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Stereoselective syntheses & modified amino acids

1. Research axes

M. CALMES

Methodologies in asymmetric synthesis. Chiral auxiliaries. Solution and solid-phase synthesis. -aminoacids. Constrained amino acids and derivatives. Oligomers.


F. CAVELIER

Non-natural silylated amino acids. Peptides. Cellular targeting. Transport of metals in plants. Elicitors.


Patrick MEFFRE

Non-usual polyfunctional and/or conformationally constrained amino acids : fluorinated, unsaturated, phosphorated amino acids. Potential PLP enzyme inhibitors or ligands of glutamate metabotropic receptors


I. PARROT

Medicinal chemistry. Constrained peptide mimes. Polyproline II. Asymmetrical synthesis. Asymmetrical catalysis. Heterocycles.


X. SALOM-ROIG

Non-steroidal anti-inflammatory agents. Peptidomimetics. Asymmetrical synthesis. Chiral sulfoxides.

2. Projects currently being developed

Monique CALMES

Methodology in asymmetric synthesis. Our works are focussed on access to high enantiomeric purity molecules by controlling asymmetry with a chiral couple. To that end, we have developed new chiral auxiliaries : 3-hydroxy-4,4-dimethyl-2-pyrrolidinones functionalised on the nitrogen atom (pantolactams) which can advantageously be used in homogeneous and heterogenous phase. Their efficiency, still under study, has already been demonstrated in reactions involving ketenes and in cycloaddition reactions.


Florine CAVELIER

Silylated amino acids and bioactive peptides. The objective of our research works is to increase the lifetime and the bioavailability of the active peptides while introducing non-natural amino acids therein in order to protect peptides from enzymatic degradation. Our choice was directed to analogues of amino acids containing one, very lipophilic, silicon atom. We postulate that the presence of a silylated moiety will substantially improve solubility and passage through the membranes of the synthesised analogue peptide. We are hence developing the synthesis of new silylated amino acids. We are also developing the synthesis of eliciting substances, which increase plants’ natural defences, under a contract with De Sangosse (BDI). We have synthesised nicotianamine, which is a natural compound and a metal transporter in plants’, whose ionophorous capacities we wish to test. Finally, we have initiated the synthesis of apratoxin A, which is an anticancerous cyclic peptolide (supported by the ARC).


PATRICK MEFFRE

Glutamic acid is one of the main neurotransmitters with exciting effects on the central nervous system of mammals, associated with the learning and memorisation processes. in addition to its physiological functions, it is involved in numerous neuropathologies. The excitotoxicity of glutamate is acknowledged in the case of ischemia, convulsions and epilepsy. On the other hand glutamate is also involved in the case of neurodegenerative pathologies such as Huntington’s, Parkinson’s, Alzheimer’s diseases, in pain, drug-dependence phenomena or psychiatric disorders such as anxiety or schizophrenia.

Objectives :
We are now contemplating the synthesis of new analogues of glutamic acid and of glutamine, notably fluorinated, unsaturated, analogues, alkylated in position or not and their biological and pharmacological evaluation. These structural modifications are liable to modify either the conformation of the molecule, or the acidities of the functional groups in particular at the lateral chain and may enable to generate new ligands (agonist or antagonist ligands) of the metabotropic receptors of glutamate (mGluR) whose selectivity regarding different subtypes will be studied.

Consequences expected :
The pharmacological evaluation of the new ligands will enable better knowledge of the physiological role of each of the receptors as well as of the fixing site of glutamate at molecular level, elements indispensable in the development of new medications in the field of neurodegenerative pathologies.

National and international collaborations on this project :
Dr Francine Acher (DR CNRS, Laboratory of Pharmacological and Toxicological Chemistry and Biology, CNRS UMR 8601, Université René Descartes –Paris V) specialised in designing and synthesising analogues of glutamic acid, ligands of mGluR glutamate metabotropic receptors. Dr Gianna Reginato (CNR, University of Firenze, Italy) : ethynylglycine derivatives.


Isabelle PARROT

Peptidomimetics and asymmetric synthesis. Our main project is part of a long term project initiated recently in collaboration with Professor C. Khosla (Stanford university) and the team of Doctor Y. Colette (INSERM U119, Marseilles). Our aim is to design and synthesise constrained peptidomimetics, with polyproline-II type helicity, a secondary structure characteristic of SH3 ligands playing an essential part in certain biological activities such as recognition phenomena, signal transduction, transcription, cellular mobility and immune responses. By creating a simple intra-peptidic rigidification, the resulting di-peptide will adopt a preferential conformation, by eliminating the flexibility of the parent linear peptide. We are also working on the development of original, selective, reversible tricyclic ligands, resistant to enzymatic degradations, and which after validation of their helicoidal properties may be used for instance as pharmacological tools in celiac disease or AIDS or as catalysing chemical tools in asymmetric reactions.


Xavier SALOM-ROIG
On the one hand, our works are centred on the enantioselective synthesis of natural products having numerous asymmetric carbons. We use chiral sulfoxides as chirality inducers. On the other hand we can synthesise new peptidomimetic type receptors of 2-arylpropionic acids and the study of their supramolecular interactions in fundamental condition as well as in excited conditions.

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