Piva. The activity of different stereoisomers of bistramide A showed that differentiation, cell cycle arrest and apoptosis were independant activities of the natural product.  This methodology was extended to the conversion of Boc-protected lactams to exo-enamides in collaboration with Isabelle Gillaizeau and to the synthesis of indolizidines and quinolizidines.  The methodology has been applied to the synthesis of is being applied to the synthesis of FR901483, and the regioselective indolizidine synthesis

A total synthesis of staurosporine led to the development of a reductive N-acylation methodology and to the synthesis of orthoamide analogs of rebeccamycin. These interests led to the synthesis of a large variety of ATP-competitive protein kinase inhibitors, such as macrocyclic bisindolylmaleimide inhibitors of PKC-beta in collaboration with Michael Jirousek, carbazole and azacarbazole inhibitors of oncogenic fusion proteins of ALK in collaboration with Carlo Gambacorti-Passerini, Leonardo Scappozza and Benoit Joseph, hydroxyphenyl pyrrolopyridine inhibitors of RIPK1 in collaboration with Marie-Therese Boitrel, Stephane Bach and Arnaud Comte.  We have been particularly interested in extending the use of ATP-competitive protein kinase inhibitors to non protein kinase targets (sirtuins, adenine kinase, etc.).

Recent developments in the group include natural product identification, in collaboration with the ACEPRD in Jos, Nigeria, the development of fluorescent probes in collaboration with the  biological membranes group and fluorous-tagged oligosaccharide synthesis.

 


The Systems Chemistry Group merges the synthesis of biomolecules, that of nucleic acids, peptides and phospholipids, with the creation of complex chemical systems.

The research aims at finding sets of experimentally feasible initial conditions, viz. exploring varied compositions and analysing their outcomes, of a fully synthetic chemical micro‐compartmented and evolvable macromolecular system being fed with monomers and small molecular weight-high energy compounds, to keep the system permanently out of thermodynamic equilibrium and let it self‐evolve, thus gaining: 1) import‐export control of macromolecules across the compartment membranes; 2) food-dependent increase in macromolecular size and variety, that is, in polymer length and composition, inside the compartments; 3) sustained production of particularly useful macromolecules through the establishment of a (or several) de novo genetic code(s); leading to 4) the emergence of replicating macromolecular populations and ultimately 5) the emergence of self‐evolved living cells ex inanimo.

Several sub-topics are being developed. One is the synthesis of phospholipids and similar membranogenic amphiphiles, either through directed conventional or through plausibly prebiotic pathways, in order to observe and follow the dynamic formation and regeneration of vesicles upon their slow hydration and periodic feeding with added amphiphiles.

Another sub-topic is the growth of moderately lipophilic peptides from amino acids or shorter peptides. Such peptide chain growth is possible through attaching the first monomer to a monomeric nucleotide or short nucleic acid. Under chemical activation conditions, nucleic acids may grow in size and variety as well. The gain from growing both kinds of macromolecules within growing and dividing vesicles constitutes the highest level of complexity expected to be achieved by chemical systems.

Complex chemical mixtures are difficult to analyse, therefore the synthesis of useful new fluorophores, as well as macromolecular reference compounds prepared on synthesizers, both of help to follow the dynamic changes in chemical systems by fluorescence microscopy, flow cytometry, heteronuclear NMR spectroscopy and (U)HPLC coupled to mass spectrometry, are permanently accompanying our research.

 


The Biological Membranes Group analyses the molecular, structural and mechanistic bases of biological functions by using standard biochemistry techniques (expression and purification of recombinant enzymes, biochemical characterization of these enzymes, study of the structure-function relationships of these molecules, study of protein-ligand and protein-membrane interactions, lipidomics), at the level of both proteins and lipids but also by developing multidisciplinary approaches at the interfaces with Chemistry, Physics and Biology (study of the dynamics and organization of biological membranes under physiological or pathological conditions, development of new fluorescence tools in spectroscopy and microscopy, Fourier transform infrared spectroscopy, polarization modulation-infrared reflection-adsorption spectroscopy, Brewster angle microscopy, rheological and tribological properties of biomimetic or natural vesicles...), purification and characterization of various extracellular vesicles (exosomes, matrix vesicles, synovial vesicles).

In this perspective, several biological models are studied/used ranging from liposomes, lipid monolayers, lipid bilayers to cells.

Two topics are particularly developed (2 theses are in progress) related to the study of the dynamics of biological membranes through the use of fluorescence probes developed in the team. One thesis concerns the "Biophysicochemical characterization of cell membranes during tumorigenesis", with an application to breast and prostate cancer, the other is interested in joint pathologies and is entitled "Role of membrane fluidity in the behavior of synovial vesicles from healthy and pathological sampling ".